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Sample records for cck-containing inhibitory interneurons

  1. Action potential initiation in neocortical inhibitory interneurons.

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    Tun Li

    2014-09-01

    Full Text Available Action potential (AP generation in inhibitory interneurons is critical for cortical excitation-inhibition balance and information processing. However, it remains unclear what determines AP initiation in different interneurons. We focused on two predominant interneuron types in neocortex: parvalbumin (PV- and somatostatin (SST-expressing neurons. Patch-clamp recording from mouse prefrontal cortical slices showed that axonal but not somatic Na+ channels exhibit different voltage-dependent properties. The minimal activation voltage of axonal channels in SST was substantially higher (∼7 mV than in PV cells, consistent with differences in AP thresholds. A more mixed distribution of high- and low-threshold channel subtypes at the axon initial segment (AIS of SST cells may lead to these differences. Surprisingly, NaV1.2 was found accumulated at AIS of SST but not PV cells; reducing NaV1.2-mediated currents in interneurons promoted recurrent network activity. Together, our results reveal the molecular identity of axonal Na+ channels in interneurons and their contribution to AP generation and regulation of network activity.

  2. Wide Dispersion and Diversity of Clonally Related Inhibitory Interneurons.

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    Harwell, Corey C; Fuentealba, Luis C; Gonzalez-Cerrillo, Adrian; Parker, Phillip R L; Gertz, Caitlyn C; Mazzola, Emanuele; Garcia, Miguel Turrero; Alvarez-Buylla, Arturo; Cepko, Constance L; Kriegstein, Arnold R

    2015-09-02

    The mammalian neocortex is composed of two major neuronal cell types with distinct origins: excitatory pyramidal neurons and inhibitory interneurons, generated in dorsal and ventral progenitor zones of the embryonic telencephalon, respectively. Thus, inhibitory neurons migrate relatively long distances to reach their destination in the developing forebrain. The role of lineage in the organization and circuitry of interneurons is still not well understood. Utilizing a combination of genetics, retroviral fate mapping, and lineage-specific retroviral barcode labeling, we find that clonally related interneurons can be widely dispersed while unrelated interneurons can be closely clustered. These data suggest that migratory mechanisms related to the clustering of interneurons occur largely independent of their clonal origin.

  3. Global optogenetic activation of inhibitory interneurons during epileptiform activity.

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    Ledri, Marco; Madsen, Marita Grønning; Nikitidou, Litsa; Kirik, Deniz; Kokaia, Merab

    2014-02-26

    Optogenetic techniques provide powerful tools for bidirectional control of neuronal activity and investigating alterations occurring in excitability disorders, such as epilepsy. In particular, the possibility to specifically activate by light-determined interneuron populations expressing channelrhodopsin-2 provides an unprecedented opportunity of exploring their contribution to physiological and pathological network activity. There are several subclasses of interneurons in cortical areas with different functional connectivity to the principal neurons (e.g., targeting their perisomatic or dendritic compartments). Therefore, one could optogenetically activate specific or a mixed population of interneurons and dissect their selective or concerted inhibitory action on principal cells. We chose to explore a conceptually novel strategy involving simultaneous activation of mixed populations of interneurons by optogenetics and study their impact on ongoing epileptiform activity in mouse acute hippocampal slices. Here we demonstrate that such approach results in a brief initial action potential discharge in CA3 pyramidal neurons, followed by prolonged suppression of ongoing epileptiform activity during light exposure. Such sequence of events was caused by massive light-induced release of GABA from ChR2-expressing interneurons. The inhibition of epileptiform activity was less pronounced if only parvalbumin- or somatostatin-expressing interneurons were activated by light. Our data suggest that global optogenetic activation of mixed interneuron populations is a more effective approach for development of novel therapeutic strategies for epilepsy, but the initial action potential generation in principal neurons needs to be taken in consideration.

  4. Serotonergic control of the hippocampus via local inhibitory interneurons.

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    Freund, T F; Gulyás, A I; Acsády, L.; Görcs, T; Tóth, K

    1990-01-01

    Information flow and processing in hippocampal neuronal networks is determined by a wide range of inhibitory mechanisms [e.g., feedforward or feedback, gamma-aminobutyrate (GABA) A or B receptor-mediated, perisomatic shunting, or distal dendritic inhibition], each subserving specialized functions. These forms of local inhibition are mediated by morphologically and neurochemically well-defined, mostly GABA-containing, interneurons, which control large populations of principal cells through the...

  5. Somatostatin-expressing inhibitory interneurons in cortical circuits

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    Iryna Yavorska

    2016-09-01

    Full Text Available Cortical inhibitory neurons exhibit remarkable diversity in their morphology, connectivity, and synaptic properties. Here, we review the function of somatostatin-expressing (SOM inhibitory interneurons, focusing largely on sensory cortex. SOM neurons also comprise a number of subpopulations that can be distinguished by their morphology, input and output connectivity, laminar location, firing properties, and expression of molecular markers. Several of these classes of SOM neurons show unique dynamics and characteristics, such as facilitating synapses, specific axonal projections, intralaminar input, and top-down modulation, which suggest possible computational roles. SOM cells can be differentially modulated by behavioral state depending on their class, sensory system, and behavioral paradigm. The functional effects of such modulation have been studied with optogenetic manipulation of SOM cells, which produces effects on learning and memory, task performance, and the integration of cortical activity. Different classes of SOM cells participate in distinct disinhibitory circuits with different inhibitory partners and in different cortical layers. Through these disinhibitory circuits, SOM cells help encode the behavioral relevance of sensory stimuli by regulating the activity of cortical neurons based on subcortical and intracortical modulatory input. Associative learning leads to long-term changes in the strength of connectivity of SOM cells with other neurons, often influencing the strength of inhibitory input they receive. Thus despite their heterogeneity and variability across cortical areas, current evidence shows that SOM neurons perform unique neural computations, forming not only distinct molecular but also functional subclasses of cortical inhibitory interneurons.

  6. Inhibitory Interneurons of The Human Neocortex after Clinical Death

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    V. A. Akulinin

    2016-01-01

    Full Text Available Objective: to analyze the human neocortex interneurons (areas 4, 10, 17 and 21 by Brodmann after cardiac arrest (clinical death.Materials and methods. The main group included patients (n=7, men who survived 7—10 days and 70—90 days after cardiac arrest and later died due to heart failure. The control group (n=4, men included individuals after sudden fatal accidents. The morphometric and histological analysis of 420 neocortical fields (Nissl#staining,calbindin D28k, neuropeptide Y was performed using light and confocal microscopy.Results. We verified all main types of interneurons (Basket, Martinotti, and neurogliaform interneurons in neocortex based on the morphology of their bodies and dendritic processes in both groups. The number of calbindin- and NPY-positive neurons in the neocortex was similar in the control and in the postoperative period.However, calbindin- and NPY-immunopositive structure fields including neuronal cell bodies and their dendrites were significantly more represented in neocortex of patients from the main group. Maximum increase in common square in the relative areas of calbindin-immunopositive structures was observed 90 days after ischemia. The squares of NPY#immunopositive fields became larger seven days after resuscitation and remained increased on 90th day post-resuscitation.Conclusion. Our findings demonstrate an increase of calbindin and NPY expression in human neocortex after clinical death, which can be explained by a compensatory  eaction of undamaged inhibitory cortical interneurons directed to protectbrain from ischemia.

  7. Inhibitory coupling between inhibitory interneurons in the spinal cord dorsal horn

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    Ribeiro-da-Silva Alfredo

    2009-05-01

    Full Text Available Abstract Local inhibitory interneurons in the dorsal horn play an important role in the control of excitability at the segmental level and thus determine how nociceptive information is relayed to higher structures. Regulation of inhibitory interneuron activity may therefore have critical consequences on pain perception. Indeed, disinhibition of dorsal horn neuronal networks disrupts the balance between excitation and inhibition and is believed to be a key mechanism underlying different forms of pain hypersensitivity and chronic pain states. In this context, studying the source and the synaptic properties of the inhibitory inputs that the inhibitory interneurons receive is important in order to predict the impact of drug action at the network level. To address this, we studied inhibitory synaptic transmission in lamina II inhibitory interneurons identified under visual guidance in spinal slices taken from transgenic mice expressing enhanced green fluorescent protein (EGFP under the control of the GAD promoter. The majority of these cells fired tonically to a long depolarizing current pulse. Monosynaptically evoked inhibitory postsynaptic currents (eIPSCs in these cells were mediated by both GABAA and glycine receptors. Consistent with this, both GABAA and glycine receptor-mediated miniature IPSCs were recorded in all of the cells. These inhibitory inputs originated at least in part from local lamina II interneurons as verified by simultaneous recordings from pairs of EGFP+ cells. These synapses appeared to have low release probability and displayed potentiation and asynchronous release upon repeated activation. In summary, we report on a previously unexamined component of the dorsal horn circuitry that likely constitutes an essential element of the fine tuning of nociception.

  8. Optogenetic mapping of cerebellar inhibitory circuitry reveals spatially biased coordination of interneurons via electrical synapses.

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    Kim, Jinsook; Lee, Soojung; Tsuda, Sachiko; Zhang, Xuying; Asrican, Brent; Gloss, Bernd; Feng, Guoping; Augustine, George J

    2014-06-12

    We used high-speed optogenetic mapping technology to examine the spatial organization of local inhibitory circuits formed by cerebellar interneurons. Transgenic mice expressing channelrhodopsin-2 exclusively in molecular layer interneurons allowed us to focally photostimulate these neurons, while measuring resulting responses in postsynaptic Purkinje cells. This approach revealed that interneurons converge upon Purkinje cells over a broad area and that at least seven interneurons form functional synapses with a single Purkinje cell. The number of converging interneurons was reduced by treatment with gap junction blockers, revealing that electrical synapses between interneurons contribute substantially to the spatial convergence. Remarkably, gap junction blockers affected convergence in sagittal slices, but not in coronal slices, indicating a sagittal bias in electrical coupling between interneurons. We conclude that electrical synapse networks spatially coordinate interneurons in the cerebellum and may also serve this function in other brain regions.

  9. Parvalbumin-Positive Inhibitory Interneurons Oppose Propagation But Favor Generation of Focal Epileptiform Activity.

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    Sessolo, Michele; Marcon, Iacopo; Bovetti, Serena; Losi, Gabriele; Cammarota, Mario; Ratto, Gian Michele; Fellin, Tommaso; Carmignoto, Giorgio

    2015-07-01

    Parvalbumin (Pv)-positive inhibitory interneurons effectively control network excitability, and their optogenetic activation has been reported to block epileptic seizures. An intense activity in GABAergic interneurons, including Pv interneurons, before seizures has been described in different experimental models of epilepsy, raising the hypothesis that an increased GABAergic inhibitory signal may, under certain conditions, initiate seizures. It is therefore unclear whether the activity of Pv interneurons enhances or opposes epileptiform activities. Here we use a mouse cortical slice model of focal epilepsy in which the epileptogenic focus can be identified and the role of Pv interneurons in the generation and propagation of seizure-like ictal events is accurately analyzed by a combination of optogenetic, electrophysiological, and imaging techniques. We found that a selective activation of Pv interneurons at the focus failed to block ictal generation and induced postinhibitory rebound spiking in pyramidal neurons, enhancing neuronal synchrony and promoting ictal generation. In contrast, a selective activation of Pv interneurons distant from the focus blocked ictal propagation and shortened ictal duration at the focus. We revealed that the reduced ictal duration was a direct consequence of the ictal propagation block, probably by preventing newly generated afterdischarges to travel backwards to the original focus of ictal initiation. Similar results were obtained upon individual Pv interneuron activation by intracellular depolarizing current pulses. The functional dichotomy of Pv interneurons here described opens new perspectives to our understanding of how local inhibitory circuits govern generation and spread of focal epileptiform activities.

  10. Complex synchronous behavior in interneuronal networks with delayed inhibitory and fast electrical synapses

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    Guo, Daqing; Wang, Qingyun; Perc, Matjaž

    2012-06-01

    Networks of fast-spiking interneurons are crucial for the generation of neural oscillations in the brain. Here we study the synchronous behavior of interneuronal networks that are coupled by delayed inhibitory and fast electrical synapses. We find that both coupling modes play a crucial role by the synchronization of the network. In addition, delayed inhibitory synapses affect the emerging oscillatory patterns. By increasing the inhibitory synaptic delay, we observe a transition from regular to mixed oscillatory patterns at a critical value. We also examine how the unreliability of inhibitory synapses influences the emergence of synchronization and the oscillatory patterns. We find that low levels of reliability tend to destroy synchronization and, moreover, that interneuronal networks with long inhibitory synaptic delays require a minimal level of reliability for the mixed oscillatory pattern to be maintained.

  11. Two functional inhibitory circuits are comprised of a heterogeneous population of fast-spiking cortical interneurons.

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    Li, P; Huntsman, M M

    2014-04-18

    Cortical fast spiking (FS) interneurons possess autaptic, synaptic, and electrical synapses that serve to mediate a fast, coordinated response to their postsynaptic targets. While FS interneurons are known to participate in numerous and diverse actions, functional subgroupings within this multi-functional interneuron class remain to be identified. In the present study, we examined parvalbumin-positive FS interneurons in layer 4 of the primary somatosensory (barrel) cortex - a brain region well-known for specialized inhibitory function. Here we show that FS interneurons fall into two broad categories identified by the onset of the first action potential in a depolarizing train as: "delayed firing FS interneurons (FSD) and early onset firing FS interneurons (FSE). Subtle variations in action potential firing reveal six subtypes within these two categories: delayed non-accommodating (FSD-NAC), delayed stuttering (FSD-STUT), early onset stuttering (FSE-STUT), early onset-late spiking (FSE-LS), early onset early-spiking (FSE-ES), and early onset accommodating (FSE-AC). Using biophysical criteria previously employed to distinguish neuronal cell types, the FSD and FSE categories exhibit several shared biophysical and synaptic properties that coincide with the notion of specificity of inhibitory function within the cortical FS interneuron class.

  12. Impact of inhibitory constraint of interneurons on neuronal excitability.

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    Lee, Vallent; Maguire, Jamie

    2013-12-01

    Tonic inhibition is thought to dampen the excitability of principal neurons; however, little is known about the role of tonic GABAergic inhibition in interneurons and the impact on principal neuron excitability. In many brain regions, tonic GABAergic inhibition is mediated by extrasynaptic, δ-subunit-containing GABAA receptors (GABAARs). In the present study we demonstrate the importance of GABAAR δ-subunit-mediated tonic inhibition in interneurons. Selective elimination of the GABAAR δ-subunit from interneurons was achieved by crossing a novel floxed Gabrd mouse model with GAD65-Cre mice (Gabrd/Gad mice). Deficits in GABAAR δ-subunit expression in GAD65-positive neurons result in a decrease in tonic GABAergic inhibition and increased excitability of both molecular layer (ML) and stratum radiatum (SR) interneurons. Disinhibition of interneurons results in robust alterations in the neuronal excitability of principal neurons and decreased seizure susceptibility. Gabrd/Gad mice have enhanced tonic and phasic GABAergic inhibition in both CA1 pyramidal neurons and dentate gyrus granule cells (DGGCs). Consistent with alterations in hippocampal excitability, CA1 pyramidal neurons and DGGCs from Gabrd/Gad mice exhibit a shift in the input-output relationship toward decreased excitability compared with those from Cre(-/-) littermates. Furthermore, seizure susceptibility, in response to 20 mg/kg kainic acid, is significantly decreased in Gabrd/Gad mice compared with Cre(-/-) controls. These data demonstrate a critical role for GABAAR δ-subunit-mediated tonic GABAergic inhibition of interneurons on principal neuronal excitability and seizure susceptibility.

  13. Oscillation-Driven Spike-Timing Dependent Plasticity Allows Multiple Overlapping Pattern Recognition in Inhibitory Interneuron Networks

    DEFF Research Database (Denmark)

    Garrido, Jesús A.; Luque, Niceto R.; Tolu, Silvia

    2016-01-01

    understood. Here, we have used a simple model of afferent excitatory neurons and interneurons with lateral inhibition, reproducing a network topology found in many brain areas from the cerebellum to cortical columns. When endowed with spike-timing dependent plasticity (STDP) at the excitatory input synapses...... and at the inhibitory interneuron-interneuron synapses, the interneurons rapidly learned complex input patterns. Interestingly, induction of plasticity required that the network be entrained into theta-frequency band oscillations, setting the internal phase-reference required to drive STDP. Inhibitory plasticity...... patterns. The combination of plasticity in lateral inhibitory connections and homeostatic mechanisms in the inhibitory interneurons optimized mutual information (MI) transfer. The storage of multiple complex patterns in plastic interneuron networks could be critical for the generation of sparse...

  14. Inhibitory stabilization and visual coding in cortical circuits with multiple interneuron subtypes.

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    Litwin-Kumar, Ashok; Rosenbaum, Robert; Doiron, Brent

    2016-03-01

    Recent anatomical and functional characterization of cortical inhibitory interneurons has highlighted the diverse computations supported by different subtypes of interneurons. However, most theoretical models of cortex do not feature multiple classes of interneurons and rather assume a single homogeneous population. We study the dynamics of recurrent excitatory-inhibitory model cortical networks with parvalbumin (PV)-, somatostatin (SOM)-, and vasointestinal peptide-expressing (VIP) interneurons, with connectivity properties motivated by experimental recordings from mouse primary visual cortex. Our theory describes conditions under which the activity of such networks is stable and how perturbations of distinct neuronal subtypes recruit changes in activity through recurrent synaptic projections. We apply these conclusions to study the roles of each interneuron subtype in disinhibition, surround suppression, and subtractive or divisive modulation of orientation tuning curves. Our calculations and simulations determine the architectural and stimulus tuning conditions under which cortical activity consistent with experiment is possible. They also lead to novel predictions concerning connectivity and network dynamics that can be tested via optogenetic manipulations. Our work demonstrates that recurrent inhibitory dynamics must be taken into account to fully understand many properties of cortical dynamics observed in experiments.

  15. Interneuron- and GABAA receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells

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    He, Qionger; Duguid, Ian; Clark, Beverley; Panzanelli, Patrizia; Patel, Bijal; Thomas, Philip; Fritschy, Jean-Marc; Smart, Trevor G.

    2015-07-01

    Inhibitory synaptic plasticity is important for shaping both neuronal excitability and network activity. Here we investigate the input and GABAA receptor subunit specificity of inhibitory synaptic plasticity by studying cerebellar interneuron-Purkinje cell (PC) synapses. Depolarizing PCs initiated a long-lasting increase in GABA-mediated synaptic currents. By stimulating individual interneurons, this plasticity was observed at somatodendritic basket cell synapses, but not at distal dendritic stellate cell synapses. Basket cell synapses predominantly express β2-subunit-containing GABAA receptors; deletion of the β2-subunit ablates this plasticity, demonstrating its reliance on GABAA receptor subunit composition. The increase in synaptic currents is dependent upon an increase in newly synthesized cell surface synaptic GABAA receptors and is abolished by preventing CaMKII phosphorylation of GABAA receptors. Our results reveal a novel GABAA receptor subunit- and input-specific form of inhibitory synaptic plasticity that regulates the temporal firing pattern of the principal output cells of the cerebellum.

  16. High temperatures alter physiological properties of pyramidal cells and inhibitory interneurons in hippocampus

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    Jennifer eKim

    2012-07-01

    Full Text Available Temperature has multiple effects on neurons, yet little is known about the effects of high temperature on the physiology of mammalian central neurons. Hyperthermia can influence behavior and cause febrile seizures. We studied the effects of acute hyperthermia on the immature hippocampus in vitro by recording from pyramidal neurons and inhibitory oriens-lacunosum moleculare (O-LM interneurons (identified by green fluorescent protein expression in the GIN mouse line. Warming to 41°C caused depolarization, spontaneous action potentials, reduced input resistance and membrane time constant, and increased spontaneous synaptic activity of most pyramidal cells and O-LM interneurons. Pyramidal neurons of area CA3 were more strongly excited by hyperthermia than those of area CA1. About 90% of O-LM interneurons in both CA1 and CA3 increased their firing rates at hyperthermic temperatures; interneurons in CA3 fired faster than those in CA1 on average. Blockade of fast synaptic transmission did not abolish the effect of hyperthermia on neuronal excitability. Our results suggest that hyperthermia increases hippocampal excitability, particularly in seizure-prone area CA3, by altering the intrinsic membrane properties of pyramidal cells and interneurons.

  17. High temperatures alter physiological properties of pyramidal cells and inhibitory interneurons in hippocampus.

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    Kim, Jennifer A; Connors, Barry W

    2012-01-01

    Temperature has multiple effects on neurons, yet little is known about the effects of high temperature on the physiology of mammalian central neurons. Hyperthermia can influence behavior and cause febrile seizures. We studied the effects of acute hyperthermia on the immature hippocampus in vitro by recording from pyramidal neurons and inhibitory oriens-lacunosum moleculare (O-LM) interneurons (identified by green fluorescent protein (GFP) expression in the GIN mouse line). Warming to 41°C caused depolarization, spontaneous action potentials, reduced input resistance and membrane time constant, and increased spontaneous synaptic activity of most pyramidal cells and O-LM interneurons. Pyramidal neurons of area CA3 were more strongly excited by hyperthermia than those of area CA1. About 90% of O-LM interneurons in both CA1 and CA3 increased their firing rates at hyperthermic temperatures; interneurons in CA3 fired faster than those in CA1 on average. Blockade of fast synaptic transmission did not abolish the effect of hyperthermia on neuronal excitability. Our results suggest that hyperthermia increases hippocampal excitability, particularly in seizure-prone area CA3, by altering the intrinsic membrane properties of pyramidal cells and interneurons.

  18. Parvalbumin-expressing inhibitory interneurons in auditory cortex are well-tuned for frequency.

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    Moore, Alexandra K; Wehr, Michael

    2013-08-21

    In the auditory cortex, synaptic inhibition is known to be involved in shaping receptive fields, enhancing temporal precision, and regulating gain. Cortical inhibition is provided by local GABAergic interneurons, which comprise 10-20% of the cortical population and can be separated into numerous subclasses. The morphological and physiological diversity of interneurons suggests that these different subclasses have unique roles in sound processing; however, these roles are yet unknown. Understanding the receptive field properties of distinct inhibitory cell types will be critical to elucidating their computational function in cortical circuits. Here we characterized the tuning and response properties of parvalbumin-positive (PV+) interneurons, the largest inhibitory subclass. We used channelrhodopsin-2 (ChR2) as an optogenetic tag to identify PV+ and PV- neurons in vivo in transgenic mice. In contrast to PV+ neurons in mouse visual cortex, which are broadly tuned for orientation, we found that auditory cortical PV+ neurons were well tuned for frequency, although very tightly tuned PV+ cells were uncommon. This suggests that PV+ neurons play a minor role in shaping frequency tuning, and is consistent with the idea that PV+ neurons nonselectively pool input from the local network. PV+ interneurons had shallower response gain and were less intensity-tuned than PV- neurons, suggesting that PV+ neurons provide dynamic gain control and shape intensity tuning in auditory cortex. PV+ neurons also had markedly faster response latencies than PV- neurons, consistent with a computational role in enhancing the temporal precision of cortical responses.

  19. Evidence that histamine is the inhibitory transmitter of the auditory interneuron ON1 of crickets.

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    Skiebe, P; Corrette, B J; Wiese, K

    1990-08-24

    The omega neurons of crickets are connected with each other by reciprocal inhibition. This inhibition could be mimicked by bath-applied histamine and blocked by histamine H1-antagonists. Histamine, like ON1, also influenced the ascending interneuron AN2, so that its response pattern more closely reflected the temporal structure of the calling song. This evidence strongly suggests that histamine is the inhibitory transmitter of the ON1s.

  20. Fluctuating inhibitory inputs promote reliable spiking at theta frequencies in hippocampal interneurons

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    Duluxan eSritharan; Frances K Skinner

    2012-01-01

    Theta frequency (4-12 Hz) rhythms in the hippocampus play important roles in learning and memory. CA1 interneurons located at the stratum lacunosum-moleculare and radiatum junction (LM/RAD) are thought to contribute to hippocampal theta population activities by rhythmically pacing pyramidal cells with inhibitory postsynaptic potentials. This implies that LM/RAD cells need to fire reliably at theta frequencies in vivo. To determine whether this could occur, we use biophysically-based LM/RAD mo...

  1. High temperatures alter physiological properties of pyramidal cells and inhibitory interneurons in hippocampus

    OpenAIRE

    Kim, Jennifer A; Barry W Connors

    2012-01-01

    Temperature has multiple effects on neurons, yet little is known about the effects of high temperature on the physiology of mammalian central neurons. Hyperthermia can influence behavior and cause febrile seizures. We studied the effects of acute hyperthermia on the immature hippocampus in vitro by recording from pyramidal neurons and inhibitory oriens-lacunosum moleculare (O-LM) interneurons (identified by green fluorescent protein (GFP) expression in the GIN mouse line). Warming to 41°C cau...

  2. Developmental expression of potassium-channel subunit Kv3.2 within subpopulations of mouse hippocampal inhibitory interneurons.

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    Tansey, Emily Phillips; Chow, Alan; Rudy, Bernardo; McBain, Chris J

    2002-01-01

    The developmental expression of the voltage-gated potassium channel subunit, Kv3.2, and its localization within specific mouse hippocampal inhibitory interneuron populations were determined using immunoblotting and immunohistochemical techniques. Using immunoblotting techniques, the Kv3.2 protein was weakly detected at postnatal age day 7 (P7), and full expression was attained at P21 in tissue extracts from homogenized hippocampal preparations. A similar developmental profile was observed using immunohistochemical techniques in hippocampal tissue sections. Kv3.2 protein expression was clustered on the somata and proximal dendrites of presumed inhibitory interneurons. Using double immunofluorescence, Kv3.2 subunit expression was detected on subpopulations of GABAergic inhibitory interneurons. Kv3.2 was detected in approximately 100% of parvalbumin-positive interneurons, 86% of interneurons expressing nitric oxide synthase, and approximately 50% of somatostatin-immunoreactive cells. Kv3.2 expression was absent from both calbindin- and calretinin-containing interneurons. Using immunoprecipitation, we further demonstrate that Kv3.2 and its related subunit Kv3.1b are coexpressed within the same protein complexes in the hippocampus. These data demonstrate that potassium channel subunit Kv3.2 expression is developmentally regulated in a specific set of interneurons. The vast majority of these interneuron subpopulations possess a "fast-spiking" phenotype, consistent with a role for currents through Kv3.2 containing channels in determining action potential kinetics in these cells.

  3. High Stimulus-Related Information in Barrel Cortex Inhibitory Interneurons.

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    Vicente Reyes-Puerta

    2015-06-01

    Full Text Available The manner in which populations of inhibitory (INH and excitatory (EXC neocortical neurons collectively encode stimulus-related information is a fundamental, yet still unresolved question. Here we address this question by simultaneously recording with large-scale multi-electrode arrays (of up to 128 channels the activity of cell ensembles (of up to 74 neurons distributed along all layers of 3-4 neighboring cortical columns in the anesthetized adult rat somatosensory barrel cortex in vivo. Using two different whisker stimulus modalities (location and frequency we show that individual INH neurons--classified as such according to their distinct extracellular spike waveforms--discriminate better between restricted sets of stimuli (≤6 stimulus classes than EXC neurons in granular and infra-granular layers. We also demonstrate that ensembles of INH cells jointly provide as much information about such stimuli as comparable ensembles containing the ~20% most informative EXC neurons, however presenting less information redundancy - a result which was consistent when applying both theoretical information measurements and linear discriminant analysis classifiers. These results suggest that a consortium of INH neurons dominates the information conveyed to the neocortical network, thereby efficiently processing incoming sensory activity. This conclusion extends our view on the role of the inhibitory system to orchestrate cortical activity.

  4. Oscillation-Driven Spike-Timing Dependent Plasticity Allows Multiple Overlapping Pattern Recognition in Inhibitory Interneuron Networks.

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    Garrido, Jesús A; Luque, Niceto R; Tolu, Silvia; D'Angelo, Egidio

    2016-08-01

    The majority of operations carried out by the brain require learning complex signal patterns for future recognition, retrieval and reuse. Although learning is thought to depend on multiple forms of long-term synaptic plasticity, the way this latter contributes to pattern recognition is still poorly understood. Here, we have used a simple model of afferent excitatory neurons and interneurons with lateral inhibition, reproducing a network topology found in many brain areas from the cerebellum to cortical columns. When endowed with spike-timing dependent plasticity (STDP) at the excitatory input synapses and at the inhibitory interneuron-interneuron synapses, the interneurons rapidly learned complex input patterns. Interestingly, induction of plasticity required that the network be entrained into theta-frequency band oscillations, setting the internal phase-reference required to drive STDP. Inhibitory plasticity effectively distributed multiple patterns among available interneurons, thus allowing the simultaneous detection of multiple overlapping patterns. The addition of plasticity in intrinsic excitability made the system more robust allowing self-adjustment and rescaling in response to a broad range of input patterns. The combination of plasticity in lateral inhibitory connections and homeostatic mechanisms in the inhibitory interneurons optimized mutual information (MI) transfer. The storage of multiple complex patterns in plastic interneuron networks could be critical for the generation of sparse representations of information in excitatory neuron populations falling under their control.

  5. Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons.

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    Mao, Wenjie; Watanabe, Takuya; Cho, Sukhee; Frost, Jeffrey L; Truong, Tina; Zhao, Xiaohu; Futai, Kensuke

    2015-04-01

    The Shank genes (SHANK1, 2, 3) encode scaffold proteins highly enriched in postsynaptic densities where they regulate synaptic structure in spiny neurons. Mutations in human Shank genes are linked to autism spectrum disorder and schizophrenia. Shank1 mutant mice exhibit intriguing cognitive phenotypes reminiscent of individuals with autism spectrum disorder. However, the molecular mechanisms leading to the human pathophysiological phenotypes and mouse behaviors have not been elucidated. In this study it is shown that Shank1 protein is highly localized in parvalbumin-expressing (PV+) fast-spiking inhibitory interneurons in the hippocampus. Importantly, a lack of Shank1 in hippocampal CA1 PV+ neurons reduced excitatory synaptic inputs and inhibitory synaptic outputs to pyramidal neurons. Furthermore, it is demonstrated that hippocampal CA1 pyramidal neurons in Shank1 mutant mice exhibit a shift in the excitatory and inhibitory balance (E-I balance), a pathophysiological hallmark of autism spectrum disorder. The mutant mice also exhibit lower expression of gephyrin (a scaffold component of inhibitory synapses), supporting the dysregulation of E-I balance in the hippocampus. These results suggest that Shank1 scaffold in PV+ interneurons regulates excitatory synaptic strength and participates in the maintenance of E-I balance in excitatory neurons.

  6. Activation of kinetically distinct synaptic conductances on inhibitory interneurons by electrotonically overlapping afferents.

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    Walker, Harrison C; Lawrence, J Josh; McBain, Chris J

    2002-07-03

    Mossy fiber (MF) and CA3 collateral (CL) axons activate common interneurons via synapses comprised of different AMPA receptors to provide feedforward and feedback inhibitory control of the CA3 hippocampal network. Because synapses potentially occur over variable electrotonic distances that distort somatically recorded synaptic currents, it is not known whether the underlying afferent-specific synaptic conductances are associated with different time courses. Using a somatic voltage jump technique to alter the driving force at the site of the synapse, we demonstrate that MF and CL synapses overlap in electrotonic location yet differ in conductance time course. Thus, afferent-specific conductance time courses allow single interneurons to differentially integrate feedforward and feedback information without the need to segregate distinct AMPA receptor subunits to different electrotonic domains.

  7. NR2 subunits and NMDA receptors on lamina II inhibitory and excitatory interneurons of the mouse dorsal horn

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    MacDermott Amy B

    2010-05-01

    Full Text Available Abstract Background NMDA receptors expressed by spinal cord neurons in the superficial dorsal horn are involved in the development of chronic pain associated with inflammation and nerve injury. The superficial dorsal horn has a complex and still poorly understood circuitry that is mainly populated by inhibitory and excitatory interneurons. Little is known about how NMDA receptor subunit composition, and therefore pharmacology and voltage dependence, varies with neuronal cell type. NMDA receptors are typically composed of two NR1 subunits and two of four NR2 subunits, NR2A-2D. We took advantage of the differences in Mg2+ sensitivity of the NMDA receptor subtypes together with subtype preferring antagonists to identify the NR2 subunit composition of NMDA receptors expressed on lamina II inhibitory and excitatory interneurons. To distinguish between excitatory and inhibitory interneurons, we used transgenic mice expressing enhanced green fluorescent protein driven by the GAD67 promoter. Results Analysis of conductance ratio and selective antagonists showed that lamina II GABAergic interneurons express both the NR2A/B containing Mg2+ sensitive receptors and the NR2C/D containing NMDA receptors with less Mg2+ sensitivity. In contrast, excitatory lamina II interneurons express primarily NR2A/B containing receptors. Despite this clear difference in NMDA receptor subunit expression in the two neuronal populations, focally stimulated synaptic input is mediated exclusively by NR2A and 2B containing receptors in both neuronal populations. Conclusions Stronger expression of NMDA receptors with NR2C/D subunits by inhibitory interneurons compared to excitatory interneurons may provide a mechanism to selectively increase activity of inhibitory neurons during intense excitatory drive that can provide inhibitory feedback.

  8. Fluctuating Inhibitory Inputs Promote Reliable Spiking at Theta Frequencies in Hippocampal Interneurons

    OpenAIRE

    Sritharan, Duluxan; Frances K Skinner

    2012-01-01

    Theta-frequency (4–12 Hz) rhythms in the hippocampus play important roles in learning and memory. CA1 interneurons located at the stratum lacunosum-moleculare and radiatum junction (LM/RAD) are thought to contribute to hippocampal theta population activities by rhythmically pacing pyramidal cells with inhibitory postsynaptic potentials. This implies that LM/RAD cells need to fire reliably at theta frequencies in vivo. To determine whether this could occur, we use biophysically based LM/RAD mo...

  9. GABA through the Ages: Regulation of Cortical Function and Plasticity by Inhibitory Interneurons

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    Konrad Lehmann

    2012-01-01

    Full Text Available Inhibitory interneurons comprise only about 20% of cortical neurons and thus constitute a clear minority compared to the vast number of excitatory projection neurons. They are, however, an influential minority with important roles in cortical maturation, function, and plasticity. In this paper, we will highlight the functional importance of cortical inhibition throughout brain development, starting with the embryonal formation of the cortex, proceeding by the regulation of sensory cortical plasticity in adulthood, and finishing with the GABA involvement in sensory information processing in old age.

  10. A role for sodium and chloride in kainic acid-induced beading of inhibitory interneuron dendrites.

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    Al-Noori, S; Swann, J W

    2000-01-01

    Excitotoxic injury of the dendrites of inhibitory interneurons could lead to decreases in their synaptic activation and explain subsequent local circuit hyperexcitability and epilepsy. A hallmark of dendrotoxicity, at least in principal neurons of the hippocampus and cortex, is focal or varicose swellings of dendritic arbors. In experiments reported here, transient (1h) exposure of hippocampal explant cultures to kainic acid produced marked focal swellings of the dendrites of parvalbumin-immunoreactive pyramidal basket cells in a highly reproducible and dose-dependent manner. At 5mM kainic acid, more than half of the immunopositive apical dendrites in area CA(1) had a beaded appearance. However, the somal volumes of these cells were unaltered by the same treatment. The presence of focal swellings was reversible with kainate washout and was not accompanied by interneuronal cell death. In contrast, exposure to much higher concentrations (300mM) of kainic acid resulted in the total loss of parvalbumin-positive interneurons from explants. Surprisingly, kainic acid-induced dendritic beading does not appear to be mediated by extracellular calcium. Beading was unaltered in the presence of N-methyl-D-aspartate receptor antagonists, the L-type calcium channel antagonist, nimodipine, cadmium, or by removing extracellular calcium. However, blockade of voltage-gated sodium channels by either tetrodotoxin or lidocaine abolished dendritic beading, while the activation of existing voltage-gated sodium channels by veratridine mimicked the kainic acid-induced dendritic beading. Finally, the removal of extracellular chloride prevented the kainic acid-induced dendritic beading.Thus, we suggest that the movement of Na(+) and Cl(-), rather than Ca(2+), into cells underlies the focal swellings of interneuron dendrites in hippocampus.

  11. Interneurons are the local targets of hippocampal inhibitory cells which project to the medial septum.

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    Gulyás, A I; Hájos, N; Katona, I; Freund, T F

    2003-05-01

    A subset of GABAergic neurons projecting to the medial septum has long been described in the hippocampus. However, the lack of information about their local connectivity pattern or their correspondence with any of the well-established hippocampal interneuron types has hampered the understanding of their functional role. Retrograde tracing combined with immunostaining for neurochemical markers in the adult rat hippocampus showed that nearly all hippocampo-septal (HS) neurons express somatostatin (>95%) and, in the hilus and CA3 stratum lucidum, many contain calretinin (>45%). In contrast, in stratum oriens of the CA1 and CA3 subfields, the majority of HS neurons contain somatostatin (>86%) and calbindin (>73%), but not calretinin. Because somatostatin-positive hippocampal interneurons have been most extensively characterized in the stratum oriens of CA1, we focused our further analysis on HS cells found in this region. In 18-20-day-old rats, intracellularly filled CA1-HS cells had extensive local axon collaterals crossing subfield boundaries and innervating the CA3 region and the dentate gyrus. Electron microscopic analysis provided evidence that the axon terminals of CA1-HS cells form symmetrical synapses selectively on GABAergic interneurons, both locally and in the CA3 region. In addition, double retrograde labelling experiments revealed that many CA1-HS neurons of the dorsal hippocampus also have collateral projections to the ventral hippocampus. Thus, CA1-HS cells innervate inhibitory interneurons locally and in remote hippocampal regions, in addition to targeting mostly GABAergic neurons in the medial septum. This dual projection with striking target selectivity for GABAergic neurons may be ideally suited to synchronize neuronal activity along the septo-hippocampal axis.

  12. GABA B receptor modulation of excitatory and inhibitory synaptic transmission onto rat CA3 hippocampal interneurons.

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    Lei, Saobo; McBain, Chris J

    2003-01-15

    Hippocampal stratum radiatum inhibitory interneurons receive glutamatergic excitatory innervation via the recurrent collateral fibers of CA3 pyramidal neurons and GABAergic inhibition from other interneurons. We examined both presynaptic- and postsynaptic-GABA(B) receptor-mediated responses at both synapse types. Postsynaptic GABA(B) receptor-mediated responses were absent in recordings from young (P16-18) but present in recordings from older animals (> or =P30) suggesting developmental regulation. In young animals, the GABA(B) receptor agonist, baclofen, inhibited the amplitude of evoked EPSCs and IPSCs, an effect blocked by prior application of the selective antagonist CGP55845. Baclofen enhanced the paired-pulse ratio and coefficient of variation of evoked EPSCs and IPSCs, consistent with a presynaptic mechanism of regulation. In addition, baclofen reduced the frequency of miniature IPSCs but not mEPSCs. However, baclofen reduced the frequency of KCl-induced mEPSCs; an effect blocked by Cd(2+), implicating presynaptic voltage-gated Ca(2+) channels as a target for baclofen modulation. In contrast, although Cd(2+) prevented the KCl-induced increase in mIPSC frequency, it failed to block baclofen's reduction of mIPSC frequency. Whereas N- and P/Q-types of Ca(2+) channels contributed equally to GABA(B) receptor-mediated inhibition of EPSCs, more P/Q-type Ca(2+) channels were involved in GABA(B) receptor-mediated inhibition of IPSCs. Finally, baclofen blocked the frequency-dependent depression of EPSCs and IPSCs, but was less effective at blocking frequency-dependent facilitation of EPSCs. Our results demonstrate that presynaptic GABA(B) receptors are expressed on the terminals of both excitatory and inhibitory synapses onto CA3 interneurons and that their activation modulates essential components of the release process underlying transmission at these two synapse types.

  13. A Subtype of Inhibitory Interneuron with Intrinsic Persistent Activity in Human and Monkey Neocortex

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    Bo Wang

    2015-03-01

    Full Text Available A critical step in understanding the neural basis of human cognitive functions is to identify neuronal types in the neocortex. In this study, we performed whole-cell recording from human cortical slices and found a distinct subpopulation of neurons with intrinsic persistent activity that could be triggered by single action potentials (APs but terminated by bursts of APs. This persistent activity was associated with a depolarizing plateau potential induced by the activation of a persistent Na+ current. Single-cell RT-PCR revealed that these neurons were inhibitory interneurons. This type of neuron was found in different cortical regions, including temporal, frontal, occipital, and parietal cortices in human and also in frontal and temporal lobes of nonhuman primate but not in rat cortical tissues, suggesting that it could be unique to primates. The characteristic persistent activity in these inhibitory interneurons may contribute to the regulation of pyramidal cell activity and participate in cortical processing.

  14. Prenatal protein malnutrition results in increased frequency of miniature inhibitory postsynaptic currents in rat CA3 interneurons.

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    Chang, Yu-Ming; Galler, Janina R; Luebke, Jennifer I

    2003-08-01

    Electrophysiological studies have revealed an increase in the level of tonic inhibition in the hippocampus following prenatal protein malnutrition in rats. In the present study, whole cell patch clamp recordings of bipolar interneurons in the stratum radiatum of the CA3 subfield were used to determine whether this increase in inhibition can be accounted for by a change in the electrophysiological properties of GABAergic interneurons. Hippocampal slices were prepared from juvenile rats whose dams were fed either a normal (25% casein) or low (6% casein) protein diet throughout pregnancy. Intrinsic membrane and action potential properties were unaltered by the prenatal nutritional insult. In most respects the characteristics of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) and the modulation of such currents by the benzodiazepine agonist zolpidem were also similar in cells from the two nutritional groups. While the frequency of spontaneous inhibitory currents was unaltered, miniature (Tetrodotoxin resistant) inhibitory currents occurred at a significantly increased frequency in interneurons from prenatally protein malnourished rats. Thus, while the basic membrane properties of interneurons are preserved, there is a significant increase in the probability of GABA release from interneurons following prenatal protein malnutrition.

  15. Parvalbumin-producing cortical interneurons receive inhibitory inputs on proximal portions and cortical excitatory inputs on distal dendrites.

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    Kameda, Hiroshi; Hioki, Hiroyuki; Tanaka, Yasuyo H; Tanaka, Takuma; Sohn, Jaerin; Sonomura, Takahiro; Furuta, Takahiro; Fujiyama, Fumino; Kaneko, Takeshi

    2012-03-01

    To examine inputs to parvalbumin (PV)-producing interneurons, we generated transgenic mice expressing somatodendritic membrane-targeted green fluorescent protein specifically in the interneurons, and completely visualized their dendrites and somata. Using immunolabeling for vesicular glutamate transporter (VGluT)1, VGluT2, and vesicular GABA transporter, we found that VGluT1-positive terminals made contacts 4- and 3.1-fold more frequently with PV-producing interneurons than VGluT2-positive and GABAergic terminals, respectively, in the primary somatosensory cortex. Even in layer 4, where VGluT2-positive terminals were most densely distributed, VGluT1-positive inputs to PV-producing interneurons were 2.4-fold more frequent than VGluT2-positive inputs. Furthermore, although GABAergic inputs to PV-producing interneurons were as numerous as VGluT2-positive inputs in most cortical layers, GABAergic inputs clearly preferred the proximal dendrites and somata of the interneurons, indicating that the sites of GABAergic inputs were more optimized than those of VGluT2-positive inputs. Simulation analysis with a PV-producing interneuron model compatible with the present morphological data revealed a plausible reason for this observation, by showing that GABAergic and glutamatergic postsynaptic potentials evoked by inputs to distal dendrites were attenuated to 60 and 87%, respectively, of those evoked by somatic inputs. As VGluT1-positive and VGluT2-positive axon terminals were presumed to be cortical and thalamic glutamatergic inputs, respectively, cortical excitatory inputs to PV-producing interneurons outnumbered the thalamic excitatory and intrinsic inhibitory inputs more than two-fold in any cortical layer. Although thalamic inputs are known to evoke about two-fold larger unitary excitatory postsynaptic potentials than cortical ones, the present results suggest that cortical inputs control PV-producing interneurons at least as strongly as thalamic inputs.

  16. Reduction in parvalbumin-positive interneurons and inhibitory input in the cortex of mice with experimental autoimmune encephalomyelitis.

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    Falco, Anna; Pennucci, Roberta; Brambilla, Elena; de Curtis, Ivan

    2014-07-01

    In multiple sclerosis (MS), inflammation leads to damage of central nervous system myelin and axons. Previous studies have postulated impaired GABA transmission in MS, and recent postmortem analysis has shown that GABAergic parvalbumin (PV)-positive interneurons are decreased in the primary motor cortex (M1) of patients with MS. In this report, we present evidence for the loss of a specific population of GABAergic interneurons in the experimental autoimmune encephalomyelitis mouse model of MS. Using experimental autoimmune encephalomyelitis, we evaluated the distribution of both PV-positive interneurons and of the inhibitory presynaptic input in the M1 of experimental autoimmune encephalomyelitis and control mice. Our results demonstrate a specific decrease in the number of PV-positive interneurons in the M1 of mice with experimental autoimmune encephalomyelitis. We detected a significant reduction in the number of PV-positive interneurons in the layers II and III of the M1 of diseased mice, while there was no difference in the number of calretinin (CR)-positive cells between animals with experimental autoimmune encephalomyelitis and control animals. Moreover, we observed a significant reduction in the inhibitory presynaptic input in the M1 of treated mice. These changes were specific for the mice with elevated clinical score, while they were not detectable in the mice with low clinical score. Our results support the hypothesis that reinforcing the action of the GABAergic network may represent a therapeutic alternative to limit the progression of the neuronal damage in MS patients.

  17. Galanin-immunoreactivity identifies a distinct population of inhibitory interneurons in laminae I-III of the rat spinal cord

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    Watanabe Masahiko

    2011-05-01

    Full Text Available Abstract Background Inhibitory interneurons constitute 30-40% of neurons in laminae I-III and have an important anti-nociceptive role. However, because of the difficulty in classifying them we know little about their organisation. Previous studies have identified 3 non-overlapping groups of inhibitory interneuron, which contain neuropeptide Y (NPY, neuronal nitric oxide synthase (nNOS or parvalbumin, and have shown that these differ in postsynaptic targets. Some inhibitory interneurons contain galanin and the first aim of this study was to determine whether these form a different population from those containing NPY, nNOS or parvalbumin. We also estimated the proportion of neurons and GABAergic axons that contain galanin in laminae I-III. Results Galanin cells were concentrated in laminae I-IIo, with few in laminae IIi-III. Galanin showed minimal co-localisation with NPY, nNOS or parvalbumin in laminae I-II, but most galanin-containing cells in lamina III were nNOS-positive. Galanin cells constituted ~7%, 3% and 2% of all neurons in laminae I, II and III, and we estimate that this corresponds to 26%, 10% and 5% of the GABAergic neurons in these laminae. However, galanin was only found in ~6% of GABAergic boutons in laminae I-IIo, and ~1% of those in laminae IIi-III. Conclusions These results show that galanin, NPY, nNOS and parvalbumin can be used to define four distinct neurochemical populations of inhibitory interneurons. Together with results of a recent study, they suggest that the galanin and NPY populations account for around half of the inhibitory interneurons in lamina I and a quarter of those in lamina II.

  18. Parvalbumin and neuropeptide Y expressing hippocampal GABA-ergic inhibitory interneuron numbers decline in a model of Gulf War illness.

    Science.gov (United States)

    Megahed, Tarick; Hattiangady, Bharathi; Shuai, Bing; Shetty, Ashok K

    2014-01-01

    Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf War illness (GWI). Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR) chemicals and mild stress for 4 weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. In this study, we tested whether reduced numbers of hippocampal gamma-amino butyric acid (GABA)-ergic interneurons are among the pathological changes induced by GWIR-chemicals and stress. Animals were exposed to low doses of GWIR-chemicals and mild stress for 4 weeks. Three months after this exposure, subpopulations of GABA-ergic interneurons expressing the calcium binding protein parvalbumin (PV), the neuropeptide Y (NPY) and somatostatin (SS) in the hippocampus were stereologically quantified. Animals exposed to GWIR-chemicals and stress for 4 weeks displayed reduced numbers of PV-expressing GABA-ergic interneurons in the dentate gyrus and NPY-expressing interneurons in the CA1 and CA3 subfields. However, no changes in SS+ interneuron population were observed in the hippocampus. Furthermore, GABA-ergic interneuron deficiency in these animals was associated with greatly diminished hippocampus neurogenesis. Because PV+ and NPY+ interneurons play roles in maintaining normal cognitive function and neurogenesis, and controlling the activity of excitatory neurons in the hippocampus, reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. Hence, strategies that improve inhibitory neurotransmission in the hippocampus may prove beneficial for reversing cognitive dysfunction in GWI.

  19. Parvalbumin and Neuropeptide Y Expressing Hippocampal GABA-ergic Inhibitory Interneuron Numbers Decline in a Model of Gulf War illness

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    Tarick eMegahed

    2015-01-01

    Full Text Available Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf war illness (GWI. Combined exposure to the nerve gas antidote pyridostigmine bromide, pesticides and stress during the Persian Gulf War-1 are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR chemicals and mild stress for four weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. In this study, we tested whether reduced numbers of hippocampal gamma-amino butyric acid (GABA-ergic interneurons are among the pathological changes induced by GWIR-chemicals and stress. Animals were exposed to low doses of GWIR-chemicals and mild stress for four weeks. Three months after this exposure, subpopulations of GABA-ergic interneurons expressing the calcium binding protein parvalbumin (PV, the neuropeptide Y (NPY and somatostatin (SS in the hippocampus were stereologically quantified. Animals exposed to GWIR-chemicals and stress for four weeks displayed reduced numbers of PV-expressing GABA-ergic interneurons in the dentate gyrus and NPY-expressing interneurons in the CA1 and CA3 subfields. However, no changes in SS+ interneuron population were observed in the hippocampus. Furthermore, GABA-ergic interneuron deficiency in these animals was associated with greatly diminished hippocampus neurogenesis. Because PV+ and NPY+ interneurons play roles in maintaining normal cognitive function and neurogenesis, and controlling the activity of excitatory neurons in the hippocampus, reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. Hence, strategies that improve inhibitory neurotransmission in the hippocampus may prove beneficial for reversing cognitive dysfunction in GWI.

  20. Differential GABAergic and glycinergic inputs of inhibitory interneurons and Purkinje cells to principal cells of the cerebellar nuclei.

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    Husson, Zoé; Rousseau, Charly V; Broll, Ilja; Zeilhofer, Hanns Ulrich; Dieudonné, Stéphane

    2014-07-09

    The principal neurons of the cerebellar nuclei (CN), the sole output of the olivo-cerebellar system, receive a massive inhibitory input from Purkinje cells (PCs) of the cerebellar cortex. Morphological evidence suggests that CN principal cells are also contacted by inhibitory interneurons, but the properties of this connection are unknown. Using transgenic, tracing, and immunohistochemical approaches in mice, we show that CN interneurons form a large heterogeneous population with GABA/glycinergic phenotypes, distinct from GABAergic olive-projecting neurons. CN interneurons are found to contact principal output neurons, via glycine receptor (GlyR)-enriched synapses, virtually devoid of the main GABA receptor (GABAR) subunits α1 and γ2. Those clusters account for 5% of the total number of inhibitory receptor clusters on principal neurons. Brief optogenetic stimulations of CN interneurons, through selective expression of channelrhodopsin 2 after viral-mediated transfection of the flexed gene in GlyT2-Cre transgenic mice, evoked fast IPSCs in principal cells. GlyR activation accounted for 15% of interneuron IPSC amplitude, while the remaining current was mediated by activation of GABAR. Surprisingly, small GlyR clusters were also found at PC synapses onto principal CN neurons in addition to α1 and γ2 GABAR subunits. However, GlyR activation was found to account for <3% of the PC inhibitory synaptic currents evoked by electrical stimulation. This work establishes CN glycinergic neurons as a significant source of inhibition to CN principal cells, forming contacts molecularly distinct from, but functionally similar to, Purkinje cell synapses. Their impact on CN output, motor learning, and motor execution deserves further investigation.

  1. Acetylcholine release in mouse hippocampal CA1 preferentially activates inhibitory-selective interneurons via alpha4 beta2* nicotinic receptor activation

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    L. Andrew Bell

    2015-04-01

    Full Text Available Acetylcholine (ACh release onto nicotinic receptors directly activates subsets of inhibitory interneurons in hippocampal CA1. However, the specific interneurons activated and their effect on the hippocampal network is not completely understood. Therefore, we investigated subsets of hippocampal CA1 interneurons that respond to ACh release through the activation of nicotinic receptors and the potential downstream effects this may have on hippocampal CA1 network function. ACh was optogenetically released in mouse hippocampal slices by expressing the excitatory optogenetic protein oChIEF-tdTomato in medial septum/diagonal band of Broca cholinergic neurons using Cre recombinase-dependent adeno-associated viral mediated transfection. The actions of optogenetically released ACh were assessed on both pyramidal neurons and different interneuron subtypes via whole cell patch clamp methods. Vasoactive intestinal peptide (VIP-expressing interneurons that selectively innervate other interneurons (VIP/IS were excited by ACh through the activation of nicotinic receptors containing alpah4 and beta2 subunits (alpha4 beta2*. ACh release onto VIP/IS was presynaptically inhibited by M2 muscarinic autoreceptors. ACh release produced spontaneous inhibitory postsynaptic current (sIPSC barrages blocked by dihydro-beta-erythroidine in interneurons but not pyramidal neurons. Optogenetic suppression of VIP interneurons did not inhibit these sIPSC barrages suggesting other interneuron-selective interneurons were also excited by 42* nicotinic receptor activation. In contrast, interneurons that innervate pyramidal neuron perisomatic regions were not activated by ACh release onto nicotinic receptors. Therefore, we propose ACh release in CA1 facilitates disinhibition through activation of 42* nicotinic receptors on interneuron-selective interneurons whereas interneurons that innervate pyramidal neurons are less affected by nicotinic receptor activation.

  2. Action potential modulation in CA1 pyramidal neuron axons facilitates OLM interneuron activation in recurrent inhibitory microcircuits of rat hippocampus.

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    Sooyun Kim

    Full Text Available Oriens-lacunosum moleculare (O-LM interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outside-out patch recordings from CA1 pyramidal neuron axons revealed a high density of α-dendrotoxin (α-DTX-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron-O-LM interneuron excitatory postsynaptic currents (EPSCs showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron-interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.

  3. Action potential modulation in CA1 pyramidal neuron axons facilitates OLM interneuron activation in recurrent inhibitory microcircuits of rat hippocampus.

    Science.gov (United States)

    Kim, Sooyun

    2014-01-01

    Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outside-out patch recordings from CA1 pyramidal neuron axons revealed a high density of α-dendrotoxin (α-DTX)-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron-O-LM interneuron excitatory postsynaptic currents (EPSCs) showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron-interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.

  4. LTS and FS inhibitory interneurons, short-term synaptic plasticity, and cortical circuit dynamics.

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    Itai Hayut

    2011-10-01

    Full Text Available Somatostatin-expressing, low threshold-spiking (LTS cells and fast-spiking (FS cells are two common subtypes of inhibitory neocortical interneuron. Excitatory synapses from regular-spiking (RS pyramidal neurons to LTS cells strongly facilitate when activated repetitively, whereas RS-to-FS synapses depress. This suggests that LTS neurons may be especially relevant at high rate regimes and protect cortical circuits against over-excitation and seizures. However, the inhibitory synapses from LTS cells usually depress, which may reduce their effectiveness at high rates. We ask: by which mechanisms and at what firing rates do LTS neurons control the activity of cortical circuits responding to thalamic input, and how is control by LTS neurons different from that of FS neurons? We study rate models of circuits that include RS cells and LTS and FS inhibitory cells with short-term synaptic plasticity. LTS neurons shift the RS firing-rate vs. current curve to the right at high rates and reduce its slope at low rates; the LTS effect is delayed and prolonged. FS neurons always shift the curve to the right and affect RS firing transiently. In an RS-LTS-FS network, FS neurons reach a quiescent state if they receive weak input, LTS neurons are quiescent if RS neurons receive weak input, and both FS and RS populations are active if they both receive large inputs. In general, FS neurons tend to follow the spiking of RS neurons much more closely than LTS neurons. A novel type of facilitation-induced slow oscillations is observed above the LTS firing threshold with a frequency determined by the time scale of recovery from facilitation. To conclude, contrary to earlier proposals, LTS neurons affect the transient and steady state responses of cortical circuits over a range of firing rates, not only during the high rate regime; LTS neurons protect against over-activation about as well as FS neurons.

  5. GAD67 deficiency in parvalbumin interneurons produces deficits in inhibitory transmission and network disinhibition in mouse prefrontal cortex.

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    Lazarus, Matthew S; Krishnan, Keerthi; Huang, Z Josh

    2015-05-01

    In mammalian neocortex, the delicate balance of neural circuits is regulated by a rich repertoire of inhibitory control mechanisms mediated by diverse classes of GABAergic interneurons. A key step common to all GABAergic neurons is the synthesis of GABA, catalyzed by 2 isoforms of glutamic acid decarboxylases (GAD). Among these, GAD67 is the rate-limiting enzyme. GAD67 level is regulated by neural activity and is altered in multiple neuropsychiatric disorders. The significance of altered GAD67 levels on inhibitory transmission, however, remains unclear. The presence of GAD65, postsynaptic GABA receptor regulation, and the diversity of cortical interneurons make the link from GAD67 levels to GABA transmission less than straightforward. Here, we selectively removed one allele of the GAD67 gene, Gad1, in PV interneurons in juvenile mice. We found substantial deficits in transmission from PV to pyramidal neurons in prefrontal cortex, along with increases of pyramidal cell excitability and excitation/inhibition balance in PV cells. Synaptic deficits recovered in adult mice, suggesting engagement of homeostatic and compensatory mechanisms. These results demonstrate that GAD67 levels directly influence synaptic inhibition. Thus, GAD67 deficiency in PV cells likely contributes to cortical dysfunction in disease states; the reversibility of synaptic deficits suggests nonpermanent damage to inhibitory circuitry.

  6. The treasury of the commons: making use of public gene expression resources to better characterize the molecular diversity of inhibitory interneurons in the cerebellar cortex.

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    Schilling, Karl; Oberdick, John

    2009-12-01

    We mined the Allen Mouse Brain Atlas for genes expressed in cerebellar cortical inhibitory interneurons that would allow identification and possibly distinction of these cells. We identified some 90 genes that are highly expressed in specific subsets of cerebellar cortical inhibitory interneurons or various combinations thereof. Four genes are exclusively expressed, within the cerebellar cortex, in molecular layer interneurons, and ten genes label exclusively inhibitory interneurons in the granule cell layer or subsets thereof. Differential expression of many of these genes in cells residing in the lower versus the upper molecular layer provides evidence that these cells, traditionally referred to as basket and stellate cells, are indeed molecularly distinct. Two genes could be identified as novel markers for unipolar brush cells. Intersection of these data with embryonic expression patterns as documented in the genepaint repository does not support a hierarchical model of cerebellar interneuron development, but may be more easily reconciled with the view that cerebellar inhibitory interneurons derive from a common precursor pool from which they are specified only late into their development. The novel markers identified here should prove useful for probing the timing and mechanisms supporting cerebellar cortical interneuron specification and diversification.

  7. Substance P receptor expression by inhibitory interneurons of the rat hippocampus: enhanced detection using improved immunocytochemical methods for the preservation and colocalization of GABA and other neuronal markers.

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    Sloviter, R S; Ali-Akbarian, L; Horvath, K D; Menkens, K A

    2001-02-12

    Two unresolved issues regarding the identification and characterization of hippocampal interneurons were addressed in this study. One issue was the longstanding inability to detect gamma-aminobutyric acid (GABA) in the somata of several hippocampal interneuron subpopulations, which has prevented the unequivocal identification of all hippocampal interneurons as GABA neurons. The second issue was related to the identification of the hippocampal interneurons that constitutively express substance P (neurokinin-1) receptors (SPRs). The recent development of neurotoxins that specifically target SPR-expressing cells suggests that it may be possible to destroy hippocampal inhibitory interneurons selectively for experimental purposes. Although SPRs are apparently expressed in the hippocampus only by interneurons, colocalization studies have found that most interneurons of several subtypes and hippocampal subregions appear SPR-negative. Thus, the identities and locations of the inhibitory interneurons that are potential targets of an SPR-directed neurotoxin remain in doubt. Using newly developed methods designed to copreserve and colocalize GABA and polypeptide immunoreactivities with increased sensitivity, the authors report that virtually all hippocampal interneuron somata that are immunoreactive for parvalbumin (PV), calbindin, calretinin, somatostatin (SS), neuropeptide Y, cholecystokinin, and vasoactive intestinal peptide exhibited clearly detectable, somal, GABA-like immunoreactivity (LI). Hippocampal SPR-LI was detected only on the somata and dendrites of GABA-immunopositive interneurons. All glutamate receptor subunit 2-immunoreactive principal cells, including dentate granule cells, hilar mossy cells, and hippocampal pyramidal cells, were devoid of detectable SPR-LI, even after prolonged electrical stimulation of the perforant pathway that induced the expression of other neuronal proteins in principal cells. Thus, hippocampal interneurons of all subtypes and

  8. Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Aβ accumulation.

    Science.gov (United States)

    Tong, Leslie M; Djukic, Biljana; Arnold, Christine; Gillespie, Anna K; Yoon, Seo Yeon; Wang, Max M; Zhang, Olivia; Knoferle, Johanna; Rubenstein, John L R; Alvarez-Buylla, Arturo; Huang, Yadong

    2014-07-16

    Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Aβ accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases.

  9. Use-dependent shift from inhibitory to excitatory GABAA receptor action in SP-O interneurons in the rat hippocampal CA3 area.

    Science.gov (United States)

    Lamsa, Karri; Taira, Tomi

    2003-09-01

    Cortical inhibitory interneurons set the pace of synchronous neuronal oscillations implicated in synaptic plasticity and various cognitive functions. The hyperpolarizing nature of inhibitory postsynaptic potentials (IPSPs) in interneurons has been considered crucial for the generation of oscillations at beta (15-30 Hz) and gamma (30-100 Hz) frequency. Hippocampal basket cells and axo-axonic cells in stratum pyramidale-oriens (S-PO) play a central role in the synchronization of the local interneuronal network as well as in pacing of glutamatergic principal cell firing. A lack of conventional forms of plasticity in excitatory synapses onto interneurons facilitates their function as stable neuronal oscillators. We have used gramicidin-perforated and whole cell clamp recordings to study properties of GABAAR-mediated transmission in CA3 SP-O interneurons and in CA3 pyramidal cells in rat hippocampal slices during electrical 5- to 100-Hz stimulation and during spontaneous activity. We show that GABAergic synapses onto SP-O interneurons can easily switch their mode from inhibitory to excitatory during heightened activity. This is based on a depolarizing shift in the GABAA reversal potential (EGABA-A), which is much faster and more pronounced in interneurons than in pyramidal cells. We also found that the shift in interneuronal function was frequency dependent, being most prominent at 20- to 40-Hz activation of the GABAergic synapses. After 40-Hz tetanic stimulation (100 pulses), GABAA responses remained depolarizing for approximately 45 s in the interneurons, promoting bursting in the GABAergic network. Hyperpolarizing EGABA-A was restored >60 s after the stimulus train. Similar but spontaneous GABAergic bursting was induced by application of 4-aminopyridine (100 microM) to slices. A shift to depolarizing IPSPs by the GABAAR permeant weak acid anion formate provoked interneuronal population bursting, supporting the role of GABAergic excitation in burst generation

  10. 5-HT3a Receptors Modulate Hippocampal Gamma Oscillations by Regulating Synchrony of Parvalbumin-Positive Interneurons.

    Science.gov (United States)

    Huang, Ying; Yoon, Kristopher; Ko, Ho; Jiao, Song; Ito, Wataru; Wu, Jian-Young; Yung, Wing-Ho; Lu, Bai; Morozov, Alexei

    2016-02-01

    Gamma-frequency oscillatory activity plays an important role in information integration across brain areas. Disruption in gamma oscillations is implicated in cognitive impairments in psychiatric disorders, and 5-HT3 receptors (5-HT3Rs) are suggested as therapeutic targets for cognitive dysfunction in psychiatric disorders. Using a 5-HT3aR-EGFP transgenic mouse line and inducing gamma oscillations by carbachol in hippocampal slices, we show that activation of 5-HT3aRs, which are exclusively expressed in cholecystokinin (CCK)-containing interneurons, selectively suppressed and desynchronized firings in these interneurons by enhancing spike-frequency accommodation in a small conductance potassium (SK)-channel-dependent manner. Parvalbumin-positive interneurons therefore received diminished inhibitory input leading to increased but desynchronized firings of PV cells. As a consequence, the firing of pyramidal neurons was desynchronized and gamma oscillations were impaired. These effects were independent of 5-HT3aR-mediated CCK release. Our results therefore revealed an important role of 5-HT3aRs in gamma oscillations and identified a novel crosstalk among different types of interneurons for regulation of network oscillations. The functional link between 5-HT3aR and gamma oscillations may have implications for understanding the cognitive impairments in psychiatric disorders.

  11. The effect of propofol postconditioning on the expression of K(+)-Cl(-)-co-transporter 2 in GABAergic inhibitory interneurons of acute ischemia/reperfusion injury rats.

    Science.gov (United States)

    Wang, Hongbai; Liu, Shuying; Wang, Haiyun; Wang, Guolin; Zhu, Ai

    2015-02-09

    It has been shown in our previous study that propofol postconditioning enhanced the activity of phosphatidylinositol-3-kinase (PI3K) and prevented the internalization of GluR2 subunit of α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, thus provided neuroprotection in cerebral ischemia/reperfusion (I/R) injury. Regarding inhibitory system in CNS, K(+)-Cl(-)-co-transporter 2 (KCC2), a Cl(-) extruder, plays a critical role in gamma-aminobutyric acid (GABA) inhibitory effect in mature central neurons. However, the effect of propofol postconditioning on the expression of KCC2 in GABAergic interneurons is unclear. Therefore, in this article we describe the role of KCC2 in GABAergic interneurons in the ipsilateral hippocampal CA1 region of adult rats and the effects of propofol postconditioning on this region. Herein we demonstrate that propofol postconditioning (20mg/kg/h, 2h) improved rats' neurobehavioral abilities, increased the number of survival neurons, and up-regulated neuronal KCC2 expression in glutamic acid decarboxylase 67 (GAD67) expressing GABAergic interneurons in hippocampal CA1 region at 24h after I/R. In contrast, when rats were injected with the KCC2 antagonist, [(dihydroindenyl)oxy] alkanoic acid (DIOA), the neuroprotective effects induced by propofol postconditioning were reversed. Our study indicated that propofol postconditioning increased the expression of KCC2 in inhibitory GABAergic interneurons, thus providing acute neuroprotection to rats who had undergone cerebral I/R injury.

  12. Two interconnected kernels of reciprocally inhibitory interneurons underlie alternating left-right swim motor pattern generation in the mollusk Melibe leonina.

    Science.gov (United States)

    Sakurai, Akira; Gunaratne, Charuni A; Katz, Paul S

    2014-09-15

    The central pattern generator (CPG) underlying the rhythmic swimming behavior of the nudibranch Melibe leonina (Mollusca, Gastropoda, Heterobranchia) has been described as a simple half-center oscillator consisting of two reciprocally inhibitory pairs of interneurons called swim interneuron 1 (Si1) and swim interneuron 2 (Si2). In this study, we identified two additional pairs of interneurons that are part of the swim CPG: swim interneuron 3 (Si3) and swim interneuron 4 (Si4). The somata of Si3 and Si4 were both located in the pedal ganglion, near that of Si2, and both had axons that projected through the pedal commissure to the contralateral pedal ganglion. These neurons fulfilled the criteria for inclusion as members of the swim CPG: 1) they fired at a fixed phase in relation to Si1 and Si2, 2) brief changes in their activity reset the motor pattern, 3) prolonged changes in their activity altered the periodicity of the motor pattern, 4) they had monosynaptic connections with each other and with Si1 and Si2, and 5) their synaptic actions helped explain the phasing of the motor pattern. The results of this study show that the motor pattern has more complex internal dynamics than a simple left/right alternation of firing; the CPG circuit appears to be composed of two kernels of reciprocally inhibitory neurons, one consisting of Si1, Si2, and the contralateral Si4 and the other consisting of Si3. These two kernels interact with each other to produce a stable rhythmic motor pattern.

  13. Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome

    OpenAIRE

    Cheah, Christine S.; Yu, Frank H.; Westenbroek, Ruth E.; Kalume, Franck K.; Oakley, John C; Potter, Gregory B.; Rubenstein, John L.; Catterall, William A.

    2012-01-01

    Heterozygous loss-of-function mutations in the brain sodium channel NaV1.1 cause Dravet syndrome (DS), a pharmacoresistant infantile-onset epilepsy syndrome with comorbidities of cognitive impairment and premature death. Previous studies using a mouse model of DS revealed reduced sodium currents and impaired excitability in GABAergic interneurons in the hippocampus, leading to the hypothesis that impaired excitability of GABAergic inhibitory neurons is the cause of epilepsy and premature deat...

  14. Inhibitory interneuron circuits at cortical and spinal levels are associated with individual differences in corticomuscular coherence during isometric voluntary contraction

    Science.gov (United States)

    Matsuya, Ryosuke; Ushiyama, Junichi; Ushiba, Junichi

    2017-01-01

    Corticomuscular coherence (CMC) is an oscillatory synchronization of 15–35 Hz (β-band) between electroencephalogram (EEG) of the sensorimotor cortex and electromyogram of contracting muscles. Although we reported that the magnitude of CMC varies among individuals, the physiological mechanisms underlying this variation are still unclear. Here, we aimed to investigate the associations between CMC and intracortical inhibition (ICI) in the primary motor cortex (M1)/recurrent inhibition (RI) in the spinal cord, which probably affect oscillatory neural activities. Firstly, we quantified ICI from changes in motor-evoked potentials induced by paired-pulse transcranial magnetic stimulation in M1 during tonic isometric voluntary contraction of the first dorsal interosseous. ICI showed a significant, negative correlation with the strength of EEG β-oscillation, but not with the magnitude of CMC across individuals. Next, we quantified RI from changes in H-reflexes induced by paired-pulse electrical nerve stimulation to the posterior tibial nerve during isometric contraction of the soleus muscle. We observed a significant, positive correlation between RI and peak CMC across individuals. These results suggest that the local inhibitory interneuron networks in cortical and spinal levels are associated with the oscillatory activity in corticospinal loop. PMID:28290507

  15. Estimating intracellular Ca2+ concentrations and buffering in a dendritic inhibitory hippocampal interneuron.

    Science.gov (United States)

    Liao, C W; Lien, C C

    2009-12-29

    Calcium is known to regulate several phenomena like neuronal excitability and plasticity. Interestingly, the spatiotemporal profile of dendritic calcium depends on several processes, specific to each neuronal type. In this study, we investigated Ca(2+) buffering and action potential (AP)-evoked Ca(2+) signaling in the dendrites of anatomically identified oriens lacunosum-moleculare (O-LM) cells, a major type of dendrite-targeting interneurons in the hippocampal CA1 region, using a combination of whole-cell patch-clamp recording and fast Ca(2+) imaging in acute rat brain slices. Cells were loaded with fluorescent Ca(2+) indicators fura-2 or Oregon Green BAPTA-1 (OGB-1) via patch-clamping electrode, and the effect of fura-2 on AP-evoked dendritic Ca(2+) transients was determined by ratiometric Ca(2+) imaging. To estimate intracellular Ca(2+) concentrations ([Ca(2+)](i)) and endogenous Ca(2+)-binding ratio (kappa(s)) in the proximal dendrite, fluorescence signals were converted into [Ca(2+)](i) using the ratioing method and were analyzed on the basis of the "single compartment model." Resting [Ca(2+)](i) was 22+/-5 nM and the build-up of [Ca(2+)](i) during a single AP was up to 656+/-226 nM. Analysis of Ca(2+) transients revealed that O-LM cells have a relatively low endogenous Ca(2+)-binding ratio (kappa(s)): the kappa(s) was 20+/-8 estimated during fura-2 loading and 27 estimated under steady-state fura-2 concentrations, respectively. To further examine the spatial profile of dendritic Ca(2+) transients, we measured somatic AP-evoked Ca(2+) transients beyond proximal dendrites using OGB-1. Dendritic Ca(2+) transients evoked by single APs or AP trains are not limited to regions close to the soma. The amplitude and decay of [Ca(2+)](i) associated with backpropagating APs are relatively independent of the distance from the soma. In sum, O-LM cells exhibit low endogenous Ca(2+)-binding ratios and relatively distance-independent Ca(2+) dynamics in the dendrites. These

  16. Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity.

    Science.gov (United States)

    Xu, Jin-Chong; Fan, Jing; Wang, Xueqing; Eacker, Stephen M; Kam, Tae-In; Chen, Li; Yin, Xiling; Zhu, Juehua; Chi, Zhikai; Jiang, Haisong; Chen, Rong; Dawson, Ted M; Dawson, Valina L

    2016-04-06

    Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1(+) neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuronal cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and poly(ADP-ribose) polymerase (PARP) (a cell death pathway called parthanatos that is distinct from apoptosis, necroptosis, and other forms of cell death). Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons.

  17. A combined electrophysiological and morphological study of neuropeptide Y-expressing inhibitory interneurons in the spinal dorsal horn of the mouse.

    Science.gov (United States)

    Iwagaki, Noboru; Ganley, Robert P; Dickie, Allen C; Polgár, Erika; Hughes, David I; Del Rio, Patricia; Revina, Yulia; Watanabe, Masahiko; Todd, Andrew J; Riddell, John S

    2016-03-01

    The spinal dorsal horn contains numerous inhibitory interneurons that control transmission of somatosensory information. Although these cells have important roles in modulating pain, we still have limited information about how they are incorporated into neuronal circuits, and this is partly due to difficulty in assigning them to functional populations. Around 15% of inhibitory interneurons in laminae I-III express neuropeptide Y (NPY), but little is known about this population. We therefore used a combined electrophysiological/morphological approach to investigate these cells in mice that express green fluorescent protein (GFP) under control of the NPY promoter. We show that GFP is largely restricted to NPY-immunoreactive cells, although it is only expressed by a third of those in lamina I-II. Reconstructions of recorded neurons revealed that they were morphologically heterogeneous, but never islet cells. Many NPY-GFP cells (including cells in lamina III) appeared to be innervated by C fibres that lack transient receptor potential vanilloid-1, and consistent with this, we found that some lamina III NPY-immunoreactive cells were activated by mechanical noxious stimuli. Projection neurons in lamina III are densely innervated by NPY-containing axons. Our results suggest that this input originates from a small subset of NPY-expressing interneurons, with the projection cells representing only a minority of their output. Taken together with results of previous studies, our findings indicate that somatodendritic morphology is of limited value in classifying functional populations among inhibitory interneurons in the dorsal horn. Because many NPY-expressing cells respond to noxious stimuli, these are likely to have a role in attenuating pain and limiting its spread.

  18. Afferent-specific properties of interneuron synapses underlie selective long-term regulation of feedback inhibitory circuits in CA1 hippocampus.

    Science.gov (United States)

    Croce, Ariane; Pelletier, Joe Guillaume; Tartas, Maylis; Lacaille, Jean-Claude

    2010-06-15

    Hebbian long-term potentiation (LTP) develops at specific synapses onto hippocampal CA1 oriens/alveus interneurons (OA-INs), suggesting selective regulation of distinct input pathways. Afferent-specific properties at interneuron synapses have been characterized extensively in CA3 stratum lucidum cells, but given interneuron diversity these rules of transmission and plasticity may not hold in other interneuron types. Here, we used paired recordings and demonstrate that CA2/3 pyramidal cell (PC) feedforward and CA1 PC feedback synapses onto OA-INs show distinct AMPA receptor rectification and Ca(2+) permeability, short-term plasticity and mGluR2/3-mediated inhibition. Only feedback synapses undergo Hebbian LTP. OA-IN firing during repeated synaptic stimulation displays onset-transient or late-persistent responses consistent with activation of feedforward and feedback inputs, respectively. Input-output functions are preserved after theta-burst stimulation, but late-persistent responses selectively show mGluR1-dependent long-term increases. Thus, cell type- and afferent-specific rules of transmission and plasticity underlie distinct OA-IN input-output functions, providing selective long-term regulation in feedback inhibitory networks.

  19. Direct excitation of parvalbumin-positive interneurons by M1 muscarinic acetylcholine receptors: roles in cellular excitability, inhibitory transmission and cognition.

    Science.gov (United States)

    Yi, Feng; Ball, Jackson; Stoll, Kurt E; Satpute, Vaishali C; Mitchell, Samantha M; Pauli, Jordan L; Holloway, Benjamin B; Johnston, April D; Nathanson, Neil M; Deisseroth, Karl; Gerber, David J; Tonegawa, Susumu; Lawrence, J Josh

    2014-08-15

    Parvalbumin-containing (PV) neurons, a major class of GABAergic interneurons, are essential circuit elements of learning networks. As levels of acetylcholine rise during active learning tasks, PV neurons become increasingly engaged in network dynamics. Conversely, impairment of either cholinergic or PV interneuron function induces learning deficits. Here, we examined PV interneurons in hippocampus (HC) and prefrontal cortex (PFC) and their modulation by muscarinic acetylcholine receptors (mAChRs). HC PV cells, visualized by crossing PV-CRE mice with Rosa26YFP mice, were anatomically identified as basket cells and PV bistratified cells in the stratum pyramidale; in stratum oriens, HC PV cells were electrophysiologically distinct from somatostatin-containing cells. With glutamatergic transmission pharmacologically blocked, mAChR activation enhanced PV cell excitability in both CA1 HC and PFC; however, CA1 HC PV cells exhibited a stronger postsynaptic depolarization than PFC PV cells. To delete M1 mAChRs genetically from PV interneurons, we created PV-M1 knockout mice by crossing PV-CRE and floxed M1 mice. The elimination of M1 mAChRs from PV cells diminished M1 mAChR immunoreactivity and muscarinic excitation of HC PV cells. Selective cholinergic activation of HC PV interneurons using Designer Receptors Exclusively Activated by Designer Drugs technology enhanced the frequency and amplitude of inhibitory synaptic currents in CA1 pyramidal cells. Finally, relative to wild-type controls, PV-M1 knockout mice exhibited impaired novel object recognition and, to a lesser extent, impaired spatial working memory, but reference memory remained intact. Therefore, the direct activation of M1 mAChRs on PV cells contributes to some forms of learning and memory.

  20. Action Potential Modulation in CA1 Pyramidal Neuron Axons Facilitates OLM Interneuron Activation in Recurrent Inhibitory Microcircuits of Rat Hippocampus

    OpenAIRE

    Sooyun Kim

    2014-01-01

    Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive ...

  1. Identification of Inhibitory Premotor Interneurons Activated at a Late Phase in a Motor Cycle during Drosophila Larval Locomotion.

    Science.gov (United States)

    Itakura, Yuki; Kohsaka, Hiroshi; Ohyama, Tomoko; Zlatic, Marta; Pulver, Stefan R; Nose, Akinao

    2015-01-01

    Rhythmic motor patterns underlying many types of locomotion are thought to be produced by central pattern generators (CPGs). Our knowledge of how CPG networks generate motor patterns in complex nervous systems remains incomplete, despite decades of work in a variety of model organisms. Substrate borne locomotion in Drosophila larvae is driven by waves of muscular contraction that propagate through multiple body segments. We use the motor circuitry underlying crawling in larval Drosophila as a model to try to understand how segmentally coordinated rhythmic motor patterns are generated. Whereas muscles, motoneurons and sensory neurons have been well investigated in this system, far less is known about the identities and function of interneurons. Our recent study identified a class of glutamatergic premotor interneurons, PMSIs (period-positive median segmental interneurons), that regulate the speed of locomotion. Here, we report on the identification of a distinct class of glutamatergic premotor interneurons called Glutamatergic Ventro-Lateral Interneurons (GVLIs). We used calcium imaging to search for interneurons that show rhythmic activity and identified GVLIs as interneurons showing wave-like activity during peristalsis. Paired GVLIs were present in each abdominal segment A1-A7 and locally extended an axon towards a dorsal neuropile region, where they formed GRASP-positive putative synaptic contacts with motoneurons. The interneurons expressed vesicular glutamate transporter (vGluT) and thus likely secrete glutamate, a neurotransmitter known to inhibit motoneurons. These anatomical results suggest that GVLIs are premotor interneurons that locally inhibit motoneurons in the same segment. Consistent with this, optogenetic activation of GVLIs with the red-shifted channelrhodopsin, CsChrimson ceased ongoing peristalsis in crawling larvae. Simultaneous calcium imaging of the activity of GVLIs and motoneurons showed that GVLIs' wave-like activity lagged behind that of

  2. Identification of Inhibitory Premotor Interneurons Activated at a Late Phase in a Motor Cycle during Drosophila Larval Locomotion.

    Directory of Open Access Journals (Sweden)

    Yuki Itakura

    Full Text Available Rhythmic motor patterns underlying many types of locomotion are thought to be produced by central pattern generators (CPGs. Our knowledge of how CPG networks generate motor patterns in complex nervous systems remains incomplete, despite decades of work in a variety of model organisms. Substrate borne locomotion in Drosophila larvae is driven by waves of muscular contraction that propagate through multiple body segments. We use the motor circuitry underlying crawling in larval Drosophila as a model to try to understand how segmentally coordinated rhythmic motor patterns are generated. Whereas muscles, motoneurons and sensory neurons have been well investigated in this system, far less is known about the identities and function of interneurons. Our recent study identified a class of glutamatergic premotor interneurons, PMSIs (period-positive median segmental interneurons, that regulate the speed of locomotion. Here, we report on the identification of a distinct class of glutamatergic premotor interneurons called Glutamatergic Ventro-Lateral Interneurons (GVLIs. We used calcium imaging to search for interneurons that show rhythmic activity and identified GVLIs as interneurons showing wave-like activity during peristalsis. Paired GVLIs were present in each abdominal segment A1-A7 and locally extended an axon towards a dorsal neuropile region, where they formed GRASP-positive putative synaptic contacts with motoneurons. The interneurons expressed vesicular glutamate transporter (vGluT and thus likely secrete glutamate, a neurotransmitter known to inhibit motoneurons. These anatomical results suggest that GVLIs are premotor interneurons that locally inhibit motoneurons in the same segment. Consistent with this, optogenetic activation of GVLIs with the red-shifted channelrhodopsin, CsChrimson ceased ongoing peristalsis in crawling larvae. Simultaneous calcium imaging of the activity of GVLIs and motoneurons showed that GVLIs' wave-like activity lagged

  3. Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus.

    Science.gov (United States)

    Gulyás, A I; Megías, M; Emri, Z; Freund, T F

    1999-11-15

    The least known aspect of the functional architecture of hippocampal microcircuits is the quantitative distribution of synaptic inputs of identified cell classes. The complete dendritic trees of functionally distinct interneuron types containing parvalbumin (PV), calbindin D(28k) (CB), or calretinin (CR) were reconstructed at the light microscopic level to describe their geometry, total length, and laminar distribution. Serial electron microscopic reconstruction and postembedding GABA immunostaining was then used to determine the density of GABA-negative asymmetrical (excitatory) and GABA-positive symmetrical (inhibitory) synaptic inputs on their dendrites, somata, and axon initial segments. The total convergence and the distribution of excitatory and inhibitory inputs were then calculated using the light and electron microscopic data sets. The three populations showed characteristic differences in dendritic morphology and in the density and distribution of afferent synapses. PV cells possessed the most extensive dendritic tree (4300 microm) and the thickest dendrites. CR cells had the smallest dendritic tree (2500 microm) and the thinnest shafts. The density of inputs as well as the total number of excitatory plus inhibitory synapses was several times higher on PV cells (on average, 16,294) than on CB (3839) or CR (2186) cells. The ratio of GABAergic inputs was significantly higher on CB (29.4%) and CR (20.71%) cells than on PV cells (6.4%). The density of inhibitory terminals was higher in the perisomatic region than on the distal dendrites. These anatomical data are essential to understand the distinct behavior and role of these interneuron types during hippocampal activity patterns and represent fundamental information for modeling studies.

  4. Direct excitation of inhibitory interneurons by extracellular ATP mediated by P2Y1 receptors in the hippocampal slice.

    Science.gov (United States)

    Kawamura, Masahito; Gachet, Christian; Inoue, Kazuhide; Kato, Fusao

    2004-12-01

    ATP is an important cell-to-cell signaling molecule mediating the interactions between astrocytes and neurons in the CNS. In the hippocampal slices, ATP suppresses excitatory transmission mostly through activation of adenosine A1 receptors, because the ectoenzyme activity for the extracellular breakdown of ATP to adenosine is high in slice preparations in contrast to culture environments. Because the hippocampus is also rich in the expression of P2 receptors activated specifically by ATP, we examined whether ATP modulates neuronal excitability in the acute slice preparations independently of adenosine receptors. Although ATP decreased the frequency of spontaneously occurring EPSCs in the CA3 pyramidal neurons through activation of adenosine A1 receptors, ATP concurrently increased the frequency of IPSCs in a manner dependent on action potential generation. This effect was mediated by P2Y1 receptors because (1) 2-methylthio-ATP (2meSATP) was the most potent agonist, (2) 2'-deoxy-N6-methyladenosine-3',5'-bisphosphate diammonium (MRS2179) abolished this effect, and (3) this increase in IPSC frequency was not observed in the transgenic mice lacking P2Y1 receptor proteins. Application of 2meSATP elicited MRS2179-sensitive time- and voltage-dependent inward currents in the interneurons, which depolarized the cell to firing threshold. Also, it increased [Ca2+]i in both astrocytes and interneurons, but, unlike the former effect, the latter was entirely dependent on Ca2+ entry. Thus, in hippocampal slices, in addition to activating A1 receptors of the excitatory terminals after being converted to adenosine, ATP activates P2Y1 receptors in the interneurons, which is linked to activation of unidentified excitatory conductance, through mechanisms distinct from those in the astrocytes.

  5. The effects of anodal transcranial direct current stimulation and patterned electrical stimulation on spinal inhibitory interneurons and motor function in patients with spinal cord injury.

    Science.gov (United States)

    Yamaguchi, Tomofumi; Fujiwara, Toshiyuki; Tsai, Yun-An; Tang, Shuen-Chang; Kawakami, Michiyuki; Mizuno, Katsuhiro; Kodama, Mitsuhiko; Masakado, Yoshihisa; Liu, Meigen

    2016-06-01

    Supraspinal excitability and sensory input may play an important role for the modulation of spinal inhibitory interneurons and functional recovery among patients with incomplete spinal cord injury (SCI). Here, we investigated the effects of anodal transcranial direct current stimulation (tDCS) combined with patterned electrical stimulation (PES) on spinal inhibitory interneurons in patients with chronic incomplete SCI and in healthy individuals. Eleven patients with incomplete SCI and ten healthy adults participated in a single-masked, sham-controlled crossover study. PES involved stimulating the common peroneal nerve with a train of ten 100 Hz pulses every 2 s for 20 min. Anodal tDCS (1 mA) was simultaneously applied to the primary motor cortex that controls the tibialis anterior muscle. We measured reciprocal inhibition and presynaptic inhibition of a soleus H-reflex by stimulating the common peroneal nerve prior to tibial nerve stimulation, which elicits the H-reflex. The inhibition was assessed before, immediately after, 10 min after and 20 min after the stimulation. Compared with baseline, simultaneous application of anodal tDCS with PES significantly increased changes in disynaptic reciprocal inhibition and long-latency presynaptic inhibition in both healthy and SCI groups for at least 20 min after the stimulation (all, p stimulation (p = 0.004). In conclusion, anodal tDCS combined with PES could induce spinal plasticity and improve ankle movement in patients with incomplete SCI.

  6. Unusual target selectivity of perisomatic inhibitory cells in the hilar region of the rat hippocampus.

    Science.gov (United States)

    Acsády, L; Katona, I; Martínez-Guijarro, F J; Buzsáki, G; Freund, T F

    2000-09-15

    Perisomatic inhibitory innervation of all neuron types profoundly affects their firing characteristics and vulnerability. In this study we examined the postsynaptic targets of perisomatic inhibitory cells in the hilar region of the dentate gyrus where the proportion of potential target cells (excitatory mossy cells and inhibitory interneurons) is approximately equal. Both cholecystokinin (CCK)- and parvalbumin-immunoreactive basket cells formed multiple contacts on the somata and proximal dendrites of mossy cells. Unexpectedly, however, perisomatic inhibitory terminals arriving from these cell types largely ignored hilar GABAergic cell populations. Eighty-ninety percent of various GABAergic neurons including other CCK-containing basket cells received no input from CCK-positive terminals. Parvalbumin-containing cells sometimes innervated each other but avoided 75% of other GABAergic cells. Overall, a single mossy cell received 40 times more CCK-immunoreactive terminals and 15 times more parvalbumin-positive terminals onto its soma than the cell body of an average hilar GABAergic cell. In contrast to the pronounced target selectivity in the hilar region, CCK- and parvalbumin-positive neurons innervated each other via collaterals in stratum granulosum and moleculare. Our observations indicate that the inhibitory control in the hilar region is qualitatively different from other cortical areas at both the network level and the level of single neurons. The paucity of perisomatic innervation of hilar interneurons should have profound consequences on their action potential generation and on their ensemble behavior. These findings may help explain the unique physiological patterns observed in the hilus and the selective vulnerability of the hilar cell population in various pathophysiological conditions.

  7. Focal inhibitory interneuron loss and principal cell hyperexcitability in the rat hippocampus after microinjection of a neurotoxic conjugate of saporin and a peptidase-resistant analog of Substance P.

    Science.gov (United States)

    Martin, J L; Sloviter, R S

    2001-07-23

    Episodes of prolonged seizures or head trauma produce chronic hippocampal network hyperexcitability hypothesized to result primarily from inhibitory interneuron loss or dysfunction. The possibly causal role of inhibitory neuron failure in the development of epileptiform pathophysiology remains unclear because global neurologic injuries produce such a multitude of effects. The recent finding that Substance P receptors (SPRs) are expressed exclusively in the rat hippocampus by inhibitory interneurons provided the rationale for attempting to ablate interneurons selectively by using neurotoxic conjugates of SPR ligands and the ribosome inactivating protein saporin that specifically target Substance P receptor-expressing cells. Whereas intrahippocampal microinjection of a conjugate of native SP and saporin produced significant nonspecific damage at concentrations needed to produce even limited selective loss of SPR-positive cells, a conjugate of saporin and the more potent and peptidase-resistant SP analog [Sar(9), Met(O(2))(11)] Substance P (SSP-saporin) caused negligible nonspecific damage at the injection site, and a virtually complete loss of SPR-like immunoreactivity (LI) up to 1 mm from the injection site. Within the SPR depletion zone, immunoreactivities for most GABA-, parvalbumin-, somatostatin-, and cholecystokinin-immunoreactive cells and fibers were eliminated. The few interneurons detectable within the affected zone were devoid of SPR-LI. The apparent loss of interneurons was selective in that calbindin- and glutamate receptor subunit 2 (GluR2) -positive principal cells survived within the affected zone, as did myelinated fibers and the extrinsic calretinin- and tyrosine hydroxylase--immunoreactive terminals of subcortical afferents. An apparent lack of reactive synaptic reorganization in response to interneuron loss was indicated by zinc transporter-3 (ZnT3)-- and beta-synuclein--LI, as well as by Timm staining, all of which revealed relatively normal

  8. Postsynaptic potentials mediated by excitatory and inhibitory amino acids in interneurons of stratum pyramidale of the CA1 region of rat hippocampal slices in vitro.

    Science.gov (United States)

    Lacaille, J C

    1991-11-01

    1. Because interneurons of stratum pyramidale partly mediate the feed-forward inhibition of pyramidal cells, intracellular postsynaptic potentials (PSPs) evoked by activation of afferent fibers were examined in 32 nonpyramidal cells of stratum pyramidale of the CA1 region of rat hippocampal slices. 2. Electrical stimulation of stratum radiatum at the CA1-CA3 border elicited, in interneurons, PSPs that were composed of four components: a fast excitatory postsynaptic potential (EPSP), an early inhibitory postsynaptic potential (IPSPA), a late IPSPB, and in some cells a delayed, slower EPSP. These synaptic potentials summated and elicited single action potentials in 57% of cells (17/30) and burst of action potentials (2-10) in the remaining 43%. 3. The fast EPSP was observed in all cells, and the mean stimulation intensity at its threshold was 53.4 microA. Its amplitude increased with membrane hyperpolarization, and it was associated with a 45.4% decrease in cellular input resistance. The fast EPSP always elicited an action potential at short latencies (3.6-6.4 ms poststimulation). It was reversibly reduced by 6-cyano-7-nitroquinoxaline-2,3- dione (CNQX), a blocker of non-N-methyl-D-aspartate (non-NMDA) excitatory amino acid receptors. 4. The IPSPA was observed in 28/32 cells, and the mean intensity of stimulation was 57.6 microA at its threshold. The mean latency of its peak amplitude was 17.4 ms. The mean equilibrium potential (Erev) was -72.8 mV, and it was associated with a 38.9% decrease in cellular input resistance. IPSPA was blocked by the GABAA antagonist bicuculline. 5. The IPSPB was seen in 29/32 cells, and the mean intensity of stimulation at its threshold was 80.3 microA. Its latency to peak was 130.6 ms, its Erev was -107.6 mV, and it was associated with a small (7.6%) decrease in cellular input resistance. IPSPB was blocked by the GABAB antagonist phaclofen. 6. In 11/32 cells a slower EPSP was also observed. Its mean latency to peak was 53.3 ms, and the

  9. Commissurally projecting inhibitory interneurons of the rat hippocampal dentate gyrus: a colocalization study of neuronal markers and the retrograde tracer Fluoro-gold.

    Science.gov (United States)

    Zappone, C A; Sloviter, R S

    2001-12-24

    Improved methods for detecting neuronal markers and the retrograde tracer Fluoro-Gold (FG) were used to identify commissurally projecting neurons of the rat hippocampus. In addition to the dentate hilar mossy cells and CA3 pyramidal cells shown previously to transport retrograde tracers after injection into the dorsal hippocampus, FG-positive interneurons of the dentate granule cell layer and hilus were detected in numbers greater than previously reported. FG labeling of interneurons was variable among animals, but was as high as 96% of hilar somatostatin-positive interneurons, 84% of parvalbumin-positive cells of the granule cell layer and hilus combined, and 33% of hilar calretinin-positive cells. By comparison, interneurons of the dentate molecular layer and all hippocampal subregions were conspicuously FG-negative. Whereas hilar mossy cells and CA3 pyramidal cells were FG-labeled throughout the longitudinal axis, FG-positive interneurons exhibited a relatively homotopic distribution. "Control" injections of FG into the neocortex, septum, and ventral hippocampus demonstrated that the homotopic labeling of dentate interneurons was injection site-specific, and that the CA1-CA3 interneurons unlabeled by contralateral hippocampal FG injection were nonetheless able to transport FG from the septum. These data suggest a hippocampal organizing principle according to which virtually all commissurally projecting hippocampal neurons share the property of being monosynaptic targets of dentate granule cells. Because granule cells innervate their exclusively ipsilateral target cells in a highly lamellar pattern, these results suggest that focal granule cell excitation may result in commissural inhibition of the corresponding "twin" granule cell lamella, thereby lateralizing and amplifying the influence of the initiating discharge.

  10. Neurocalcin-immunoreactive cells in the rat hippocampus are GABAergic interneurons.

    Science.gov (United States)

    Martínez-Guijarro, F J; Briñón, J G; Blasco-Ibáñez, J M; Okazaki, K; Hidaka, H; Alonso, J R

    1998-01-01

    dentate gyrus; however, 9% of the NC-IR cells in the CA fields also contained CCK. No coexistence of NC with PV, SOM or NPY was found in any hippocampal region. We conclude that NC is exclusively expressed by interneurons in the rat hippocampus. NC-IR cells are a morphologically and neurochemically heterogeneous subset of GABAergic non-principal cells, which, on the basis of the known termination pattern of the colocalizing markers, are also functionally heterogeneous and are mainly involved in feed-forward dendritic inhibition in the commissural-associational and Schaffer collateral termination zones (CB containing cells), in innervation of other interneurons (CR- and VIP-containing cells), and in perisomatic inhibition (CCK-containing cells). NC is never present in perisomatic inhibitory PV-containing cells, or in feed-back distal dendritic inhibitory SOM/NPY-containing cells.

  11. Migratory pathways of GABAergic interneurons when they enter the neocortex.

    Science.gov (United States)

    Tanaka, Daisuke H; Nakajima, Kazunori

    2012-06-01

    Inhibitory gamma-aminobutyric-acid-containing interneurons play important roles in the functions of the neocortex. During rodent development, most neocortical interneurons are generated in the subpallium and migrate tangentially toward the neocortex. They migrate through multiple pathways to enter the neocortex. Failure of interneuron migration through these pathways during development leads to an abnormal distribution and abnormal functions of interneurons in the postnatal brain. Because of recent discoveries regarding the novel origins and migratory pathways of neocortical interneurons, in this article we review the literature on the migratory pathways of interneurons when they enter the neocortex.

  12. Single dendrite-targeting interneurons generate branch-specific inhibition.

    Directory of Open Access Journals (Sweden)

    Caleb eStokes

    2014-11-01

    Full Text Available Microcircuits composed of dendrite-targeting inhibitory interneurons and pyramidal cells are fundamental elements of cortical networks, however, the impact of individual interneurons on pyramidal dendrites is unclear. Here, we combine paired recordings and calcium imaging to determine the spatial domain over which single dendrite-targeting interneurons influence pyramidal cells in olfactory cortex. We show that a major action of individual interneurons is to inhibit dendrites in a branch-specific fashion.

  13. RGMa regulates cortical interneuron migration and differentiation.

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    Conor O'Leary

    Full Text Available The etiology of neuropsychiatric disorders, including schizophrenia and autism, has been linked to a failure to establish the intricate neural network comprising excitatory pyramidal and inhibitory interneurons during neocortex development. A large proportion of cortical inhibitory interneurons originate in the medial ganglionic eminence (MGE of the ventral telencephalon and then migrate through the ventral subventricular zone, across the corticostriatal junction, into the embryonic cortex. Successful navigation of newborn interneurons through the complex environment of the ventral telencephalon is governed by spatiotemporally restricted deployment of both chemorepulsive and chemoattractive guidance cues which work in concert to create a migratory corridor. Despite the expanding list of interneuron guidance cues, cues responsible for preventing interneurons from re-entering the ventricular zone of the ganglionic eminences have not been well characterized. Here we provide evidence that the chemorepulsive axon guidance cue, RGMa (Repulsive Guidance Molecule a, may fulfill this function. The ventricular zone restricted expression of RGMa in the ganglionic eminences and the presence of its receptor, Neogenin, in the ventricular zone and on newborn and maturing MGE-derived interneurons implicates RGMa-Neogenin interactions in interneuron differentiation and migration. Using an in vitro approach, we show that RGMa promotes interneuron differentiation by potentiating neurite outgrowth. In addition, using in vitro explant and migration assays, we provide evidence that RGMa is a repulsive guidance cue for newborn interneurons migrating out of the ganglionic eminence ventricular zone. Intriguingly, the alternative Neogenin ligand, Netrin-1, had no effect on migration. However, we observed complete abrogation of RGMa-induced chemorepulsion when newborn interneurons were simultaneously exposed to RGMa and Netrin-1 gradients, suggesting a novel mechanism for

  14. Inhibition by somatostatin interneurons in olfactory cortex

    Directory of Open Access Journals (Sweden)

    Adam M Large

    2016-08-01

    Full Text Available Inhibitory circuitry plays an integral cortical network activity. The development of transgenic mouse lines targeting unique interneuron classes has significantly advanced our understanding of the functional roles of specific inhibitory circuits in neocortical sensory processing. In contrast, considerably less is known about the circuitry and function of interneuron classes in piriform cortex, a paleocortex responsible for olfactory processing. In this study, we sought to utilize transgenic technology to investigate inhibition mediated by somatostatin (SST interneurons onto pyramidal cells, parvalbumin (PV interneurons and other interneuron classes. As a first step, we characterized the anatomical distributions and intrinsic properties of SST and PV interneurons in four transgenic lines (SST-cre, GIN, PV-cre and G42 that are commonly interbred to investigate inhibitory connectivity. Surprisingly, the distributions SST and PV cell subtypes targeted in the GIN and G42 lines were sparse in piriform cortex compared to neocortex. Moreover, two-thirds of interneurons recorded in the SST-cre line had electrophysiological properties similar to fast spiking (FS interneurons rather than regular (RS or low threshold spiking (LTS phenotypes. Nonetheless, like neocortex, we find that SST-cells broadly inhibit a number of unidentified interneuron classes including putatively identified PV cells and surprisingly, other SST cells. We also confirm that SST-cells inhibit pyramidal cell dendrites and thus, influence dendritic integration of afferent and recurrent inputs to the piriform cortex. Altogether, our findings suggest that somatostatin interneurons play an important role in regulating both excitation and the global inhibitory network during olfactory processing.

  15. Neonatal administration of phencyclidine decreases the number of putative inhibitory interneurons and increases neural excitability to auditory paired clicks in the hippocampal CA3 region of freely moving adult mice.

    Science.gov (United States)

    Okamoto, M; Katayama, T; Suzuki, Y; Hoshino, K-Y; Yamada, H; Matsuoka, N; Jodo, E

    2012-11-08

    Animals exposed to phencyclidine (PCP) during the neonatal period have fewer GABAergic interneurons in the corticolimbic area, including the hippocampus, and exhibit abnormal behaviors after attaining maturation that correspond with schizophrenic symptoms. Since a lack of inhibitory interneurons in the hippocampus has also been reported in postmortem studies of patients with schizophrenia, the deficit may induce abnormal activity of hippocampal neurons that underlies pathological states in schizophrenia. However, it remains unclear how PCP treatment during the neonatal period affects the discharge activity of hippocampal neurons in adulthood. In the current study, single unit responses of hippocampal CA3 neurons to paired auditory clicks were recorded in freely moving mice repeatedly injected with PCP or saline during the neonatal period. The recorded neurons were classified into two subpopulations, narrow-spike neurons and broad-spike neurons, based on the spike width. The spontaneous discharge rate was higher in the narrow-spike neurons than in the broad-spike neurons, indicating that the narrow-spike neurons correspond with hippocampal inhibitory neurons. The proportion of narrow-spike neurons was significantly smaller in neonatally PCP-treated mice than in saline-treated mice. The broad-spike neurons that exhibited a response magnitude to the second click as large as that to the first click (E/E-type response) showed longer response duration to the paired clicks in PCP-treated mice than in the saline-treated mice. Further, the number of neurons with E/E-type response was higher in the PCP-treated mice than in the saline-treated mice. Finally, the attenuation of an auditory-evoked potential component, N40, to the second click (sensory gating) was blunted in the PCP-treated mice when compared with that in the saline-treated mice. These results suggest that the neonatal administration of PCP induced a deficit of inhibitory interneurons and altered discharge

  16. Firing regulation of fast-spiking interneurons by autaptic inhibition

    Science.gov (United States)

    Guo, Daqing; Chen, Mingming; Perc, Matjaž; Wu, Shengdun; Xia, Chuan; Zhang, Yangsong; Xu, Peng; Xia, Yang; Yao, Dezhong

    2016-05-01

    Fast-spiking (FS) interneurons in the brain are self-innervated by powerful inhibitory GABAergic autaptic connections. By computational modelling, we investigate how autaptic inhibition regulates the firing response of such interneurons. Our results indicate that autaptic inhibition both boosts the current threshold for action potential generation and modulates the input-output gain of FS interneurons. The autaptic transmission delay is identified as a key parameter that controls the firing patterns and determines multistability regions of FS interneurons. Furthermore, we observe that neuronal noise influences the firing regulation of FS interneurons by autaptic inhibition and extends their dynamic range for encoding inputs. Importantly, autaptic inhibition modulates noise-induced irregular firing of FS interneurons, such that coherent firing appears at an optimal autaptic inhibition level. Our results reveal the functional roles of autaptic inhibition in taming the firing dynamics of FS interneurons.

  17. A hippocampal interneuron associated with the mossy fiber system

    OpenAIRE

    Vida, Imre; Frotscher, Michael

    2000-01-01

    Network properties of the hippocampus emerge from the interaction of principal cells and a heterogeneous population of interneurons expressing γ-aminobutyric acid (GABA). To understand these interactions, the synaptic connections of different types of interneurons need to be elucidated. Here we describe a type of inhibitory interneuron of the hippocampal CA3 region that has an axon coaligned with the mossy fibers. Whole-cell patch-clamp recordings, in combination with intracellular biocytin f...

  18. Presynaptic kainate receptors that enhance the release of GABA on CA1 hippocampal interneurons.

    Science.gov (United States)

    Cossart, R; Tyzio, R; Dinocourt, C; Esclapez, M; Hirsch, J C; Ben-Ari, Y; Bernard, C

    2001-02-01

    We report that kainate receptors are present on presynaptic GABAergic terminals contacting interneurons and that their activation increases GABA release. Application of kainate increased the frequency of miniature inhibitory postsynaptic currents recorded in CA1 interneurons. Local applications of glutamate but not of AMPA or NMDA also increased GABA quantal release. Application of kainate as well as synaptically released glutamate reduced the number of failures of GABAergic neurotransmission between interneurons. Thus, activation of presynaptic kainate receptors increases the probability of GABA release at interneuron-interneuron synapses. Glutamate may selectively control the communication between interneurons by increasing their mutual inhibition.

  19. Immunohistochemical visualization of mouse interneuron subtypes

    DEFF Research Database (Denmark)

    Jensen, Simon Mølgaard; Ulrichsen, Maj; Boggild, Simon;

    2014-01-01

    The activity of excitatory neurons is controlled by a small, but highly diverse population of inhibitory interneurons. These cells show a high level of physiological, morphological and neurochemical heterogeneity, and play highly specific roles in neuronal circuits. In the mammalian hippocampus...

  20. Hilar somatostatin interneuron loss reduces dentate gyrus inhibition in a mouse model of temporal lobe epilepsy.

    Science.gov (United States)

    Hofmann, Gabrielle; Balgooyen, Laura; Mattis, Joanna; Deisseroth, Karl; Buckmaster, Paul S

    2016-06-01

    In patients with temporal lobe epilepsy, seizures usually start in the hippocampus, and dentate granule cells are hyperexcitable. Somatostatin interneurons are a major subpopulation of inhibitory neurons in the dentate gyrus, and many are lost in patients and animal models. However, surviving somatostatin interneurons sprout axon collaterals and form new synapses, so the net effect on granule cell inhibition remains unclear. The present study uses optogenetics to activate hilar somatostatin interneurons and measure the inhibitory effect on dentate gyrus perforant path-evoked local field potential responses in a mouse model of temporal lobe epilepsy. In controls, light activation of hilar somatostatin interneurons inhibited evoked responses up to 40%. Epileptic pilocarpine-treated mice exhibited loss of hilar somatostatin interneurons and less light-induced inhibition of evoked responses. These findings suggest that severe epilepsy-related loss of hilar somatostatin interneurons can overwhelm the surviving interneurons' capacity to compensate by sprouting axon collaterals. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  1. Inhibitory Interneurons That Express GFP in the PrP-GFP Mouse Spinal Cord Are Morphologically Heterogeneous, Innervated by Several Classes of Primary Afferent and Include Lamina I Projection Neurons among Their Postsynaptic Targets.

    Science.gov (United States)

    Ganley, Robert P; Iwagaki, Noboru; del Rio, Patricia; Baseer, Najma; Dickie, Allen C; Boyle, Kieran A; Polgár, Erika; Watanabe, Masahiko; Abraira, Victoria E; Zimmerman, Amanda; Riddell, John S; Todd, Andrew J

    2015-05-13

    The superficial dorsal horn of the spinal cord contains numerous inhibitory interneurons, which regulate the transmission of information perceived as touch, pain, or itch. Despite the importance of these cells, our understanding of their roles in the neuronal circuitry is limited by the difficulty in identifying functional populations. One group that has been identified and characterized consists of cells in the mouse that express green fluorescent protein (GFP) under control of the prion protein (PrP) promoter. Previous reports suggested that PrP-GFP cells belonged to a single morphological class (central cells), received inputs exclusively from unmyelinated primary afferents, and had axons that remained in lamina II. However, we recently reported that the PrP-GFP cells expressed neuronal nitric oxide synthase (nNOS) and/or galanin, and it has been shown that nNOS-expressing cells are more diverse in their morphology and synaptic connections. We therefore used a combined electrophysiological, pharmacological, and anatomical approach to reexamine the PrP-GFP cells. We provide evidence that they are morphologically diverse (corresponding to "unclassified" cells) and receive synaptic input from a variety of primary afferents, with convergence onto individual cells. We also show that their axons project into adjacent laminae and that they target putative projection neurons in lamina I. This indicates that the neuronal circuitry involving PrP-GFP cells is more complex than previously recognized, and suggests that they are likely to have several distinct roles in regulating the flow of somatosensory information through the dorsal horn.

  2. GABAergic interneuron migration and the evolution of the neocortex.

    Science.gov (United States)

    Tanaka, Daisuke H; Nakajima, Kazunori

    2012-04-01

    A neocortex is present in all mammals but is not present in other classes of vertebrates, and the neocortex is extremely elaborate in humans. Changes in excitatory projection neurons and their progenitors within the developing dorsal pallium in the most recent common ancestor of mammals are thought to have been involved in the evolution of the neocortex. Our recent findings suggest that changes in the migratory ability of inhibitory interneurons derived from outside the neocortex may also have been involved in the evolution of the neocortex. In this article we review the literature on the migratory profile of inhibitory interneurons in several different species and the literature on comparisons between the intrinsic migratory ability of interneurons derived from different species. Finally, we propose a hypothesis about the mammalian-specific evolution of the migratory ability of interneurons and its potential contribution to the establishment of a functional neocortex.

  3. Striatal cholinergic interneurons Drive GABA release from dopamine terminals.

    Science.gov (United States)

    Nelson, Alexandra B; Hammack, Nora; Yang, Cindy F; Shah, Nirao M; Seal, Rebecca P; Kreitzer, Anatol C

    2014-04-01

    Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically driven IPSCs were not affected by ablation of striatal fast-spiking interneurons but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons.

  4. Mu opioid receptors are in discrete hippocampal interneuron subpopulations.

    Science.gov (United States)

    Drake, Carrie T; Milner, Teresa A

    2002-01-01

    In the rat hippocampal formation, application of mu opioid receptor (MOR) agonists disinhibits principal cells, promoting excitation-dependent processes such as epileptogenesis and long-term potentiation. However, the precise location of MORs in particular inhibitory circuits, has not been determined, and the roles of MORs in endogenous functioning are unclear. To address these issues, the distribution of MOR-like immunoreactivity (-li) was examined in several populations of inhibitory hippocampal neurons in the CA1 region using light and electron microscopy. We found that MOR-li was present in many parvalbumin-containing basket cells, but absent from cholecystokinin-labeled basket cells. MOR-li was also commonly in interneurons containing somatostatin-li or neuropeptide Y-li that resembled the "oriens-lacunosum-moleculare" (O-LM) interneurons innervating pyramidal cell distal dendrites. Finally, MOR-li was in some vasoactive intestinal peptide- or calretinin-containing profiles resembling interneurons that primarily innervate other interneurons. These findings indicate that MOR-containing neurons form a neurochemically and functionally heterogeneous subset of hippocampal GABAergic neurons. MORs are most frequently on interneurons that are specialized to inhibit pyramidal cells, and are on a limited number of interneurons that target other interneurons. Moreover, the distribution of MORs to different neuronal types in several laminae, some relatively far from endogenous opioids, suggests normal functional roles that are different from the actions seen with exogenous agonists such as morphine.

  5. A hippocampal interneuron associated with the mossy fiber system.

    Science.gov (United States)

    Vida, I; Frotscher, M

    2000-02-01

    Network properties of the hippocampus emerge from the interaction of principal cells and a heterogeneous population of interneurons expressing gamma-aminobutyric acid (GABA). To understand these interactions, the synaptic connections of different types of interneurons need to be elucidated. Here we describe a type of inhibitory interneuron of the hippocampal CA3 region that has an axon coaligned with the mossy fibers. Whole-cell patch-clamp recordings, in combination with intracellular biocytin filling, were made from nonpyramidal cells of the stratum lucidum under visual control. Mossy fiber-associated (MFA) interneurons generated brief action potentials followed by a prominent after-hyperpolarization. Subsequent visualization revealed an extensive axonal arbor which was preferentially located in the stratum lucidum of CA3 and often invaded the hilus. The dendrites of MFA interneurons were mainly located in the strata radiatum and oriens, suggesting that these cells are primarily activated by associational and commissural fibers. Electron microscopic analysis showed that axon terminals of MFA interneurons established symmetric synaptic contacts predominantly on proximal apical dendritic shafts, and to a lesser degree, on somata of pyramidal cells. Synaptic contacts were also found on GABAergic interneurons of the CA3 region and putative mossy cells of the hilus. Inhibitory postsynaptic currents (IPSCs) elicited by MFA interneurons in simultaneously recorded pyramidal cells had fast kinetics (half duration, 3.6 ms) and were blocked by the GABA(A) receptor antagonist bicuculline. Thus, MFA interneurons are GABAergic cells in a position to selectively suppress the mossy fiber input, an important requirement for the recall of memory traces from the CA3 network.

  6. Hilar GABAergic interneuron activity controls spatial learning and memory retrieval.

    Directory of Open Access Journals (Sweden)

    Yaisa Andrews-Zwilling

    Full Text Available BACKGROUND: Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD, the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear. METHODOLOGY AND PRINCIPAL FINDINGS: We explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0--a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity. CONCLUSIONS AND SIGNIFICANCE: Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD.

  7. Multiple clusters of release sites formed by individual thalamic afferents onto cortical interneurons ensure reliable transmission.

    Science.gov (United States)

    Bagnall, Martha W; Hull, Court; Bushong, Eric A; Ellisman, Mark H; Scanziani, Massimo

    2011-07-14

    Thalamic afferents supply the cortex with sensory information by contacting both excitatory neurons and inhibitory interneurons. Interestingly, thalamic contacts with interneurons constitute such a powerful synapse that even one afferent can fire interneurons, thereby driving feedforward inhibition. However, the spatial representation of this potent synapse on interneuron dendrites is poorly understood. Using Ca imaging and electron microscopy we show that an individual thalamic afferent forms multiple contacts with the interneuronal proximal dendritic arbor, preferentially near branch points. More contacts are correlated with larger amplitude synaptic responses. Each contact, consisting of a single bouton, can release up to seven vesicles simultaneously, resulting in graded and reliable Ca transients. Computational modeling indicates that the release of multiple vesicles at each contact minimally reduces the efficiency of the thalamic afferent in exciting the interneuron. This strategy preserves the spatial representation of thalamocortical inputs across the dendritic arbor over a wide range of release conditions.

  8. Neuregulin 3 Mediates Cortical Plate Invasion and Laminar Allocation of GABAergic Interneurons

    Directory of Open Access Journals (Sweden)

    Giorgia Bartolini

    2017-01-01

    Full Text Available Neural circuits in the cerebral cortex consist of excitatory pyramidal cells and inhibitory interneurons. These two main classes of cortical neurons follow largely different genetic programs, yet they assemble into highly specialized circuits during development following a very precise choreography. Previous studies have shown that signals produced by pyramidal cells influence the migration of cortical interneurons, but the molecular nature of these factors has remained elusive. Here, we identified Neuregulin 3 (Nrg3 as a chemoattractive factor expressed by developing pyramidal cells that guides the allocation of cortical interneurons in the developing cortical plate. Gain- and loss-of-function approaches reveal that Nrg3 modulates the migration of interneurons into the cortical plate in a process that is dependent on the tyrosine kinase receptor ErbB4. Perturbation of Nrg3 signaling in conditional mutants leads to abnormal lamination of cortical interneurons. Nrg3 is therefore a critical mediator in the assembly of cortical inhibitory circuits.

  9. Local connections of layer 5 GABAergic interneurons to corticospinal neurons

    Directory of Open Access Journals (Sweden)

    Yasuyo H Tanaka

    2011-09-01

    Full Text Available In the local circuit of the cerebral cortex, GABAergic inhibitory interneurons are considered to work in collaboration with excitatory neurons. Although many interneuron subgroups have been described in the cortex, local inhibitory connections of each interneuron subgroup are only partially understood with respect to the functional neuron groups that receive these inhibitory connections. In the present study, we morphologically examined local inhibitory inputs to corticospinal neurons (CSNs in motor areas using transgenic rats in which GABAergic neurons expressed fluorescent protein Venus. By analysis of biocytin-filled axons obtained with whole-cell recording/staining in cortical slices, we classified fast-spiking (FS neurons in layer (L 5 into two types, FS1 and FS2, by their high and low densities of axonal arborization, respectively. We then investigated the connections of FS1, FS2, somatostatin-immunopositive (SOM and other (non-FS/non-SOM interneurons to CSNs that were retrogradely labeled in a Golgi-like manner in motor areas. When close appositions between the axon boutons of the intracellularly labeled interneurons and the somata/dendrites of the retrogradely labeled CSNs were examined electron-microscopically, 74% of these appositions made symmetric synaptic contacts. The axon boutons of single FS1 neurons were 2–4-fold more frequent in appositions to the somata/dendrites of CSNs than those of FS2, SOM and non-FS/non-SOM neurons. Axosomatic appositions were most frequently formed with axon boutons of FS1 and FS2 neurons (approximately 30% and least frequently formed with those of SOM neurons (7%. In contrast, SOM neurons most extensively sent axon boutons to the apical dendrites of CSNs. These results might suggest that motor outputs are controlled differentially by the subgroups of L5 GABAergic interneurons in cortical motor areas. 

  10. CBP regulates the differentiation of interneurons from ventral forebrain neural precursors during murine development.

    Science.gov (United States)

    Tsui, David; Voronova, Anastassia; Gallagher, Denis; Kaplan, David R; Miller, Freda D; Wang, Jing

    2014-01-15

    The mechanisms that regulate appropriate genesis and differentiation of interneurons in the developing mammalian brain are of significant interest not only because interneurons play key roles in the establishment of neural circuitry, but also because when they are deficient, this can cause epilepsy. In this regard, one genetic syndrome that is associated with deficits in neural development and epilepsy is Rubinstein-Taybi Syndrome (RTS), where the transcriptional activator and histone acetyltransferase CBP is mutated and haploinsufficient. Here, we have asked whether CBP is necessary for the appropriate genesis and differentiation of interneurons in the murine forebrain, since this could provide an explanation for the epilepsy that is associated with RTS. We show that CBP is expressed in neural precursors within the embryonic medial ganglionic eminence (MGE), an area that generates the vast majority of interneurons for the cortex. Using primary cultures of MGE precursors, we show that knockdown of CBP causes deficits in differentiation of these precursors into interneurons and oligodendrocytes, and that overexpression of CBP is by itself sufficient to enhance interneuron genesis. Moreover, we show that levels of the neurotransmitter synthesis enzyme GAD67, which is expressed in inhibitory interneurons, are decreased in the dorsal and ventral forebrain of neonatal CBP(+/-) mice, indicating that CBP plays a role in regulating interneuron development in vivo. Thus, CBP normally acts to ensure the differentiation of appropriate numbers of forebrain interneurons, and when its levels are decreased, this causes deficits in interneuron development, providing a potential explanation for the epilepsy seen in individuals with RTS.

  11. GABAergic input onto CA3 hippocampal interneurons remains shunting throughout development.

    Science.gov (United States)

    Banke, Tue G; McBain, Chris J

    2006-11-08

    In hippocampus, the net flow of excitability is controlled by inhibitory input provided by the many populations of local circuit inhibitory interneurons. In principal cells, GABA(A) receptor-mediated synaptic input undergoes a highly coordinated shift from depolarizing early in life to a more conventional hyperpolarizing inhibition on maturation. This switch in inhibitory input polarity is controlled by the developmental regulation of two chloride cotransporters (NKCC1 and KCC2) that results in a net shift from high to low intracellular Cl(-). Whether inhibitory input onto inhibitory interneurons demonstrates a similar developmental shift in intracellular Cl(-) is unexplored. Using the gramicidin perforated-patch configuration, we recorded from CA3 hippocampal stratum lucidum interneurons and pyramidal cells to monitor inhibitory input across a broad developmental range. GABA(A) receptor-mediated synaptic input onto stratum lucidum inhibitory interneurons was shunting in nature across the entire developmental age range tested, as resting membrane potential and the IPSC reversal potential remained within a few millivolts (1-4 mV) between postnatal day 5 (P5) and P31. Furthermore, sensitivity to block of the two chloride cotransporters KCC2 and NKCC1 did not differ across the same age range, suggesting that their relative expression is fixed across development. In contrast, pyramidal cell synaptic inhibition demonstrated the well described switch from depolarizing to hyperpolarizing over the same age range. Thus, in contrast to principal cells, inhibitory synaptic input onto CA3 interneurons remains shunting throughout development.

  12. Aging in the rat hippocampus is associated with widespread reductions in the number of glutamate decarboxylase-67 positive interneurons but not interneuron degeneration.

    Science.gov (United States)

    Stanley, Dirk P; Shetty, Ashok K

    2004-04-01

    Increased excitability of principal excitatory neurons is one of the hallmarks of aging in the hippocampus, signifying a diminution in the number and/or function of inhibitory interneurons with aging. To elucidate this, we performed comprehensive GABA-ergic interneuron cell counts in all layers of the dentate gyrus and the CA1 and CA3 subfields, using serial sections from adult, middle-aged and aged Fischer 344 rats. Sections were immunostained for glutamate decarboxylase-67 (GAD-67, a synthesizing enzyme of GABA) and GAD-67 immunopositive interneurons were counted using an unbiased cell counting method, the optical fractionator. Substantial declines in the absolute number of GAD-67 immunopositive interneurons were found in all hippocampal layers/subfields of middle-aged and aged animals, in comparison with the adult animals. However, the counts were comparable between the middle-aged and aged groups for all regions. Interestingly, determination of the absolute number of interneurons using neuron-specific nuclear antigen (NeuN) expression in the strata oriens and radiatum of CA1 and CA3 subfields revealed an analogous number of interneurons across the three age groups. Furthermore, the ratio of GAD-67 immunopositive and NeuN positive interneurons decreased from adult age to middle age but remained relatively static between middle age and old age. Collectively, the results underscore that aging in the hippocampus is associated with wide-ranging decreases in the number of GAD-67 immunopositive interneurons and most of the age-related changes in GAD-67 immunopositive interneuron numbers transpire by middle age. Additionally, this study provides novel evidence that age-related reductions in hippocampal GAD-67 immunopositive interneuron numbers are due to loss of GAD-67 expression in interneurons rather than interneuron degeneration.

  13. Synaptic polarity of the interneuron circuit controlling C. elegans locomotion

    Directory of Open Access Journals (Sweden)

    Franciszek eRakowski

    2013-10-01

    Full Text Available C. elegans is the only animal for which a detailed neural connectivity diagram has been constructed. However, synaptic polarities in this diagram, and thus, circuit functions are largely unknown. Here, we deciphered the likely polarities of 7 pre-motor neurons implicated in the control of worm's locomotion, using a combination of experimental and computational tools. We performed single and multiple laser ablations in the locomotor interneuron circuit and recorded times the worms spent in forward and backward locomotion. We constructed a theoretical model of the locomotor circuit and searched its all possible synaptic polarity combinations and sensory input patterns in order to find the best match to the timing data. The optimal solution is when either all or most of the interneurons are inhibitory and forward interneurons receive the strongest input, which suggests that inhibition governs the dynamics of the locomotor interneuron circuit. From the five pre-motor interneurons, only AVB and AVD are equally likely to be excitatory, i.e. they have probably similar number of inhibitory and excitatory connections to distant targets. The method used here has a general character and thus can be also applied to other neural systems consisting of small functional networks.

  14. Synaptic polarity of the interneuron circuit controlling C. elegans locomotion.

    Science.gov (United States)

    Rakowski, Franciszek; Srinivasan, Jagan; Sternberg, Paul W; Karbowski, Jan

    2013-01-01

    Caenorhabditis elegans is the only animal for which a detailed neural connectivity diagram has been constructed. However, synaptic polarities in this diagram, and thus, circuit functions are largely unknown. Here, we deciphered the likely polarities of seven pre-motor neurons implicated in the control of worm's locomotion, using a combination of experimental and computational tools. We performed single and multiple laser ablations in the locomotor interneuron circuit and recorded times the worms spent in forward and backward locomotion. We constructed a theoretical model of the locomotor circuit and searched its all possible synaptic polarity combinations and sensory input patterns in order to find the best match to the timing data. The optimal solution is when either all or most of the interneurons are inhibitory and forward interneurons receive the strongest input, which suggests that inhibition governs the dynamics of the locomotor interneuron circuit. From the five pre-motor interneurons, only AVB and AVD are equally likely to be excitatory, i.e., they have probably similar number of inhibitory and excitatory connections to distant targets. The method used here has a general character and thus can be also applied to other neural systems consisting of small functional networks.

  15. Vulnerability of hippocampal GABA-ergic interneurons to kainate-induced excitotoxic injury during old age.

    Science.gov (United States)

    Shetty, Ashok K; Hattiangady, Bharathi; Rao, Muddanna S

    2009-08-01

    Hippocampal inhibitory interneurons expressing glutamate decarboxylase-67 (GAD-67) considerably decline in number during old age. Studies in young adult animals further suggest that hippocampal GAD-67+ interneuron population is highly vulnerable to excitotoxic injury. However, the relative susceptibility of residual GAD-67+ interneurons in the aged hippocampus to excitotoxic injury is unknown. To elucidate this, using both adult and aged F344 rats, we performed stereological counting of GAD-67+ interneurons in different layers of the dentate gyrus and CA1 & CA3 sub-fields, at 3 months post-excitotoxic hippocampal injury inflicted through an intracerebroventricular administration of kainic acid (KA). Substantial reductions of GAD-67+ interneurons were found in all hippocampal layers and sub-fields after KA-induced injury in adult animals. Contrastingly, there was no significant change in GAD-67+ interneuron population in any of the hippocampal layers and sub-fields following similar injury in aged animals. Furthermore, the stability of GAD-67+ interneurons in aged rats after KA was not attributable to milder injury, as the overall extent of KA-induced hippocampal principal neuron loss was comparable between adult and aged rats. Interestingly, because of the age-related disparity in vulnerability of interneurons to injury, the surviving GAD-67+ interneuron population in the injured aged hippocampus remained comparable to that observed in the injured adult hippocampus despite enduring significant reductions in interneuron number with aging. Thus, unlike in the adult hippocampus, an excitotoxic injury to the aged hippocampus does not result in significantly decreased numbers of GAD-67+ interneurons. Persistence of GAD-67+ interneuron population in the injured aged hippocampus likely reflects an age-related change in the response of GAD-67+ interneurons to excitotoxic hippocampal injury. These results have implications towards understanding mechanisms underlying the

  16. An interneuron progenitor maintains neurogenic potential in vivo and differentiates into GABAergic interneurons after transplantation in the postnatal rat brain.

    Science.gov (United States)

    Wang, Qi; Hong, Peiwei; Gao, Hui; Chen, Yuntian; Yang, Qi; Jiang, Mei; Li, Hedong

    2016-01-11

    Dysfunction of cortical GABAergic interneurons are involved in numerous neurological disorders including epilepsy, schizophrenia and autism; and replenishment of these cells by transplantation strategy has proven to be a feasible and effective method to help revert the symptoms in several animal models. To develop methodology of generating transplantable GABAergic interneurons for therapy, we previously reported the isolation of a v-myc-induced GABAergic interneuron progenitor clone GE6 from embryonic ganglionic eminence (GE). These cells can proliferate and form functional inhibitory synapses in culture. Here, we tested their differentiation behavior in vivo by transplanting them into the postnatal rat forebrain. We found that GE6 cells migrate extensively in the neonatal forebrain and differentiate into both neurons and glia, but preferentially into neurons when compared with a sister progenitor clone CTX8. The neurogenic potential of GE6 cells is also maintained after transplantation into a non-permissive environment such as adult cortex or when treated with inflammatory cytokine in culture. The GE6-derived neurons were able to mature in vivo as GABAergic interneurons expressing GABAergic, not glutamatergic, presynaptic puncta. Finally, we propose that v-myc-induced human interneuron progenitor clones could be an alternative cell source of transplantable GABAergic interneurons for treating related neurological diseases in future clinic.

  17. Selective loss and axonal sprouting of GABAergic interneurons in the sclerotic hippocampus induced by LiCl-pilocarpine.

    Science.gov (United States)

    Long, Lili; Xiao, Bo; Feng, Li; Yi, Fang; Li, Guoliang; Li, Shuyu; Mutasem, M Abuhamed; Chen, Si; Bi, Fangfang; Li, Yi

    2011-02-01

    In this study, we performed immunohistochemistry for somatostatin (SS), neuropeptide Y (NPY), and parvalbumin (PV) in LiCl-pilocarpine-treated rats to observe quantitative changes and axonal sprouting of GABAergic interneurons in the hippocampus, especially in the sclerotic hippocampus. Fluoro-Jade B (FJB) was performed to detect the specific degeneration of GABAergic interneurons. Compared with age-matched control rats, there were fewer SS/NPY/PV-immunoreactive (IR) interneurons in the hilus of the sclerotic hippocampus in pilocarpine-treated rats; hilar dentritic inhibitory interneurons were most vulnerable. FJB stain revealed degeneration was evident at 2 months after status epilepticus. Some SS-IR and NPY-IR interneurons were also stained for FJB, but there was no evidence of degeneration of PV-IR interneurons. Axonal sprouting of GABAergic interneurons was present in the hippocampus of epileptic rats, and a dramatic increase of SS-IR fibers was observed throughout all layers of CA1 region in the sclerotic hippocampus. These results confirm selective loss and degeneration of a specific subset of GABAergic interneurons in specific subfields of the hippocampus. Axonal sprouting of inhibitory GABAergic interneurons, especially numerous increase of SS-IR neutrophils within CA1 region of the sclerotic hippocampus, may constitute the aberrant inhibitory circum and play a significant role in the generation and compensation of temporal lobe epilepsy.

  18. Hippocampal interneurons expressing glutamic acid decarboxylase and calcium-binding proteins decrease with aging in Fischer 344 rats.

    Science.gov (United States)

    Shetty, A K; Turner, D A

    1998-05-04

    Aging leads to alterations in the function and plasticity of hippocampal circuitry in addition to behavioral changes. To identify critical alterations in the substrate for inhibitory circuitry as a function of aging, we evaluated the numbers of hippocampal interneurons that were positive for glutamic acid decarboxylase and those that expressed calcium-binding proteins (parvalbumin, calbindin, and calretinin) in young adult (4-5 months old) and aged (23-25 months old) male Fischer 344 rats. Both the overall interneuron population and specific subpopulations of interneurons demonstrated a commensurate decline in numbers throughout the hippocampus with aging. Interneurons positive for glutamic acid decarboxylase were significantly depleted in the stratum radiatum of CA1, the strata oriens, radiatum and pyramidale of CA3, the dentate molecular layer, and the dentate hilus. Parvalbumin interneurons showed significant reductions in the strata oriens and pyramidale of CA1, the stratum pyramidale of CA3, and the dentate hilus. The reductions in calbindin interneurons were more pronounced than other calcium-binding protein-positive interneurons and were highly significant in the strata oriens and radiatum of both CA1 and CA3 subfields and in the dentate hilus. Calretinin interneurons were decreased significantly in the strata oriens and radiatum of CA3, in the dentate granule cell and molecular layers, and in the dentate hilus. However, the relative ratio of parvalbumin-, calbindin-, and calretinin-positive interneurons compared with glutamic acid decarboxylase-positive interneurons remained constant with aging, suggesting actual loss of interneurons expressing calcium-binding proteins with age. This loss contrasts with the reported preservation of pyramidal neurons with aging in the hippocampus. Functional decreases in inhibitory drive throughout the hippocampus may occur due to this loss, particularly alterations in the processing of feed-forward information through the

  19. Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations.

    Science.gov (United States)

    Stark, Eran; Roux, Lisa; Eichler, Ronny; Senzai, Yuta; Royer, Sebastien; Buzsáki, György

    2014-07-16

    High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation, frequency control, and spatial coherence of the rhythm are poorly understood. Using multisite optogenetic manipulations in freely behaving rodents, we found that depolarization of a small group of nearby pyramidal cells was sufficient to induce high-frequency oscillations, whereas closed-loop silencing of pyramidal cells or activation of parvalbumin- (PV) or somatostatin-immunoreactive interneurons aborted spontaneously occurring ripples. Focal pharmacological blockade of GABAA receptors abolished ripples. Localized PV interneuron activation paced ensemble spiking, and simultaneous induction of high-frequency oscillations at multiple locations resulted in a temporally coherent pattern mediated by phase-locked interneuron spiking. These results constrain competing models of ripple generation and indicate that temporally precise local interactions between excitatory and inhibitory neurons support ripple generation in the intact hippocampus.

  20. Multiple forms of long-term synaptic plasticity at hippocampal mossy fiber synapses on interneurons.

    Science.gov (United States)

    Galván, Emilio J; Cosgrove, Kathleen E; Barrionuevo, Germán

    2011-04-01

    The hippocampal mossy fiber (MF) pathway originates from the dentate gyrus granule cells and provides a powerful excitatory synaptic drive to neurons in the dentate gyrus hilus and area CA3. Much of the early work on the MF pathway focused on its electrophysiological properties, and ability to drive CA3 pyramidal cell activity. Over the last ten years, however, a new focus on the synaptic interaction between granule cells and inhibitory interneurons has emerged. These data have revealed an immense heterogeneity of long-term plasticity at MF synapses on various interneuron targets. Interestingly, these studies also indicate that the mechanisms of MF long-term plasticity in some interneuron subtypes may be more similar to pyramidal cells than previously appreciated. In this review, we first define the synapse types at each of the interneuron targets based on the receptors present. We then describe the different forms of long-term plasticity observed, and the mechanisms underlying each form as they are currently understood. Finally we highlight various open questions surrounding MF long-term plasticity in interneurons, focusing specifically on the induction and maintenance of LTP, and what the functional impact of persistent changes in efficacy at MF-interneuron synapses might be on the emergent properties of the inhibitory network dynamics in area CA3. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'.

  1. Alpha-bungarotoxin binding to hippocampal interneurons: immunocytochemical characterization and effects on growth factor expression.

    Science.gov (United States)

    Freedman, R; Wetmore, C; Strömberg, I; Leonard, S; Olson, L

    1993-05-01

    The nicotinic cholinergic antagonist alpha-bungarotoxin (alpha-BT) binds throughout the rat hippocampal formation. The binding is displaceable by d-tubocurarine. The most heavily labeled cells are GABA-containing interneurons in the dentate and in Ammon's horn. These neurons have several different morphologies and contain several neuropeptides. alpha-BT-labeled interneurons in the dentate are small cells between the granular and molecular layers that often contain neuropeptide Y. alpha-BT-labeled interneurons in CA1 are medium-sized interneurons, occasionally found in stratum pyramidale, but more often found in stratum radiatum and stratum lacunosum moleculare. These neurons often contain cholecystokinin. The largest alpha-BT-labeled interneurons are found in CA3, in both stratum radiatum and stratum lucidum. These neurons are multipolar and frequently are autofluorescent. They often contain somatostatin or cholecystokinin. These large interneurons have been found to receive medial septal innervation and may also have projections that provide inhibitory feedback directly to the medial septal nucleus. The cholinergic innervation of the hippocampus from the medial septal nucleus is under the trophic regulation of NGF and brain-derived neurotrophic factor, even in adult life. Expression of mRNA for both these factors is increased in CA3 and the dentate after intraventricular administration of alpha-BT, but not after administration of the muscarinic antagonist atropine. alpha-BT-sensitive cholinergic receptors on inhibitory interneurons may be critical to medial septal regulation of the hippocampal activity, including the habituation of response to sensory input.

  2. Loss of cyclin-dependent kinase 5 from parvalbumin interneurons leads to hyperinhibition, decreased anxiety, and memory impairment.

    Science.gov (United States)

    Rudenko, Andrii; Seo, Jinsoo; Hu, Ji; Su, Susan C; de Anda, Froylan Calderon; Durak, Omer; Ericsson, Maria; Carlén, Marie; Tsai, Li-Huei

    2015-02-11

    Perturbations in fast-spiking parvalbumin (PV) interneurons are hypothesized to be a major component of various neuropsychiatric disorders; however, the mechanisms regulating PV interneurons remain mostly unknown. Recently, cyclin-dependent kinase 5 (Cdk5) has been shown to function as a major regulator of synaptic plasticity. Here, we demonstrate that genetic ablation of Cdk5 in PV interneurons in mouse brain leads to an increase in GABAergic neurotransmission and impaired synaptic plasticity. PVCre;fCdk5 mice display a range of behavioral abnormalities, including decreased anxiety and memory impairment. Our results reveal a central role of Cdk5 expressed in PV interneurons in gating inhibitory neurotransmission and underscore the importance of such regulation during behavioral tasks. Our findings suggest that Cdk5 can be considered a promising therapeutic target in a variety of conditions attributed to inhibitory interneuronal dysfunction, such as epilepsy, anxiety disorders, and schizophrenia.

  3. Synapse-specific compartmentalization of signaling cascades for LTP induction in CA3 interneurons

    OpenAIRE

    Galván, Emilio J; Pérez-Rosello, Tamara; Gómez-Lira, Gisela; Lara, Erika; Gutiérrez, Rafael; Barrionuevo, Germán

    2015-01-01

    Inhibitory interneurons with somata in strata radiatum and lacunosun-moleculare (SR/L-M) of hippocampal area CA3 receive excitatory input from pyramidal cells via the recurrent collaterals (RC), and the dentate gyrus granule cells via the mossy fibers (MFs). Here we demonstrate that Hebbian long-term potentiation (LTP) at RC synapses on SR/L-M interneurons requires the concomitant activation of calcium-impermeable AMPARs (CI- AMPARs) and NMDARs. RC LTP was prevented by voltage clamping the po...

  4. Distribution of interneurons in the CA2 region of the rat hippocampus.

    OpenAIRE

    Botcher, N. A.; Falck, J. E.; Thomson, A. M.; Mercer, A.

    2014-01-01

    The CA2 region of the mammalian hippocampus is a unique region with its own distinctive properties, inputs and pathologies. Disruption of inhibitory circuits in this region appears to be linked with the pathology of specific psychiatric disorders, promoting interest in its local circuitry, its role in hippocampal function and its dysfunction in disease. In previous studies, CA2 interneurons, including a novel subclass of CA2 dendrite-preferring interneurons that has not been identified in oth...

  5. 5-HT and GABA modulate intrinsic excitability of type I interneurons in Hermissenda.

    Science.gov (United States)

    Jin, Nan Ge; Tian, Lian-Ming; Crow, Terry

    2009-11-01

    The sensory neurons (photoreceptors) in the visual system of Hermissenda are one site of plasticity produced by Pavlovian conditioning. A second site of plasticity produced by conditioning is the type I interneurons in the cerebropleural ganglia. Both photoreceptors and statocyst hair cells of the graviceptive system form monosynaptic connections with identified type I interneurons. Two proposed neurotransmitters in the graviceptive system, serotonin (5-HT) and gamma-aminobutyric acid (GABA), have been shown to modify synaptic strength and intrinsic neuronal excitability in identified photoreceptors. However, the potential role of 5-HT and GABA in plasticity of type I interneurons has not been investigated. Here we show that 5-HT increased the peak amplitude of light-evoked complex excitatory postsynaptic potentials (EPSPs), enhanced intrinsic excitability, and increased spike activity of identified type I(e(A)) interneurons. In contrast, 5-HT decreased spike activity and intrinsic excitability of type I(e(B)) interneurons. The classification of two categories of type I(e) interneurons was also supported by the observation that 5-HT produced opposite effects on whole cell steady-state outward currents in type I(e) interneurons. Serotonin produced a reduction in the amplitude of light-evoked complex inhibitory PSPs (IPSPs), increased spontaneous spike activity, decreased intrinsic excitability, and depolarized the resting membrane potential of identified type I(i) interneurons. In contrast to the effects of 5-HT, GABA produced inhibition in both types of I(e) interneurons and type I(i) interneurons. These results show that 5-HT and GABA can modulate the intrinsic excitability of type I interneurons independent of the presynaptic effects of the same transmitters on excitability and synaptic efficacy of photoreceptors.

  6. Molecular and Electrophysiological Characterization of GABAergic Interneurons Expressing the Transcription Factor COUP-TFII in the Adult Human Temporal Cortex.

    Science.gov (United States)

    Varga, Csaba; Tamas, Gabor; Barzo, Pal; Olah, Szabolcs; Somogyi, Peter

    2015-11-01

    Transcription factors contribute to the differentiation of cortical neurons, orchestrate specific interneuronal circuits, and define synaptic relationships. We have investigated neurons expressing chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), which plays a role in the migration of GABAergic neurons. Whole-cell, patch-clamp recording in vitro combined with colocalization of molecular cell markers in the adult cortex differentiates distinct interneurons. The majority of strongly COUP-TFII-expressing neurons were in layers I-III. Most calretinin (CR) and/or cholecystokinin- (CCK) and/or reelin-positive interneurons were also COUP-TFII-positive. CR-, CCK-, or reelin-positive neurons formed 80%, 20%, or 17% of COUP-TFII-positive interneurons, respectively. About half of COUP-TFII-/CCK-positive interneurons were CR-positive, a quarter of them reelin-positive, but none expressed both. Interneurons positive for COUP-TFII fired irregular, accommodating and adapting trains of action potentials (APs) and innervated mostly small dendritic shafts and rarely spines or somata. Paired recording showed that a calretinin-/COUP-TFII-positive interneuron elicited inhibitory postsynaptic potentials (IPSPs) in a reciprocally connected pyramidal cell. Calbindin, somatostatin, or parvalbumin-immunoreactive interneurons and most pyramidal cells express no immunohistochemically detectable COUP-TFII. In layers V and VI, some pyramidal cells expressed a low level of COUP-TFII in the nucleus. In conclusion, COUP-TFII is expressed in a diverse subset of GABAergic interneurons predominantly innervating small dendritic shafts originating from both interneurons and pyramidal cells.

  7. Contact-associated neurite outgrowth and branching of immature cortical interneurons.

    Science.gov (United States)

    Sang, Qian; Tan, Seong-Seng

    2003-06-01

    When juvenile interneurons arrive at the cortical environment following tangential migration, they are faced with the task of positioning themselves in cortical space in preparation for local circuit wiring. This includes integration into different cortical layers and cessation of migration at various positions to ensure adequate coverage. Little is known about the signals or mechanisms that initiate a conversion from the migratory phenotype to the arborization phenotype. This study looks at the immediate changes in interneuron morphology after culturing for 24 h in a three-dimensional collagen gel. Immature interneurons taken from different stages of corticogenesis showed increased neurite branching and outgrowth after interneuronal contacts were made. These responses were suppressed in the presence of Slit and brain-derived neurotrophic factor (BDNF) if the interneurons were sourced from early to mid-stages of corticogenesis. However, interneurons taken from the late period of corticogenesis responded to Slit and BDNF by increasing branching and neurite outgrowth. These results suggest an initial interneuronal cell contact as a stimulus for propagating neuronal arborization that may lead to the formation of inhibitory neuronal circuits. In addition, we have identified the late corticogenetic period when interneurons are most sensitive to the neurite promoting effects of Slit and BDNF.

  8. Intermediate Progenitors Facilitate Intracortical Progression of Thalamocortical Axons and Interneurons through CXCL12 Chemokine Signaling.

    Science.gov (United States)

    Abe, Philipp; Molnár, Zoltán; Tzeng, Yi-Shiuan; Lai, Dar-Ming; Arnold, Sebastian J; Stumm, Ralf

    2015-09-23

    Glutamatergic principal neurons, GABAergic interneurons and thalamocortical axons (TCAs) are essential elements of the cerebrocortical network. Principal neurons originate locally from radial glia and intermediate progenitors (IPCs), whereas interneurons and TCAs are of extrinsic origin. Little is known how the assembly of these elements is coordinated. C-X-C motif chemokine 12 (CXCL12), which is known to guide axons outside the neural tube and interneurons in the cortex, is expressed in the meninges and IPCs. Using mouse genetics, we dissected the influence of IPC-derived CXCL12 on TCAs and interneurons by showing that Cxcl12 ablation in IPCs, leaving meningeal Cxcl12 intact, attenuates intracortical TCA growth and disrupts tangential interneuron migration in the subventricular zone. In accordance with strong CXCR4 expression in the forming thalamus and TCAs, we identified a CXCR4-dependent growth-promoting effect of CXCL12 on TCAs in thalamus explants. Together, our findings indicate a cell-autonomous role of CXCR4 in promoting TCA growth. We propose that CXCL12 signals from IPCs link cortical neurogenesis to the progression of TCAs and interneurons spatially and temporally. Significance statement: The cerebral cortex exerts higher brain functions including perceptual and emotional processing. Evolutionary expansion of the mammalian cortex is mediated by intermediate progenitors, transient amplifying cells generating cortical excitatory neurons. During the peak period of cortical neurogenesis, migrating precursors of inhibitory interneurons originating in subcortical areas and thalamic axons invade the cortex. Although defects in the assembly of cortical network elements cause neurological and mental disorders, little is known how neurogenesis, interneuron recruitment, and axonal ingrowth are coordinated. We demonstrate that intermediate progenitors release the chemotactic cytokine CXCL12 to promote intracortical interneuron migration and growth of thalamic axons

  9. Chronic fluoxetine treatment alters the structure, connectivity and plasticity of cortical interneurons.

    Science.gov (United States)

    Guirado, Ramon; Perez-Rando, Marta; Sanchez-Matarredona, David; Castrén, Eero; Nacher, Juan

    2014-10-01

    Novel hypotheses suggest that antidepressants, such as the selective serotonin reuptake inhibitor fluoxetine, induce neuronal structural plasticity, resembling that of the juvenile brain, although the underlying mechanisms of this reopening of the critical periods still remain unclear. However, recent studies suggest that inhibitory networks play an important role in this structural plasticity induced by fluoxetine. For this reason we have analysed the effects of a chronic fluoxetine treatment in the hippocampus and medial prefrontal cortex (mPFC) of transgenic mice displaying eGFP labelled interneurons. We have found an increase in the expression of molecules related to critical period plasticity, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), GAD67/65 and synaptophysin, as well as a reduction in the number of parvalbumin expressing interneurons surrounded by perineuronal nets. We have also described a trend towards decrease in the perisomatic inhibitory puncta on pyramidal neurons in the mPFC and an increase in the density of inhibitory puncta on eGFP interneurons. Finally, we have found that chronic fluoxetine treatment affects the structure of interneurons in the mPFC, increasing their dendritic spine density. The present study provides evidence indicating that fluoxetine promotes structural changes in the inhibitory neurons of the adult cerebral cortex, probably through alterations in plasticity-related molecules of neurons or the extracellular matrix surrounding them, which are present in interneurons and are known to be crucial for the development of the critical periods of plasticity in the juvenile brain.

  10. Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility

    Science.gov (United States)

    Dutton, Stacey B.; Makinson, Christopher D.; Papale, Ligia A.; Shankar, Anupama; Balakrishnan, Bindu; Nakazawa, Kazu; Escayg, Andrew

    2012-01-01

    Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials in electrically excitable cells. Dominant mutations in SCN1A, which encodes the Nav1.1 VGSC α-subunit, underlie several forms of epilepsy, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Electrophysiological analyses of DS and GEFS+ mouse models have led to the hypothesis that SCN1A mutations reduce the excitability of inhibitory cortical and hippocampal interneurons. To more directly examine the relative contribution of inhibitory interneurons and excitatory pyramidal cells to SCN1A-derived epilepsy, we first compared the expression of Nav1.1 in inhibitory parvalbumin (PV) interneurons and excitatory neurons from P22 mice using fluorescent immunohistochemistry. In the hippocampus and neocortex, 69% of Nav1.1 immunoreactive neurons were also positive for PV. In contrast, 13% and 5% of Nav1.1 positive cells in the hippocampus and neocortex, respectively, were found to co-localize with excitatory cells identified by CaMK2α immunoreactivity. Next, we reduced the expression of Scn1a in either a subset of interneurons (mainly PV interneurons) or excitatory cells by crossing mice heterozygous for a floxed Scn1a allele to either the Ppp1r2-Cre or EMX1-Cre transgenic lines, respectively. The inactivation of one Scn1a allele in interneurons of the neocortex and hippocampus was sufficient to reduce thresholds to flurothyl- and hyperthermia-induced seizures, whereas thresholds were unaltered following inactivation in excitatory cells. Reduced interneuron Scn1a expression also resulted in the generation of spontaneous seizures. These findings provide direct evidence for an important role of PV interneurons in the pathogenesis of Scn1a-derived epilepsies. PMID:22926190

  11. Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility.

    Science.gov (United States)

    Dutton, Stacey B; Makinson, Christopher D; Papale, Ligia A; Shankar, Anupama; Balakrishnan, Bindu; Nakazawa, Kazu; Escayg, Andrew

    2013-01-01

    Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials in electrically excitable cells. Dominant mutations in SCN1A, which encodes the Nav1.1 VGSC α-subunit, underlie several forms of epilepsy, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Electrophysiological analyses of DS and GEFS+ mouse models have led to the hypothesis that SCN1A mutations reduce the excitability of inhibitory cortical and hippocampal interneurons. To more directly examine the relative contribution of inhibitory interneurons and excitatory pyramidal cells to SCN1A-derived epilepsy, we first compared the expression of Nav1.1 in inhibitory parvalbumin (PV) interneurons and excitatory neurons from P22 mice using fluorescent immunohistochemistry. In the hippocampus and neocortex, 69% of Nav1.1 immunoreactive neurons were also positive for PV. In contrast, 13% and 5% of Nav1.1 positive cells in the hippocampus and neocortex, respectively, were found to co-localize with excitatory cells identified by CaMK2α immunoreactivity. Next, we reduced the expression of Scn1a in either a subset of interneurons (mainly PV interneurons) or excitatory cells by crossing mice heterozygous for a floxed Scn1a allele to either the Ppp1r2-Cre or EMX1-Cre transgenic lines, respectively. The inactivation of one Scn1a allele in interneurons of the neocortex and hippocampus was sufficient to reduce thresholds to flurothyl- and hyperthermia-induced seizures, whereas thresholds were unaltered following inactivation in excitatory cells. Reduced interneuron Scn1a expression also resulted in the generation of spontaneous seizures. These findings provide direct evidence for an important role of PV interneurons in the pathogenesis of Scn1a-derived epilepsies.

  12. Reduced chemical and electrical connections of fast-spiking interneurons in experimental cortical dysplasia.

    Science.gov (United States)

    Zhou, Fu-Wen; Roper, Steven N

    2014-09-15

    Aberrant neural connections are regarded as a principal factor contributing to epileptogenesis. This study examined chemical and electrical connections between fast-spiking (FS), parvalbumin (PV)-immunoreactive (FS-PV) interneurons and regular-spiking (RS) neurons (pyramidal neurons or spiny stellate neurons) in a rat model of prenatal irradiation-induced cortical dysplasia. Presynaptic action potentials were evoked by current injection and the elicited unitary inhibitory or excitatory postsynaptic potentials (uIPSPs or uEPSPs) were recorded in the postsynaptic cell. In dysplastic cortex, connection rates between presynaptic FS-PV interneurons and postsynaptic RS neurons and FS-PV interneurons, and uIPSP amplitudes were significantly smaller than controls, but both failure rates and coefficient of variation of uIPSP amplitudes were larger than controls. In contrast, connection rates from RS neurons to FS-PV interneurons and uEPSPs amplitude were similar in the two groups. Assessment of the paired pulse ratio showed a significant decrease in synaptic release probability at FS-PV interneuronal terminals, and the density of terminal boutons on axons of biocytin-filled FS-PV interneurons was also decreased, suggesting presynaptic dysfunction in chemical synapses formed by FS-PV interneurons. Electrical connections were observed between FS-PV interneurons, and the connection rates and coupling coefficients were smaller in dysplastic cortex than controls. In dysplastic cortex, we found a reduced synaptic efficiency for uIPSPs originating from FS-PV interneurons regardless of the type of target cell, and impaired electrical connections between FS-PV interneurons. This expands our understanding of the fundamental impairment of inhibition in this model and may have relevance for certain types of human cortical dysplasia.

  13. Unit Activity of Hippocampal Interneurons before Spontaneous Seizures in an Animal Model of Temporal Lobe Epilepsy.

    Science.gov (United States)

    Toyoda, Izumi; Fujita, Satoshi; Thamattoor, Ajoy K; Buckmaster, Paul S

    2015-04-22

    Mechanisms of seizure initiation are unclear. To evaluate the possible roles of inhibitory neurons, unit recordings were obtained in the dentate gyrus, CA3, CA1, and subiculum of epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Most interneurons in the dentate gyrus, CA1, and subiculum increased their firing rate before seizures, and did so with significant consistency from seizure to seizure. Identification of CA1 interneuron subtypes based on firing characteristics during theta and sharp waves suggested that a parvalbumin-positive basket cell and putative bistratified cells, but not oriens lacunosum moleculare cells, were activated preictally. Preictal changes occurred much earlier than those described by most previous in vitro studies. Preictal activation of interneurons began earliest (>4 min before seizure onset), increased most, was most prevalent in the subiculum, and was minimal in CA3. Preictal inactivation of interneurons was most common in CA1 (27% of interneurons) and included a putative ivy cell and parvalbumin-positive basket cell. Increased or decreased preictal activity correlated with whether interneurons fired faster or slower, respectively, during theta activity. Theta waves were more likely to occur before seizure onset, and increased preictal firing of subicular interneurons correlated with theta activity. Preictal changes by other hippocampal interneurons were largely independent of theta waves. Within seconds of seizure onset, many interneurons displayed a brief pause in firing and a later, longer drop that was associated with reduced action potential amplitude. These findings suggest that many interneurons inactivate during seizures, most increase their activity preictally, but some fail to do so at the critical time before seizure onset.

  14. Synaptic basis for intense thalamocortical activation of feedforward inhibitory cells in neocortex.

    Science.gov (United States)

    Cruikshank, Scott J; Lewis, Timothy J; Connors, Barry W

    2007-04-01

    The thalamus provides fundamental input to the neocortex. This input activates inhibitory interneurons more strongly than excitatory neurons, triggering powerful feedforward inhibition. We studied the mechanisms of this selective neuronal activation using a mouse somatosensory thalamocortical preparation. Notably, the greater responsiveness of inhibitory interneurons was not caused by their distinctive intrinsic properties but was instead produced by synaptic mechanisms. Axons from the thalamus made stronger and more frequent excitatory connections onto inhibitory interneurons than onto excitatory cells. Furthermore, circuit dynamics allowed feedforward inhibition to suppress responses in excitatory cells more effectively than in interneurons. Thalamocortical excitatory currents rose quickly in interneurons, allowing them to fire action potentials before significant feedforward inhibition emerged. In contrast, thalamocortical excitatory currents rose slowly in excitatory cells, overlapping with feedforward inhibitory currents that suppress action potentials. These results demonstrate the importance of selective synaptic targeting and precise timing in the initial stages of neocortical processing.

  15. Cell type-specific long-term plasticity at glutamatergic synapses onto hippocampal interneurons expressing either parvalbumin or CB1 cannabinoid receptor.

    Science.gov (United States)

    Nissen, Wiebke; Szabo, Andras; Somogyi, Jozsef; Somogyi, Peter; Lamsa, Karri P

    2010-01-27

    Different GABAergic interneuron types have specific roles in hippocampal function, and anatomical as well as physiological features vary greatly between interneuron classes. Long-term plasticity of interneurons has mostly been studied in unidentified GABAergic cells and is known to be very heterogeneous. Here we tested whether cell type-specific plasticity properties in distinct GABAergic interneuron types might underlie this heterogeneity. We show that long-term potentiation (LTP) and depression (LTD), two common forms of synaptic plasticity, are expressed in a highly cell type-specific manner at glutamatergic synapses onto hippocampal GABAergic neurons. Both LTP and LTD are generated in interneurons expressing parvalbumin (PV+), whereas interneurons with similar axon distributions but expressing cannabinoid receptor-1 show no lasting plasticity in response to the same protocol. In addition, LTP or LTD occurs in PV+ interneurons with different efferent target domains. Perisomatic-targeting PV+ basket and axo-axonic interneurons express LTP, whereas glutamatergic synapses onto PV+ bistratified cells display LTD. Both LTP and LTD are pathway specific, independent of NMDA receptors, and occur at synapses with calcium-permeable (CP) AMPA receptors. Plasticity in interneurons with CP-AMPA receptors strongly modulates disynaptic GABAergic transmission onto CA1 pyramidal cells. We propose that long-term plasticity adjusts the synaptic strength between pyramidal cells and interneurons in a cell type-specific manner and, in the defined CA1 interneurons, shifts the spatial pattern of inhibitory weight from pyramidal cell dendrites to the perisomatic region.

  16. Distinct roles of SOM and VIP interneurons during cortical Up states

    Directory of Open Access Journals (Sweden)

    Garrett T. Neske

    2016-07-01

    Full Text Available During cortical network activity, recurrent synaptic excitation among pyramidal neurons is approximately balanced by synaptic inhibition, which is provided by a vast diversity of inhibitory interneurons. The relative contributions of different interneuron subtypes to inhibitory tone during cortical network activity is not well understood. We previously showed that many of the major interneuron subtypes in mouse barrel cortex are highly active during Up states (Neske et al., 2015; while fast-spiking (FS, parvalbumin (PV-positive cells were the most active interneuron subtype, many non-fast-spiking (NFS, PV-negative interneurons were as active or more active than neighboring pyramidal cells. This suggests that the NFS cells could play a role in maintaining or modulating Up states. Here, using optogenetic techniques, we further dissected the functional roles during Up states of two major NFS, PV-negative interneuron subtypes: somatostatin (SOM-positive cells and vasoactive intestinal peptide (VIP-positive cells. We found that while pyramidal cell excitability during Up states significantly increased when SOM cells were optogenetically silenced, VIP cells did not influence pyramidal cell excitability either upon optogenetic silencing or activation. VIP cells failed to contribute to Up states despite their ability to inhibit SOM cells strongly. We suggest that the contribution of VIP cells to the excitability of pyramidal cells may vary with cortical state.

  17. Adenosine-mediated modulation of ventral horn interneurons and spinal motoneurons in neonatal mice.

    Science.gov (United States)

    Witts, Emily C; Nascimento, Filipe; Miles, Gareth B

    2015-10-01

    Neuromodulation allows neural networks to adapt to varying environmental and biomechanical demands. Purinergic signaling is known to be an important modulatory system in many parts of the CNS, including motor control circuitry. We have recently shown that adenosine modulates the output of mammalian spinal locomotor control circuitry (Witts EC, Panetta KM, Miles GB. J Neurophysiol 107: 1925-1934, 2012). Here we investigated the cellular mechanisms underlying this adenosine-mediated modulation. Whole cell patch-clamp recordings were performed on ventral horn interneurons and motoneurons within in vitro mouse spinal cord slice preparations. We found that adenosine hyperpolarized interneurons and reduced the frequency and amplitude of synaptic inputs to interneurons. Both effects were blocked by the A1-type adenosine receptor antagonist DPCPX. Analysis of miniature postsynaptic currents recorded from interneurons revealed that adenosine reduced their frequency but not amplitude, suggesting that adenosine acts on presynaptic receptors to modulate synaptic transmission. In contrast to interneurons, recordings from motoneurons revealed an adenosine-mediated depolarization. The frequency and amplitude of synaptic inputs to motoneurons were again reduced by adenosine, but we saw no effect on miniature postsynaptic currents. Again these effects on motoneurons were blocked by DPCPX. Taken together, these results demonstrate differential effects of adenosine, acting via A1 receptors, in the mouse spinal cord. Adenosine has a general inhibitory action on ventral horn interneurons while potentially maintaining motoneuron excitability. This may allow for adaptation of the locomotor pattern generated by interneuronal networks while helping to ensure the maintenance of overall motor output.

  18. Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition

    Directory of Open Access Journals (Sweden)

    Megan S. Wyeth

    2017-08-01

    Full Text Available Although Netos are considered auxiliary subunits critical for kainate receptor (KAR function, direct evidence for their regulation of native KARs is limited. Because Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type-specific contexts. We demonstrate Neto1/2 expression in somatostatin (SOM-, cholecystokinin/cannabinoid receptor 1 (CCK/CB1-, and parvalbumin (PV-containing interneurons. KAR-mediated excitation of these interneurons is contingent upon Neto1 because kainate yields comparable effects in Neto2 knockouts and wild-types but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation, dampening CCK/CB1 interneuron output, and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron-mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals.

  19. Area CA3 interneurons receive two spatially segregated mossy fiber inputs

    Science.gov (United States)

    Cosgrove, Kathleen E.; Galvan, Emilio J.; Meriney, Stephen D.; Barrionuevo, German

    2009-01-01

    Area CA3 receives two extrinsic excitatory inputs, the mossy fibers (MF) and the perforant path (PP). Interneurons with somata in str. lacunosum moleculare (L-M) of CA3 modulate the influence of the MF and PP on pyramidal cell activity by providing strong feed-forward inhibitory influence to pyramidal cells. Here we report that L-M interneurons receive two separate MF inputs, one to the dorsal dendrites from the suprapyramidal blade of the dentate gyrus (MFSDG), and a second to ventral dendrites from the str. lucidum (MFSL). Responses elicited from MFSDG and MFSL stimulation sites have strong paired-pulse facilitation, similar DCG-IV sensitivity, amplitude, and decay kinetics but target spatially segregated domains on the interneuron dendrites. These data demonstrate that certain interneuron subtypes are entrained by two convergent MF inputs to spatially separated regions of the dendritic tree. This anatomical arrangement could make these interneurons considerably more responsive to the excitatory drive from dentate granule cells. Furthermore, temporal summation is linear or slightly sublinear between PP and MFSL but supralinear between PP and MFSDG. This specific boosting of the excitatory drive to interneurons from the SDG location may indicate that L-M interneurons could be specifically involved in the processing of the associational component of the recognition memory. PMID:19830814

  20. Area CA3 interneurons receive two spatially segregated mossy fiber inputs.

    Science.gov (United States)

    Cosgrove, Kathleen E; Galván, Emilio J; Meriney, Stephen D; Barrionuevo, Germán

    2010-09-01

    Area CA3 receives two extrinsic excitatory inputs, the mossy fibers (MF), and the perforant path (PP). Interneurons with somata in str. lacunosum moleculare (L-M) of CA3 modulate the influence of the MF and PP on pyramidal cell activity by providing strong feed-forward inhibitory influence to pyramidal cells. Here we report that L-M interneurons receive two separate MF inputs, one to the dorsal dendrites from the suprapyramidal blade of the dentate gyrus (MF(SDG)), and a second to ventral dendrites from the str. lucidum (MF(SL)). Responses elicited from MF(SDG) and MF(SL) stimulation sites have strong paired-pulse facilitation, similar DCG-IV sensitivity, amplitude, and decay kinetics but target spatially segregated domains on the interneuron dendrites. These data demonstrate that certain interneuron subtypes are entrained by two convergent MF inputs to spatially separated regions of the dendritic tree. This anatomical arrangement could make these interneurons considerably more responsive to the excitatory drive from dentate granule cells. Furthermore, temporal summation is linear or slightly sublinear between PP and MF(SL) but supralinear between PP and MF(SDG). This specific boosting of the excitatory drive to interneurons from the SDG location may indicate that L-M interneurons could be specifically involved in the processing of the associational component of the recognition memory.

  1. Two networks of electrically coupled inhibitory neurons in neocortex

    Science.gov (United States)

    Gibson, Jay R.; Beierlein, Michael; Connors, Barry W.

    1999-11-01

    Inhibitory interneurons are critical to sensory transformations, plasticity and synchronous activity in the neocortex. There are many types of inhibitory neurons, but their synaptic organization is poorly understood. Here we describe two functionally distinct inhibitory networks comprising either fast-spiking (FS) or low-threshold spiking (LTS) neurons. Paired-cell recordings showed that inhibitory neurons of the same type were strongly interconnected by electrical synapses, but electrical synapses between different inhibitory cell types were rare. The electrical synapses were strong enough to synchronize spikes in coupled interneurons. Inhibitory chemical synapses were also common between FS cells, and between FS and LTS cells, but LTS cells rarely inhibited one another. Thalamocortical synapses, which convey sensory information to the cortex, specifically and strongly excited only the FS cell network. The electrical and chemical synaptic connections of different types of inhibitory neurons are specific, and may allow each inhibitory network to function independently.

  2. Comparison of numbers of interneurons in three thalamic nuclei of normal and epileptic rats.

    Science.gov (United States)

    Cavdar, Safiye; Bay, Hüsniye Hacioğlu; Yildiz, Sercan D; Akakin, Dilek; Sirvanci, Serap; Onat, Filiz

    2014-06-01

    The inhibitory sources in the thalamic nuclei are local interneurons and neurons of the thalamic reticular nucleus. Studies of models of absence epilepsy have shown that the seizures are associated with an excess of inhibitory neurotransmission in the thalamus. In the present study, we used light-microscopic gamma-aminobutyric acid (GABA) immunocytochemistry to quantify the interneurons in the lateral geniculate (LGN), ventral posteromedial (VPM), and ventral posterolateral (VPL) thalamic nuclei, and compared the values from normal Wistar rats and genetic absence epilepsy rats from Strasbourg (GAERS). We found that in both Wistar rats and GAERS, the proportion of interneurons was significantly higher in the LGN than in the VPM and VPL. In the LGN of Wistar rats, 16.4% of the neurons were interneurons and in the GAERS, the value was 15.1%. In the VPM, the proportion of interneurons was 4.2% in Wistar and 14.9% in GAERS; in the VPL the values were 3.7% for Wistar and 11.1% for the GAERS. There was no significant difference between Wistar rats and the GAERS regarding the counts of interneurons in the LGN, whereas the VPM and VPL showed significantly higher counts in GAERS. Comparison of the mean areas of both relay cells and interneuronal profiles showed no significant differences between Wistar rats and GAERS. These findings show that in the VPL and the VPM there are relatively more GABAergic interneurons in GAERS than in Wistar rats. This may represent a compensatory response of the thalamocortical circuitry to the absence seizures or may be related to the production of absence seizures.

  3. Properties of precise firing synchrony between synaptically coupled cortical interneurons depend on their mode of coupling.

    Science.gov (United States)

    Hu, Hang; Agmon, Ariel

    2015-07-01

    Precise spike synchrony has been widely reported in the central nervous system, but its functional role in encoding, processing, and transmitting information is yet unresolved. Of particular interest is firing synchrony between inhibitory cortical interneurons, thought to drive various cortical rhythms such as gamma oscillations, the hallmark of cognitive states. Precise synchrony can arise between two interneurons connected electrically, through gap junctions, chemically, through fast inhibitory synapses, or dually, through both types of connections, but the properties of synchrony generated by these different modes of connectivity have never been compared in the same data set. In the present study we recorded in vitro from 152 homotypic pairs of two major subtypes of mouse neocortical interneurons: parvalbumin-containing, fast-spiking (FS) interneurons and somatostatin-containing (SOM) interneurons. We tested firing synchrony when the two neurons were driven to fire by long, depolarizing current steps and used a novel synchrony index to quantify the strength of synchrony, its temporal precision, and its dependence on firing rate. We found that SOM-SOM synchrony, driven solely by electrical coupling, was less precise than FS-FS synchrony, driven by inhibitory or dual coupling. Unlike SOM-SOM synchrony, FS-FS synchrony was strongly firing rate dependent and was not evident at the prototypical 40-Hz gamma frequency. Computer simulations reproduced these differences in synchrony without assuming any differences in intrinsic properties, suggesting that the mode of coupling is more important than the interneuron subtype. Our results provide novel insights into the mechanisms and properties of interneuron synchrony and point out important caveats in current models of cortical oscillations.

  4. Local Integration Accounts for Weak Selectivity of Mouse Neocortical Parvalbumin Interneurons.

    Science.gov (United States)

    Scholl, Benjamin; Pattadkal, Jagruti J; Dilly, Geoffrey A; Priebe, Nicholas J; Zemelman, Boris V

    2015-07-15

    Dissecting the functional roles of excitatory and inhibitory neurons in cortical circuits is a fundamental goal in neuroscience. Of particular interest are their roles in emergent cortical computations such as binocular integration in primary visual cortex (V1). We measured the binocular response selectivity of genetically defined subpopulations of excitatory and inhibitory neurons. Parvalbumin (PV+) interneurons received strong inputs from both eyes but lacked selectivity for binocular disparity. Because broad selectivity could result from heterogeneous synaptic input from neighboring neurons, we examined how individual PV+ interneuron selectivity compared to that of the local neuronal network, which is primarily composed of excitatory neurons. PV+ neurons showed functional similarity to neighboring neuronal populations over spatial distances resembling measurements of synaptic connectivity. On the other hand, excitatory neurons expressing CaMKIIα displayed no such functional similarity with the neighboring population. Our findings suggest that broad selectivity of PV+ interneurons results from nonspecific integration within local networks. VIDEO ABSTRACT.

  5. Do premotor interneurons act in parallel on spinal motoneurons and on dorsal horn spinocerebellar and spinocervical tract neurons in the cat?

    Science.gov (United States)

    Krutki, Piotr; Jelen, Sabina; Jankowska, Elzbieta

    2011-04-01

    It has previously been established that ventral spinocerebellar tract (VSCT) neurons and dorsal spinocerebellar tract neurons located in Clarke's column (CC DSCT neurons) forward information on actions of premotor interneurons in reflex pathways from muscle afferents on α-motoneurons. Whether DSCT neurons located in the dorsal horn (dh DSCT neurons) and spinocervical tract (SCT) neurons are involved in forwarding similar feedback information has not yet been investigated. The aim of the present study was therefore to examine the input from premotor interneurons to these neurons. Electrical stimuli were applied within major hindlimb motor nuclei to activate axon-collaterals of interneurons projecting to these nuclei, and intracellular records were obtained from dh DSCT and SCT neurons. Direct actions of the stimulated interneurons were differentiated from indirect actions by latencies of postsynaptic potentials evoked by intraspinal stimuli and by the absence or presence of temporal facilitation. Direct actions of premotor interneurons were found in a smaller proportion of dh DSCT than of CC DSCT neurons. However, they were evoked by both excitatory and inhibitory interneurons, whereas only inhibitory premotor interneurons were previously found to affect CC DSCT neurons [as indicated by monosynaptic excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) in dh DSCT and only IPSPs in CC DSCT neurons]. No effects of premotor interneurons were found in SCT neurons, since monosynaptic EPSPs or IPSPs were only evoked in them by stimuli applied outside motor nuclei. The study thus reveals a considerable differentiation of feedback information provided by different populations of ascending tract neurons.

  6. Focal cortical lesions induce bidirectional changes in the excitability of fast spiking and non fast spiking cortical interneurons.

    Science.gov (United States)

    Imbrosci, Barbara; Neitz, Angela; Mittmann, Thomas

    2014-01-01

    A physiological brain function requires neuronal networks to operate within a well-defined range of activity. Indeed, alterations in neuronal excitability have been associated with several pathological conditions, ranging from epilepsy to neuropsychiatric disorders. Changes in inhibitory transmission are known to play a key role in the development of hyperexcitability. However it is largely unknown whether specific interneuronal subpopulations contribute differentially to such pathological condition. In the present study we investigated functional alterations of inhibitory interneurons embedded in a hyperexcitable cortical circuit at the border of chronically induced focal lesions in mouse visual cortex. Interestingly, we found opposite alterations in the excitability of non fast-spiking (Non Fs) and fast-spiking (Fs) interneurons in acute cortical slices from injured animals. Non Fs interneurons displayed a depolarized membrane potential and a higher frequency of spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, Fs interneurons showed a reduced sEPSCs amplitude. The observed downscaling of excitatory synapses targeting Fs interneurons may prevent the recruitment of this specific population of interneurons to the hyperexcitable network. This mechanism is likely to seriously affect neuronal network function and to exacerbate hyperexcitability but it may be important to protect this particular vulnerable population of GABAegic neurons from excitotoxicity.

  7. The LIM homeodomain protein Lhx6 regulates maturation of interneurons and network excitability in the mammalian cortex.

    Science.gov (United States)

    Neves, Guilherme; Shah, Mala M; Liodis, Petros; Achimastou, Angeliki; Denaxa, Myrto; Roalfe, Grant; Sesay, Abdul; Walker, Matthew C; Pachnis, Vassilis

    2013-08-01

    Deletion of LIM homeodomain transcription factor-encoding Lhx6 gene in mice results in defective tangential migration of cortical interneurons and failure of differentiation of the somatostatin (Sst)- and parvalbumin (Pva)-expressing subtypes. Here, we characterize a novel hypomorphic allele of Lhx6 and demonstrate that reduced activity of this locus leads to widespread differentiation defects in Sst(+) interneurons, but relatively minor and localized changes in Pva(+) interneurons. The reduction in the number of Sst-expressing cells was not associated with a loss of interneurons, because the migration and number of Lhx6-expressing interneurons and expression of characteristic molecular markers, such as calretinin or Neuropeptide Y, were not affected in Lhx6 hypomorphic mice. Consistent with a selective deficit in the differentiation of Sst(+) interneurons in the CA1 subfield of the hippocampus, we observed reduced expression of metabotropic Glutamate Receptor 1 in the stratum oriens and characteristic changes in dendritic inhibition, but normal inhibitory input onto the somatic compartment of CA1 pyramidal cells. Moreover, Lhx6 hypomorphs show behavioral, histological, and electroencephalographic signs of recurrent seizure activity, starting from early adulthood. These results demonstrate that Lhx6 plays an important role in the maturation of cortical interneurons and the formation of inhibitory circuits in the mammalian cortex.

  8. 大鼠杏仁体基底外侧核中小白蛋白反应阳性神经元受抑制性神经网络支配%PARVALBUMIN-IMMUNOREACTIVE INTERNEURONS ARE CONTROLLED BY AN INHIBITORY NEURONAL NETWORK IN BASOLATERAL NUCLEUS OF THE RAT AMYGDALA

    Institute of Scientific and Technical Information of China (English)

    李瑞锡; 彭裕文; 大谷 修; 西条 寿夫; 王劼; 丁忠良; 高璐; 沈馨亚

    2004-01-01

    As the elements of local neuronal circuits, parvalbumin (PV)-containing interneurons in the basolateral nucleus (BL) of the amygdala play an important role in the amygdaloid functions of emotion, learning and memory. In order to investigate how the PV-containing interneurons in the BL are controlled, the synapses established on PV- containing interneurons in the BL of the rat amygdala were examined under immunoelectron microscopy using the double labeling methods with anti-PV and anti-dopamine (DA) antibodies for a reference of dopaminergic axon terminals. The results show that the PV immunoreactive (IR) neurons formed the synapses mainly on the dendritic structures from shafts of the dendrites to median and small dendritic branches. 68% of the synapses on the PV-IR profiles were formed by unlabeled axon terminals, and 32 % of them were formed by DA- (21 % ) and PV- (11 % )IR axon terminals. Majority of the synapses on the PV-IR neurons formed by unlabeled axon terminals were symmetric type, and only a small a mount of them were asymmetric that were observed between the PV-IR spines and unlabeled axon terminals and in the serial synapses in which an unlabeled axon terminal symmetrically contacted to another unlabeled axon terminal that, in turn, synapsed asymmetrically to the PV-IR dendritic profiles. The synapses formed between the PV-IR profiles and DA- or PV-IR axon terminals were exclusively symmetric. The present results suggest that the PV-containing interneurons in the BL of the rat amygdala were controlled by an inhibitory network formed by the symmetric synapses around them, among which the DA system was included.%小白蛋白(PV)神经元作为杏仁核簇基底外侧核(BL)中局部神经环路成分,对杏仁核的情绪、学习和记忆过程等机能发挥重要作用.为探讨BL中PV中间神经元的突触形成状态,本研究用抗PV抗体标示PV神经元,以抗多巴胺(DA)抗体标示多巴胺能轴突及末梢作为传入纤维的标志,对

  9. Differential Susceptibility of Interneurons Expressing Neuropeptide Y or Parvalbumin in the Aged Hippocampus to Acute Seizure Activity

    OpenAIRE

    Ramkumar Kuruba; Bharathi Hattiangady; Vipan K Parihar; Bing Shuai; Shetty, Ashok K.

    2011-01-01

    Acute seizure (AS) activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE). Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide ...

  10. TwoB or not twoB: differential transmission at glutamatergic mossy fiber-interneuron synapses in the hippocampus.

    Science.gov (United States)

    Bischofberger, Josef; Jonas, Peter

    2002-12-01

    Mossy fiber (MF) synapses are key stations for flow of information through the hippocampal formation. A major component of the output of the MF system is directed towards inhibitory interneurons. Recent studies have revealed that the functional properties of MF-interneuron synapses differ substantially from those of MF-CA3 pyramidal neuron synapses. Mossy-fiber-interneuron synapses in the stratum lucidum represent a continuum of functional subtypes, in which the subunit composition of postsynaptic AMPA receptors and NMDA receptors appears to be regulated in a coordinated manner.

  11. Degeneration and regeneration of GABAergic interneurons in the dentate gyrus of adult mice in experimental models of epilepsy.

    Science.gov (United States)

    Wei, Dong; Yang, Fang; Wang, Ying; Yang, Feng; Wu, Chen; Wu, Sheng-Xi; Jiang, Wen

    2015-01-01

    Mounting evidence showed that GABAergic interneurons play an important role in the generation of seizures by regulating excitatory/inhibitory balance in the hippocampus; however, there is a continuous debate regarding the alteration in the number of hippocampal GABAergic interneurons during epileptogenesis. Here, we investigated the degeneration and regeneration of GABAergic interneurons in the dentate gyrus during epileptogenesis using glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mice. Pentylenetetrazol (PTZ)-induced chronic kindling model and lithium-pilocarpine-induced status epilepticus (SE) model were used in this study. We found a progressive loss of GABAergic interneurons in the dentate gyrus during post-SE epileptogenesis rather than PTZ kindling. Both types of epileptogenic insults significantly promoted the proliferation of neural progenitor cells in the dentate gyrus; however, compared to 80% neuronal differentiation ratio in the control group, there was a remarkable decrease in PTZ kindling and pilocarpine models, that is 58% and 29%, respectively. Double/triple immunofluorescence labeling revealed no newborn neurons colabeled with GFP in both intact and epileptic dentate gyrus. In addition, valproate (a first-line antiepileptic drug) treatment prevented the loss of GABAergic interneurons but still failed to induce the regeneration of GAD67-positive interneurons in the dentate gyrus during post-SE epileptogenesis. These results indicate that degeneration of GABAergic interneurons may depend on the type of epileptogenic insult and that no newborn GABAergic interneurons occur in the adult dentate gyrus during epileptogenesis. © 2014 John Wiley & Sons Ltd.

  12. EphA/ephrin A reverse signaling promotes the migration of cortical interneurons from the medial ganglionic eminence.

    Science.gov (United States)

    Steinecke, André; Gampe, Christin; Zimmer, Geraldine; Rudolph, Judith; Bolz, Jürgen

    2014-01-01

    Inhibitory interneurons control the flow of information and synchronization in the cerebral cortex at the circuit level. During embryonic development, multiple subtypes of cortical interneurons are generated in different regions of the ventral telencephalon, such as the medial and caudal ganglionic eminence (MGE and CGE), as well as the preoptic area (POA). These neurons then migrate over long distances towards their cortical target areas. Diverse families of diffusible and cell-bound signaling molecules, including the Eph/ephrin system, regulate and orchestrate interneuron migration. Ephrin A3 and A5, for instance, are expressed at the borders of the pathway of MGE-derived interneurons and prevent these cells from entering inappropriate regions via EphA4 forward signaling. We found that MGE-derived interneurons, in addition to EphA4, also express ephrin A and B ligands, suggesting Eph/ephrin forward and reverse signaling in the same cell. In vitro and in vivo approaches showed that EphA4-induced reverse signaling in MGE-derived interneurons promotes their migration and that this effect is mediated by ephrin A2 ligands. In EphA4 mutant mice, as well as after ephrin A2 knockdown using in utero electroporation, we found delayed interneuron migration at embryonic stages. Thus, besides functions in guiding MGE-derived interneurons to the cortex through forward signaling, here we describe a novel role of the ephrins in driving these neurons to their target via reverse signaling.

  13. Selective activation of parvalbumin- or somatostatin-expressing interneurons triggers epileptic seizurelike activity in mouse medial entorhinal cortex.

    Science.gov (United States)

    Yekhlef, Latefa; Breschi, Gian Luca; Lagostena, Laura; Russo, Giovanni; Taverna, Stefano

    2015-03-01

    GABAergic interneurons are thought to play a critical role in eliciting interictal spikes (IICs) and triggering ictal discharges in temporal lobe epilepsy, yet the contribution of different interneuronal subtypes to seizure initiation is still largely unknown. Here we took advantage of optogenetic techniques combined with patch-clamp and field recordings to selectively stimulate parvalbumin (PV)- or somatostatin (SOM)-positive interneurons expressing channelrhodopsin-2 (CHR-2) in layers II-III of adult mouse medial entorhinal cortical slices during extracellular perfusion with the proconvulsive compound 4-aminopyridine (4-AP, 100-200 μM). In control conditions, blue laser photostimulation selectively activated action potential firing in either PV or SOM interneurons and, in both cases, caused a robust GABAA-receptor-mediated inhibition in pyramidal cells (PCs). During perfusion with 4-AP, brief photostimuli (300 ms) activating either PV or SOM interneurons induced patterns of epileptiform activity that closely replicated spontaneously occurring IICs and tonic-clonic ictal discharges. Laser-induced synchronous firing in both interneuronal types elicited large compound GABAergic inhibitory postsynaptic currents (IPSCs) correlating with IICs and preictal spikes. In addition, spontaneous and laser-induced epileptic events were similarly initiated in concurrence with a large increase in extracellular potassium concentration. Finally, interneuron activation was unable to stop or significantly shorten the progression of seizurelike episodes. These results suggest that entorhinal PV and SOM interneurons are nearly equally effective in triggering interictal and ictal discharges that closely resemble human temporal lobe epileptic activity.

  14. Metalloproteinase inhibition prevents inhibitory synapse reorganization and seizure genesis.

    Science.gov (United States)

    Pollock, Emily; Everest, Michelle; Brown, Arthur; Poulter, Michael O

    2014-10-01

    The integrity and stability of interneurons in a cortical network are essential for proper network function. Loss of interneuron synaptic stability and precise organization can lead to disruptions in the excitation/inhibition balance, a characteristic of epilepsy. This study aimed to identify alterations to the GABAergic interneuron network in the piriform cortex (PC: a cortical area believed to be involved in the development of seizures) after kindling-induced seizures. Immunohistochemistry was used to mark perineuronal nets (PNNs: structures in the extracellular matrix that provide synaptic stability and restrict reorganization of inhibitory interneurons) and interneuron nerve terminals in control and kindled tissues. We found that PNNs were significantly decreased around parvalbumin-positive interneurons after the induction of experimental epilepsy. Additionally, we found layer-specific increases in GABA release sites originating from calbindin, calretinin, and parvalbumin interneurons, implying that there is a re-wiring of the interneuronal network. This increase in release sites was matched by an increase in GABAergic post-synaptic densities. We hypothesized that the breakdown of the PNN could be due to the activity of matrix metalloproteinases (MMP) and that the prevention of PNN breakdown may reduce the rewiring of interneuronal circuits and suppress seizures. To test this hypothesis we employed doxycycline, a broad spectrum MMP inhibitor, to stabilize PNNs in kindled rats. We found that doxycycline prevented PNN breakdown, re-organization of the inhibitory innervation, and seizure genesis. Our observations indicate that PNN degradation may be necessary for the development of seizures by facilitating interneuron plasticity and increased GABAergic activity.

  15. Parvalbumin-expressing interneurons linearly control olfactory bulb output.

    Science.gov (United States)

    Kato, Hiroyuki K; Gillet, Shea N; Peters, Andrew J; Isaacson, Jeffry S; Komiyama, Takaki

    2013-12-04

    In the olfactory bulb, odor representations by principal mitral cells are modulated by local inhibitory circuits. While dendrodendritic synapses between mitral and granule cells are typically thought to be a major source of this modulation, the contributions of other inhibitory neurons remain unclear. Here we demonstrate the functional properties of olfactory bulb parvalbumin-expressing interneurons (PV cells) and identify their important role in odor coding. Using paired recordings, we find that PV cells form reciprocal connections with the majority of nearby mitral cells, in contrast to the sparse connectivity between mitral and granule cells. In vivo calcium imaging in awake mice reveals that PV cells are broadly tuned to odors. Furthermore, selective PV cell inactivation enhances mitral cell responses in a linear fashion while maintaining mitral cell odor preferences. Thus, dense connections between mitral and PV cells underlie an inhibitory circuit poised to modulate the gain of olfactory bulb output.

  16. Assortment of GABAergic plasticity in the cortical interneuron melting pot.

    Science.gov (United States)

    Méndez, Pablo; Bacci, Alberto

    2011-01-01

    Cortical structures of the adult mammalian brain are characterized by a spectacular diversity of inhibitory interneurons, which use GABA as neurotransmitter. GABAergic neurotransmission is fundamental for integrating and filtering incoming information and dictating postsynaptic neuronal spike timing, therefore providing a tight temporal code used by each neuron, or ensemble of neurons, to perform sophisticated computational operations. However, the heterogeneity of cortical GABAergic cells is associated to equally diverse properties governing intrinsic excitability as well as strength, dynamic range, spatial extent, anatomical localization, and molecular components of inhibitory synaptic connections that they form with pyramidal neurons. Recent studies showed that similarly to their excitatory (glutamatergic) counterparts, also inhibitory synapses can undergo activity-dependent changes in their strength. Here, some aspects related to plasticity and modulation of adult cortical and hippocampal GABAergic synaptic transmission will be reviewed, aiming at providing a fresh perspective towards the elucidation of the role played by specific cellular elements of cortical microcircuits during both physiological and pathological operations.

  17. Developmental programming of cortial interneurons

    NARCIS (Netherlands)

    Welagen, J.

    2011-01-01

    AIM OF THE STUDY: The majority of interneurons originate from the MGE, including PV, SST and NPY expressing subgroups. Although the MGE has been defined as the region of origin for these subgroups, three important questions are still open. First, it was unclear if a spatial or temporal distribution

  18. Postnatal Migration of Cerebellar Interneurons

    Science.gov (United States)

    Galas, Ludovic; Bénard, Magalie; Lebon, Alexis; Komuro, Yutaro; Schapman, Damien; Vaudry, Hubert; Vaudry, David; Komuro, Hitoshi

    2017-01-01

    Due to its continuing development after birth, the cerebellum represents a unique model for studying the postnatal orchestration of interneuron migration. The combination of fluorescent labeling and ex/in vivo imaging revealed a cellular highway network within cerebellar cortical layers (the external granular layer, the molecular layer, the Purkinje cell layer, and the internal granular layer). During the first two postnatal weeks, saltatory movements, transient stop phases, cell-cell interaction/contact, and degradation of the extracellular matrix mark out the route of cerebellar interneurons, notably granule cells and basket/stellate cells, to their final location. In addition, cortical-layer specific regulatory factors such as neuropeptides (pituitary adenylate cyclase-activating polypeptide (PACAP), somatostatin) or proteins (tissue-type plasminogen activator (tPA), insulin growth factor-1 (IGF-1)) have been shown to inhibit or stimulate the migratory process of interneurons. These factors show further complexity because somatostatin, PACAP, or tPA have opposite or no effect on interneuron migration depending on which layer or cell type they act upon. External factors originating from environmental conditions (light stimuli, pollutants), nutrients or drug of abuse (alcohol) also alter normal cell migration, leading to cerebellar disorders. PMID:28587295

  19. Involvement of pre- and postsynaptic NMDA receptors at local circuit interneuron connections in rat neocortex.

    Science.gov (United States)

    De-May, C L; Ali, A B

    2013-01-03

    To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings - combined with biocytin labelling - were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II-V of rat (postnatal days 17-22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appeared to coincide with the interneuron subclass; upon depolarisation, EPSPs received by multipolar non-adapting interneurons either decreased in amplitude or appeared insensitive, multipolar adapting interneuron EPSP amplitudes increased or appeared insensitive, whereas bitufted interneuron EPSP amplitudes increased or decreased. Connections were challenged with the NMDA receptor antagonist d-(-)-2-amino-5-phosphonopentanoic acid (d-AP5) (50μM) revealing NMDA receptors to contribute to EPSPs received by all cell types, this also abolished the non-conventional voltage dependency. Reciprocal connections were frequent between pyramidal cells and multipolar interneurons, and inhibitory postsynaptic potentials (IPSPs) elicited in pyramidal cells by both multipolar adapting and multipolar non-adapting interneurons were sensitive to a significant reduction in amplitude by d-AP5. The involvement of presynaptic NMDA receptors was indicated by coefficient of variation analysis and an increase in the failures of transmission. Furthermore, by loading MK-801 into the pre- or postsynaptic neurons, we observed that a reduction in inhibition requires presynaptic and not postsynaptic NMDA receptors. These results suggest that NMDA receptors possess pre- and postsynaptic roles at selective neocortical synapses that are probably important in governing spike-timing and information flow.

  20. Local dynamics of gap-junction-coupled interneuron networks

    Science.gov (United States)

    Lau, Troy; Gage, Gregory J.; Berke, Joshua D.; Zochowski, Michal

    2010-03-01

    Interneurons coupled by both electrical gap-junctions (GJs) and chemical GABAergic synapses are major components of forebrain networks. However, their contributions to the generation of specific activity patterns, and their overall contributions to network function, remain poorly understood. Here we demonstrate, using computational methods, that the topological properties of interneuron networks can elicit a wide range of activity dynamics, and either prevent or permit local pattern formation. We systematically varied the topology of GJ and inhibitory chemical synapses within simulated networks, by changing connection types from local to random, and changing the total number of connections. As previously observed we found that randomly coupled GJs lead to globally synchronous activity. In contrast, we found that local GJ connectivity may govern the formation of highly spatially heterogeneous activity states. These states are inherently temporally unstable when the input is uniformly random, but can rapidly stabilize when the network detects correlations or asymmetries in the inputs. We show a correspondence between this feature of network activity and experimental observations of transient stabilization of striatal fast-spiking interneurons (FSIs), in electrophysiological recordings from rats performing a simple decision-making task. We suggest that local GJ coupling enables an active search-and-select function of striatal FSIs, which contributes to the overall role of cortical-basal ganglia circuits in decision-making.

  1. A role for L-type calcium channels in the maturation of parvalbumin-containing hippocampal interneurons.

    Science.gov (United States)

    Jiang, M; Swann, J W

    2005-01-01

    While inhibitory interneurons are well recognized to play critical roles in the brain, relatively little is know about the molecular events that regulate their growth and differentiation. Calcium ions are thought to be important in neuronal development and L-type voltage gated Ca(+2) channels have been implicated in activity-dependent mechanisms of early-life. However, few studies have examined the role of these channels in the maturation of interneurons. The studies reported here were conducted in hippocampal slice cultures and indicate that the L-type Ca(+2) channel agonists and antagonists accelerate and suppress respectively the growth of parvalbumin-containing interneurons. The effects of channel blockade were reversible suggesting they are not the result of interneuronal cell death. Results from immunoblotting showed that these drugs have similar effects on the expression of the GABA synthetic enzymes, glutamic acid decarboxylase65, glutamic acid decarboxylase67 and the vesicular GABA transporter. This suggests that L-type Ca(+2) channels regulate not only parvalbumin expression but also interneuron development. These effects are likely mediated by actions on the interneurons themselves since the alpha subunits of L-type channels, voltage-gated calcium channel subunit 1.2 and voltage-gated calcium channel subunit 1.3 were found to be highly expressed in neonatal mouse hippocampus and co-localized with parvalbumin in interneurons. Results also showed that while these interneurons can contain either subunit, voltage-gated calcium channel subunit 1.3 was more widely expressed. Taken together results suggest that an important subset of developing interneurons expresses L-type Ca(+2) channels alpha subunits, voltage-gated calcium channel subunit 1.2 and especially voltage-gated calcium channel subunit 1.3 and that these channels likely regulate the development of these interneurons in an activity-dependent manner.

  2. Area CA3 interneurons receive two spatially segregated mossy fiber inputs

    OpenAIRE

    Cosgrove, Kathleen E.; Galvan, Emilio J.; Meriney, Stephen D.; Barrionuevo, German

    2010-01-01

    Area CA3 receives two extrinsic excitatory inputs, the mossy fibers (MF) and the perforant path (PP). Interneurons with somata in str. lacunosum moleculare (L-M) of CA3 modulate the influence of the MF and PP on pyramidal cell activity by providing strong feed-forward inhibitory influence to pyramidal cells. Here we report that L-M interneurons receive two separate MF inputs, one to the dorsal dendrites from the suprapyramidal blade of the dentate gyrus (MFSDG), and a second to ventral dendri...

  3. Nootropic dipeptide noopept enhances inhibitory synaptic transmission in the hippocampus.

    Science.gov (United States)

    Povarov, I S; Kondratenko, R V; Derevyagin, V I; Ostrovskaya, R U; Skrebitskii, V G

    2015-01-01

    Application of nootropic agent Noopept on hippocampal slices from Wistar rats enhanced the inhibitory component of total current induced by stimulation of Shaffer collaterals in CA1 pyramidal neurons, but did not affect the excitatory component. A direct correlation between the increase in the amplitude of inhibitory current and agent concentration was found. The substance did not affect the release of inhibitory transmitters from terminals in the pyramidal neurons, which indicated changes in GABAergic interneurons.

  4. Heterogeneity and Diversity of Striatal GABAergic Interneurons

    OpenAIRE

    Tepper, James M.; Fatuel eTecuapetla; Tibor eKoos; Osvaldo eIbanez-Sandoval

    2010-01-01

    The canonical view of striatal GABAergic interneurons has evolved over several decades of neuroanatomical/neurochemical and electrophysiological studies. From the anatomical studies, three distinct GABAergic interneuronal subtypes are generally recognized. The best-studied subtype expresses the calcium-binding protein, parvalbumin. The second best known interneuron type expresses a number of neuropeptides and enzymes, including neuropeptide Y, somatostatin, and nitric oxide synthase. The last...

  5. Layer-specific processing of excitatory signals in CA1 interneurons depends on postsynaptic M₂ muscarinic receptors.

    Science.gov (United States)

    Zheng, Fang; Seeger, Thomas; Nixdorf-Bergweiler, Barbara E; Alzheimer, Christian

    2011-05-02

    The hippocampus receives a diffuse cholinergic innervation which acts on pre- and postsynaptic sites to modulate neurotransmission and excitability of pyramidal cells and interneurons in an intricate fashion. As one missing piece in this puzzle, we explored how muscarinic receptor activation modulates the somatodendritic processing of glutamatergic input in CA1 interneurons. We performed whole-cell recordings from visually identified interneurons of stratum radiatum (SR) and stratum oriens (SO) and examined the effects of the cholinergic agonist carbachol (CCh) on EPSP-like waveforms evoked by brief glutamate pulses onto their proximal dendrites. In SO interneurons, CCh consistently reduced glutamate-induced postsynaptic potentials (GPSPs) in control rat and mice, but not in M₂ muscarinic receptor knockout mice. By contrast, the overwhelming majority of interneurons recorded in SR of control and M₂ receptor-deficient hippocampi exhibited muscarinic enhancement of GPSPs. Interestingly, the non-responding interneurons were strictly confined to the SR subfield closest to the subiculum. Our data suggest that postsynaptic modulation by acetylcholine of excitatory input onto CA1 interneurons occurs in a stratum-specific fashion, which is determined by the absence or presence of M₂ receptors in their (somato-)dendritic compartments. Thus cholinergic projections might be capable of recalibrating synaptic weights in different inhibitory circuits of the CA1 region.

  6. Glutamic acid decarboxylase-67-positive hippocampal interneurons undergo a permanent reduction in number following kainic acid-induced degeneration of ca3 pyramidal neurons.

    Science.gov (United States)

    Shetty, A K; Turner, D A

    2001-06-01

    Kainic acid (KA)-induced degeneration of CA3 pyramidal neurons leads to synaptic reorganization and hyperexcitability in both dentate gyrus and CA1 region of the hippocampus. We hypothesize that the substrate for hippocampal inhibitory circuitry incurs significant and permanent alterations following degeneration of CA3 pyramidal neurons. We quantified changes in interneuron density (N(v)) in all strata of the dentate gyrus and the CA1 and CA3 subfields of adult rats at 1, 4, and 6 months following intracerebroventricular (icv) KA administration, using glutamic acid decarboxylase-67 (GAD-67) immunocytochemistry. At 1 month postlesion, GAD-67-positive interneuron density was significantly reduced in all strata of every hippocampal region except stratum pyramidale of CA1. The reduction in GAD-67-positive interneuron density either persisted or exacerbated at 4 and 6 months postlesion in every stratum of all hippocampal regions. Further, the soma of remaining GAD-67-positive interneurons in dentate gyrus and CA3 subfield showed significant hypertrophy. Thus, both permanent reductions in the density of GAD-67-positive interneurons in all hippocampal regions and somatic hypertrophy of remaining GAD-67-positive interneurons in dentate gyrus and CA3 subfield occur following icv KA. In contrast, the density of interneurons visualized with Nissl in CA1 and CA3 regions was nearly equivalent to that in the intact hippocampus at all postlesion time points. Collectively, these results suggest that persistent reductions in GAD-67-positive interneuron density observed throughout the hippocampus following CA3 lesion are largely due to a permanent loss of GAD-67 expression in a significant fraction of interneurons, rather than widespread degeneration of interneurons. Nevertheless, a persistent decrease in interneuron activity, as evidenced by permanent down-regulation of GAD-67 in a major fraction of interneurons, would likely enhance the degree of hyperexcitability in the CA3

  7. Extended Interneuronal Network of the Dentate Gyrus

    Directory of Open Access Journals (Sweden)

    Gergely G. Szabo

    2017-08-01

    Full Text Available Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network.

  8. Caudal Ganglionic Eminence Precursor Transplants Disperse and Integrate as Lineage-Specific Interneurons but Do Not Induce Cortical Plasticity

    Directory of Open Access Journals (Sweden)

    Phillip Larimer

    2016-08-01

    Full Text Available The maturation of inhibitory GABAergic cortical circuits regulates experience-dependent plasticity. We recently showed that the heterochronic transplantation of parvalbumin (PV or somatostatin (SST interneurons from the medial ganglionic eminence (MGE reactivates ocular dominance plasticity (ODP in the postnatal mouse visual cortex. Might other types of interneurons similarly induce cortical plasticity? Here, we establish that caudal ganglionic eminence (CGE-derived interneurons, when transplanted into the visual cortex of neonatal mice, migrate extensively in the host brain and acquire laminar distribution, marker expression, electrophysiological properties, and visual response properties like those of host CGE interneurons. Although transplants from the anatomical CGE do induce ODP, we found that this plasticity reactivation is mediated by a small fraction of MGE-derived cells contained in the transplant. These findings demonstrate that transplanted CGE cells can successfully engraft into the postnatal mouse brain and confirm the unique role of MGE lineage neurons in the induction of ODP.

  9. Impaired synaptic plasticity in the prefrontal cortex of mice with developmentally decreased number of interneurons.

    Science.gov (United States)

    Konstantoudaki, X; Chalkiadaki, K; Tivodar, S; Karagogeos, D; Sidiropoulou, K

    2016-05-13

    Interneurons are inhibitory neurons, which protect neural tissue from excessive excitation. They are interconnected with glutamatergic pyramidal neurons in the cerebral cortex and regulate their function. Particularly in the prefrontal cortex (PFC), interneurons have been strongly implicated in regulating pathological states which display deficits in the PFC. The aim of this study is to investigate the adaptations in the adult glutamatergic system, when defects in interneuron development do not allow adequate numbers of interneurons to reach the cerebral cortex. To this end, we used a mouse model that displays ~50% fewer cortical interneurons due to the Rac1 protein loss from Nkx2.1/Cre expressing cells (Rac1 conditional knockout (cKO) mice), to examine how the developmental loss of interneurons may affect basal synaptic transmission, synaptic plasticity and neuronal morphology in the adult PFC. Despite the decrease in the number of interneurons, basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks, is not altered in the PFC of Rac1 cKO mice. However, there is decreased paired-pulse ratio (PPR) and decreased long-term potentiation (LTP), in response to tetanic stimulation, in the layer II PFC synapses of Rac1 cKO mice. Furthermore, expression of N-methyl-d-aspartate (NMDA) subunits is decreased and dendritic morphology is altered, changes that could underlie the decrease in LTP in the Rac1 cKO mice. Finally, we find that treating Rac1 cKO mice with diazepam in early postnatal life can reverse changes in dendritic morphology observed in non-treated Rac1 cKO mice. Therefore, our data show that disruption in GABAergic inhibition alters glutamatergic function in the adult PFC, an effect that could be reversed by enhancement of GABAergic function during an early postnatal period.

  10. Medial septal and median raphe innervation of vasoactive intestinal polypeptide-containing interneurons in the hippocampus.

    Science.gov (United States)

    Papp, E C; Hajos, N; Acsády, L; Freund, T F

    1999-05-01

    Vasoactive intestinal polypeptide-immunoreactive interneurons are known to form three anatomically and neurochemically well-characterized neuron populations in the hippocampus. Two of these establish synaptic contacts selectively with other GABAergic cells (interneuron-selective cells), whereas the third type innervates pyramidal cell bodies and proximal dendrites like a conventional basket cell. Our aim was to examine which of the vasoactive intestinal polypeptide-containing interneuron populations are among the targets of GABAergic septohippocampal and serotonergic raphe-hippocampal pathways. Anterograde tracing with Phaseolus vulgaris leucoagglutinin combined with double immunocytochemistry for vasoactive intestinal polypeptide was used at the light and electron microscopic levels. Our results show that both interneuron-selective cells and vasoactive intestinal polypeptide-containing basket cells receive synaptic input from the medial septum and median raphe nucleus. The GABAergic component of the septohippocampal pathway establishes multiple contacts on both cell types. In the case of the raphe-hippocampal projection, single or double contacts were more frequent on vasoactive intestinal polypeptide-positive interneuron selective cells (76%), whereas multiple contacts predominated on basket cells (83%). The extrinsic GABAergic innervation of interneuron-selective cells in the hippocampus indicates a complex interaction among GABAergic systems, which might ensure the timing and rhythmic synchronization of inhibitory processes in the hippocampus. On the other hand, our results suggest that the serotonergic effect on perisomatic inhibition is exerted via vasoactive intestinal polypeptide-containing basket cells that are functionally distinct from their parvalbumin-positive relatives, which appear to escape control of serotonergic as well as local interneuron-selective cells.

  11. Efficient specification of interneurons from human pluripotent stem cells by dorsoventral and rostrocaudal modulation.

    Science.gov (United States)

    Kim, Tae-Gon; Yao, Ruiqin; Monnell, Travis; Cho, Jun-Hyeong; Vasudevan, Anju; Koh, Alice; Peeyush, Kumar T; Moon, Minho; Datta, Debkanya; Bolshakov, Vadim Y; Kim, Kwang-Soo; Chung, Sangmi

    2014-07-01

    GABAergic interneurons regulate cortical neural networks by providing inhibitory inputs, and their malfunction, resulting in failure to intricately regulate neural circuit balance, is implicated in brain diseases such as Schizophrenia, Autism, and Epilepsy. During early development, GABAergic interneuron progenitors arise from the ventral telencephalic area such as medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) by the actions of secreted signaling molecules from nearby organizers, and migrate to their target sites where they form local synaptic connections. In this study, using combinatorial and temporal modulation of developmentally relevant dorsoventral and rostrocaudal signaling pathways (SHH, Wnt, and FGF8), we efficiently generated MGE cells from multiple human pluripotent stem cells. Most importantly, modulation of FGF8/FGF19 signaling efficiently directed MGE versus CGE differentiation. Human MGE cells spontaneously differentiated into Lhx6-expressing GABAergic interneurons and showed migratory properties. These human MGE-derived neurons generated GABA, fired action potentials, and displayed robust GABAergic postsynaptic activity. Transplantation into rodent brains results in well-contained neural grafts enriched with GABAergic interneurons that migrate in the host and mature to express somatostatin or parvalbumin. Thus, we propose that signaling modulation recapitulating normal developmental patterns efficiently generate human GABAergic interneurons. This strategy represents a novel tool in regenerative medicine, developmental studies, disease modeling, bioassay, and drug screening.

  12. Maturation-Promoting Activity of SATB1 in MGE-Derived Cortical Interneurons

    Directory of Open Access Journals (Sweden)

    Myrto Denaxa

    2012-11-01

    Full Text Available The generation of cortical interneuron subtypes is controlled by genetic programs that are activated in the ventral forebrain and unfold during the prolonged period of inhibitory neuron development. The LIM-homeodomain protein LHX6 is critical for the development of all cortical interneurons originating in the medial ganglionic eminence, but the molecular mechanisms that operate downstream of LHX6 to control the terminal differentiation of somatostatin- and parvalbumin-expressing interneurons within the cortex remain unknown. Here, we provide evidence that the nuclear matrix and genome organizer protein SATB1 is induced by neuronal activity and functions downstream of Lhx6 to control the transition of tangentially migrating immature interneurons into the terminally differentiated Somatostatin (SST-expressing subtype. Our experiments provide a molecular framework for understanding the genetic and epigenetic mechanisms by which specified but immature cortical interneurons acquire the subtype-defining molecular and morphophysiological characteristics that allow them to integrate and function within cortical circuits.

  13. Subgroups of parvalbumin-expressing interneurons in layers 2/3 of the visual cortex.

    Science.gov (United States)

    Helm, Jessica; Akgul, Gulcan; Wollmuth, Lonnie P

    2013-03-01

    The input, processing, and output characteristics of inhibitory interneurons help shape information flow through layers 2/3 of the visual cortex. Parvalbumin (PV)-positive interneurons modulate and synchronize the gain and dynamic responsiveness of pyramidal neurons. To define the diversity of PV interneurons in layers 2/3 of the developing visual cortex, we characterized their passive and active membrane properties. Using Ward's and k-means multidimensional clustering, we identified four PV interneuron subgroups. The most notable difference between the subgroups was their firing patterns in response to moderate stimuli just above rheobase. Two subgroups showed regular and continuous firing at all stimulus intensities above rheobase. The difference between these two continuously firing subgroups was that one fired at much higher frequencies and transitioned into this high-frequency firing rate at or near rheobase. The two other subgroups showed irregular, stuttering firing patterns just above rheobase. Both of these subgroups typically transitioned to regular and continuous firing at intense stimulations, but one of these subgroups, the strongly stuttering subgroup, showed irregular firing across a wider range of stimulus intensities and firing frequencies. The four subgroups also differed in excitatory synaptic input, providing independent support for the classification of subgroups. The subgroups of PV interneurons identified here would respond differently to inputs of varying intensity and frequency, generating diverse patterns of PV inhibition in the developing neural circuit.

  14. A persistent sodium current contributes to oscillatory activity in heart interneurons of the medicinal leech.

    Science.gov (United States)

    Opdyke, C A; Calabrese, R L

    1994-12-01

    1. Normal activity in bilateral pairs of heart interneurons, from ganglia 3 or 4, in the medicinal leech (Hirudo medicinalis) is antiphasic due to their reciprocally inhibitory connections. However, Ca(++)-free Co(++)-containing salines lead to synchronous oscillations in these neurons. 2. Internal TEA+ allows expression of full plateaus during Co++ induced oscillations in heart interneurons; these plateaus are not blocked by Cs+. Similar plateaus are also observed with internal TEA+ alone, but under these conditions activity in heart interneurons from ganglia 3 or 4 is antiphasic. 3. Plateaus in heart interneurons induced by Co++ and internal TEA+ involve a conductance increase. 4. A voltage-dependent inward current, IP, showing little inactivation, was isolated using single-electrode voltage-clamp in heart interneurons. This current is carried at least in part by Na+; the current is reduced when external Na+ is reduced and is carried by Li++ when substituted for Na+. 5. Calcium channel blockers such as La3+ and Co++ block neither the TEA+ induced plateaus nor IP, suggesting that Na+ is not using Ca++ channels. Moreover, IP is enhanced by Ca(++)-free CO(++)-containing salines. Thus, IP is correlated with the TEA(+)- and Co(++)-induced plateau behavior.

  15. Roller Coaster Scanning reveals spontaneous triggering of dendritic spikes in CA1 interneurons.

    Science.gov (United States)

    Katona, Gergely; Kaszás, Attila; Turi, Gergely F; Hájos, Norbert; Tamás, Gábor; Vizi, E Sylvester; Rózsa, Balázs

    2011-02-01

    Inhibitory interneurons are considered to be the controlling units of neural networks, despite their sparse number and unique morphological characteristics compared with excitatory pyramidal cells. Although pyramidal cell dendrites have been shown to display local regenerative events--dendritic spikes (dSpikes)--evoked by artificially patterned stimulation of synaptic inputs, no such studies exist for interneurons or for spontaneous events. In addition, imaging techniques have yet to attain the required spatial and temporal resolution for the detection of spontaneously occurring events that trigger dSpikes. Here we describe a high-resolution 3D two-photon laser scanning method (Roller Coaster Scanning) capable of imaging long dendritic segments resolving individual spines and inputs with a temporal resolution of a few milliseconds. By using this technique, we found that local, NMDA receptor-dependent dSpikes can be observed in hippocampal CA1 stratum radiatum interneurons during spontaneous network activities in vitro. These NMDA spikes appear when approximately 10 spatially clustered inputs arrive synchronously and trigger supralinear integration in dynamic interaction zones. In contrast to the one-to-one relationship between computational subunits and dendritic branches described in pyramidal cells, here we show that interneurons have relatively small (∼14 μm) sliding interaction zones. Our data suggest a unique principle as to how interneurons integrate synaptic information by local dSpikes.

  16. The parvalbumin-positive interneurons in the mouse dentate gyrus express GABAA receptor subunits α1, β2, and δ along their extrasynaptic cell membrane.

    Science.gov (United States)

    Milenkovic, I; Vasiljevic, M; Maurer, D; Höger, H; Klausberger, T; Sieghart, W

    2013-12-19

    Neuronal circuitries in the hippocampus are involved in navigation and memory and are controlled by major networks of GABAergic interneurons. Parvalbumin (PV)-expressing interneurons in the dentate gyrus (DG) are identified as fast-spiking cells, playing a crucial role in network oscillation and synchrony. The inhibitory modulation of these interneurons is thought to be mediated mainly through GABAA receptors, the major inhibitory neurotransmitter receptors in the brain. Here we show that all PV-positive interneurons in the granular/subgranular layer (GL/SGL) of the mouse DG express high levels of the GABAA receptor δ subunit. PV-containing interneurons in the hilus and the molecular layer, however, express the δ subunit to a lower extent. Only 8% of the somatostatin-containing interneurons express the δ subunit, whereas calbindin- or calretinin-containing interneurons in the DG seem not to express the GABAA receptor δ subunit at all. Hence, these cells receive a GABAergic control different from that of PV-containing interneurons in the GL/SGL. Experiments investigating a possible co-expression of GABAA receptor α1, α2, α3, α4, α5, β1, β2, β3, or γ2 subunits with PV and δ subunits indicated that α1 and β2 subunits are co-expressed with δ subunits along the extrasynaptic membranes of PV-interneurons. These results suggest a robust tonic GABAergic control of PV-containing interneurons in the GL/SGL of the DG via δ subunit-containing receptors. Our data are important for better understanding of the neuronal circuitries in the DG and the role of specific cell types under pathological conditions.

  17. AMPA receptor modulators have different impact on hippocampal pyramidal cells and interneurons.

    Science.gov (United States)

    Xia, Y-F; Arai, A C

    2005-01-01

    Positive modulators of AMPA receptors enhance synaptic plasticity and memory encoding. Facilitation of AMPA receptor currents not only results in enhanced activation of excitatory neurons but also increases the activity of inhibitory interneurons by up-modulating their excitatory input. However, little is known about the effects of these modulators on cells other than pyramidal neurons and about their impact on local microcircuits. This study examined the effects of members from three subfamilies of modulators (mainly CX516, CX546 and cyclothiazide) on excitatory synaptic responses in four classes of hippocampal CA1 neurons and on excitatory and disynaptically induced inhibitory field potentials in hippocampal slices. Effects on excitatory postsynaptic currents (EPSCs) were examined in pyramidal cells, in two types of inhibitory interneurons located in stratum radiatum and oriens, and in stratum radiatum giant cells, a novel type of excitatory neuron. With CX516, increases in EPSC amplitude in pyramidal cells were two to three times larger than in interneurons and six times larger than in radiatum giant cells. The effects of CX546 on response duration similarly were largest in pyramidal cells. However, this drug also strongly differentiated between stratum oriens and radiatum interneurons with increases being four times larger in the latter. In contrast, cyclothiazide had similar effects on response duration in all cell types. In field recordings, CX516 was several times more potent in enhancing excitatory postsynaptic potentials (EPSPs) than feedback or feedforward circuits, as expected from its larger influence on pyramidal cells. In contrast, BDP-20, a CX546 analog, was more potent in enhancing feedforward inhibition than either EPSPs or feedback inhibition. This preference for feedforward over feedback circuits is probably related to its higher potency in stratum radiatum versus oriens interneurons. Taken together, AMPA receptor modulators differ substantially

  18. HDAC1 negatively regulates Bdnf and Pvalb required for parvalbumin interneuron maturation in an experience-dependent manner.

    Science.gov (United States)

    Koh, Dawn X P; Sng, Judy C G

    2016-11-01

    During early postnatal development, neuronal circuits are sculpted by sensory experience provided by the external environment. This experience-dependent regulation of circuitry development consolidates the balance of excitatory-inhibitory (E/I) neurons in the brain. The cortical barrel-column that innervates a single principal whisker is used to provide a clear reference frame for studying the consolidation of E/I circuitry. Sensory deprivation of S1 at birth disrupts the consolidation of excitatory-inhibitory balance by decreasing inhibitory transmission of parvalbumin interneurons. The molecular mechanisms underlying this decrease in inhibition are not completely understood. Our findings show that epigenetic mechanisms, in particular histone deacetylation by histone deacetylases, negatively regulate the expression of brain-derived neurotrophic factor (Bdnf) and parvalbumin (Pvalb) genes during development, which are required for the maturation of parvalbumin interneurons. After whisker deprivation, increased histone deacetylase 1 expression and activity led to increased histone deacetylase 1 binding and decreased histone acetylation at Bdnf promoters I-IV and Pvalb promoter, resulting in the repression of Bdnf and Pvalb gene transcription. The decrease in Bdnf expression further affected parvalbumin interneuron maturation at layer II/III in S1, demonstrated by decreased parvalbumin expression, a marker for parvalbumin interneuron maturation. Knockdown of HDAC1 recovered Bdnf and Pvalb gene transcription and also prevented the decrease of inhibitory synapses accompanying whisker deprivation.

  19. MODULATING EXCITATION THROUGH PLASTICITY AT INHIBITORY SYNAPSES

    Directory of Open Access Journals (Sweden)

    Vivien eChevaleyre

    2014-03-01

    Full Text Available Learning is believed to depend on lasting changes in synaptic efficacy such as long-term potentiation and long-term depression. As a result, a profusion of studies has tried to elucidate the mechanisms underlying these forms of plasticity. Traditionally, experience-dependent changes at excitatory synapses were assumed to underlie learning and memory formation. However, with the relatively more recent investigation of inhibitory transmission, it had become evident that inhibitory synapses are not only plastic, but also provide an additional way to modulate excitatory transmission and the induction of plasticity at excitatory synapses.Thanks to recent technological advances, progress has been made in understanding synaptic transmission and plasticity from particular interneuron subtypes. In this review article, we will describe various forms of synaptic plasticity that have been ascribed to two fairly well characterized populations of interneurons in the hippocampus, those expressing cholecystokinin (CCK and parvalbumin (PV. We will discuss the resulting changes in the strength and plasticity of excitatory transmission that occur in the local circuit as a result of the modulation of inhibitory transmission. We will focus on the hippocampus because this region has a relatively well-understood circuitry, numerous forms of activity-dependent plasticity and a multitude of identified interneuron subclasses.

  20. Identification of common interneurons mediating pre- and postsynaptic inhibition in the cat spinal cord.

    Science.gov (United States)

    Solodkin, M; Jiménez, I; Rudomin, P

    1984-06-29

    The spike-triggered averaging of dorsal and ventral root potentials permits the identification of two populations of interneurons in the intermediate nucleus of the cat spinal cord. One produced negative dorsal root potentials and inhibitory ventral root potentials, in some cases with monosynaptic latencies, suggesting that they mediate presynaptic inhibition of group I afferent fibers from muscles and postsynaptic inhibition of motoneurons. The other population mediated only nonreciprocal postsynaptic inhibition of motoneurons.

  1. Multiple forms of long-term synaptic plasticity at hippocampal mossy fiber synapses onto interneurons

    OpenAIRE

    Galván, Emilio J; Cosgrove, Kathleen E.; Barrionuevo, Germán

    2010-01-01

    The hippocampal mossy fiber (MF) pathway originates from the dentate gyrus granule cells and provides a powerful excitatory synaptic drive to neurons in the dentate gyrus hilus and area CA3. Much of the early work on the MF pathway focused on its electrophysiological properties, and ability to drive CA3 pyramidal cell activity. Over the last ten years, however, a new focus on the synaptic interaction between granule cells with inhibitory interneurons has emerged. These data have revealed an i...

  2. Bidirectional Hebbian Plasticity at Hippocampal Mossy Fiber Synapses on CA3 Interneurons

    OpenAIRE

    Galván, Emilio J; Calixto, Eduardo; Barrionuevo, Germán

    2008-01-01

    Hippocampal area CA3 is critically involved in the formation of non-overlapping neuronal subpopulations (“pattern separation”) to store memory representations as distinct events. Efficient pattern separation relies on the strong and sparse excitatory input from the mossy fibers (MF) to pyramidal cells and feed-forward inhibitory interneurons. However, MF synapses on CA3 pyramidal cells undergo LTP, which, if unopposed, will degrade pattern separation as MF activation will now recruit addition...

  3. Trajectory of the main GABAergic interneuron populations from early development to old age in the rat primary auditory cortex

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    Lydia eOuellet

    2014-06-01

    Full Text Available In both humans and rodents, decline in cognitive function is a hallmark of the aging process, the basis for this decrease has yet to be fully characterized. However, using aged rodent models, deficits in auditory processing have been associated with significant decreases in inhibitory signaling attributed to a loss of GABAergic interneurons. Not only are these interneurons crucial for pattern detection and other large-scale population dynamics, but they have also been linked to mechanisms mediating plasticity and learning, making them a prime candidate for study and modelling of modifications to cortical communication pathways in neurodegenerative diseases. Using the rat primary auditory cortex (A1 as a model, we probed the known markers of GABAergic interneurons with immunohistological methods, using antibodies against gamma aminobutyric acid (GABA, parvalbumin (PV, somatostatin (SOM, calretinin (CR, vasoactive intestinal peptide (VIP, choline acetyltransferase (ChAT, neuropeptide Y (NPY and cholecystokinin (CCK to document the changes observed in interneuron populations across the rat’s lifespan. This analysis provided strong evidence that several but not all GABAergic neurons were affected by the aging process, showing most dramatic changes in expression of parvalbumin (PV and somatostatin (SOM expression. With this evidence, we show how understanding these trajectories of cell counts may be factored into a simple model to quantify changes in inhibitory signalling across the course of life, which may be applied as a framework for creating more advanced simulations of interneuronal implication in normal cerebral processing, normal aging, or pathological processes.

  4. Interneurons set the tune of developing networks.

    Science.gov (United States)

    Ben-Ari, Yehezkel; Khalilov, Ilgam; Represa, Alfonso; Gozlan, Henri

    2004-07-01

    Despite a rather long migratory journey, interneurons are functional before vertically migrating pyramidal neurons and they constitute the source and target of the first functional synapses in the developing hippocampus. Interneuron-driven network patterns are already present in utero while principal cells are mostly quiescent. At that early stage, GABAergic synapses--which are formed before glutamatergic ones--are excitatory, suggesting that GABA is a pioneer, much like the neurons from which it is released. This review discusses this sequence of events, its functional significance and the role that interneurons might play in the construction of cortical networks.

  5. Characterizing the persistent CA3 interneuronal spiking activity in elevated extracellular potassium in the young rat hippocampus.

    Science.gov (United States)

    Shin, Damian Seung-Ho; Yu, Wilson; Fawcett, Adrian; Carlen, Peter Louis

    2010-05-17

    Seizures coincide with an increase in extracellular potassium concentrations [K(+)](e) yet little information is available regarding this phenomenon on the firing pattern, frequency and neuronal properties of inhibitory neurons responsible for modulating network excitability. Therefore, we investigated the effects of elevating [K(+)](e) from 2.5 to 12.5mM on CA3 rat hippocampal interneurons in vitro using whole-cell patch-clamp recordings. We found that the majority of interneurons (21/25) in artificial cerebral spinal fluid (aCSF) exhibited spontaneous tonic spiking activity. As the [K(+)](e) increased to 12.5mM, interneurons exhibited a tonic, irregular, burst firing activity, or a combination of these. The input resistance decreased significantly to 59+/-18% at 7.5mM K(+) and did not further change at higher [K(+)](e) while the amount of K(+)-induced depolarization significantly increased from 5 to 12.5mM K(+) perfusion; a depolarization block occurred in 4 of the 12 interneurons at 12.5mM. Also, as [K(+)](e) increased, a transition from lower (1.3+/-0.6Hz) to higher dominant peak frequency (15.0+/-5.0Hz) was observed. We found that non-fast spiking (NFS) interneurons represented the majority of cells recorded and exhibited mostly tonic firing activity in raised K(+). Fast spiking (FS) interneurons predominately had a tonic firing pattern with very few exhibiting bursting activity in elevated K(+). In conclusion, we report that raised [K(+)](e) in amounts observed during seizures increases hippocampal CA3 interneuronal activity and suggests that a loss or impairment of inhibitory function may be present during these events.

  6. Changes in cortical interneuron migration contribute to the evolution of the neocortex.

    Science.gov (United States)

    Tanaka, Daisuke H; Oiwa, Ryo; Sasaki, Erika; Nakajima, Kazunori

    2011-05-10

    The establishment of the mammalian neocortex is often explained phylogenetically by an evolutionary change in the pallial neuronal progenitors of excitatory projection neurons. It remains unclear, however, whether and how the evolutionary change in inhibitory interneurons, which originate outside the neocortex, has been involved in the establishment of the neocortex. In this study, we transplanted chicken, turtle, mouse, and marmoset medial ganglionic eminence (MGE) cells into the embryonic mouse MGE in utero and compared their migratory behaviors. We found that the MGE cells from all of the species were able to migrate through the mouse neocortical subventricular zone and that both the mouse and marmoset cells subsequently invaded the neocortical cortical plate (CP). However, regardless of their birthdates and interneuron subtypes, most of the chicken and turtle cells ignored the neocortical CP and passed beneath it, although they were able to invade the archicortex and paleocortex, suggesting that the proper responsiveness of MGE cells to guidance cues to enter the neocortical CP is unique to mammals. When chicken MGE cells were transplanted directly into the neocortical CP, they were able to survive and mature, suggesting that the neocortical CP itself is essentially permissive for postmigratory development of chicken MGE cells. These results suggest that an evolutionary change in the migratory ability of inhibitory interneurons, which originate outside the neocortex, was involved in the establishment of the neocortex by supplying inhibitory components to the network.

  7. Colocalization of allatotropin and tachykinin-related peptides with classical transmitters in physiologically distinct subtypes of olfactory local interneurons in the cockroach (Periplaneta americana).

    Science.gov (United States)

    Fusca, Debora; Schachtner, Joachim; Kloppenburg, Peter

    2015-07-01

    In the insect antennal lobe different types of local interneurons mediate complex excitatory and inhibitory interactions between the glomerular pathways to structure the spatiotemporal representation of odors. Mass spectrometric and immunohistochemical studies have shown that in local interneurons classical neurotransmitters are likely to colocalize with a variety of substances that can potentially act as cotransmitters or neuromodulators. In the antennal lobe of the cockroach Periplaneta americana, gamma-aminobutyric acid (GABA) has been identified as the potential inhibitory transmitter of spiking type I local interneurons, whereas acetylcholine is most likely the excitatory transmitter of nonspiking type IIa1 local interneurons. This study used whole-cell patch clamp recordings combined with single-cell labeling and immunohistochemistry to test if the GABAergic type I local interneurons and the cholinergic type IIa1 local interneurons express allatotropin and tachykinin-related neuropeptides (TKRPs). These are two of the most abundant types of peptides in the insect antennal lobe. GABA-like and choline acetyltransferase (ChAT)-like immunoreactivity were used as markers for GABAergic and cholinergic neurons, respectively. About 50% of the GABA-like immunoreactive (-lir) spiking type I local interneurons were allatotropin-lir, and ∼ 40% of these neurons were TKRP-lir. About 20% of nonspiking ChAT-lir type IIa1 local interneurons were TKRP-lir. Our results suggest that in subpopulations of GABAergic and cholinergic local interneurons, allatotropin and TKRPs might act as cotransmitters or neuromodulators. To unequivocally assign neurotransmitters, cotransmitters, and neuromodulators to identified classes of antennal lobe neurons is an important step to deepen our understanding of information processing in the insect olfactory system.

  8. Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome.

    Science.gov (United States)

    Tai, Chao; Abe, Yasuyuki; Westenbroek, Ruth E; Scheuer, Todd; Catterall, William A

    2014-07-29

    Haploinsufficiency of the voltage-gated sodium channel NaV1.1 causes Dravet syndrome, an intractable developmental epilepsy syndrome with seizure onset in the first year of life. Specific heterozygous deletion of NaV1.1 in forebrain GABAergic-inhibitory neurons is sufficient to cause all the manifestations of Dravet syndrome in mice, but the physiological roles of specific subtypes of GABAergic interneurons in the cerebral cortex in this disease are unknown. Voltage-clamp studies of dissociated interneurons from cerebral cortex did not detect a significant effect of the Dravet syndrome mutation on sodium currents in cell bodies. However, current-clamp recordings of intact interneurons in layer V of neocortical slices from mice with haploinsufficiency in the gene encoding the NaV1.1 sodium channel, Scn1a, revealed substantial reduction of excitability in fast-spiking, parvalbumin-expressing interneurons and somatostatin-expressing interneurons. The threshold and rheobase for action potential generation were increased, the frequency of action potentials within trains was decreased, and action-potential firing within trains failed more frequently. Furthermore, the deficit in excitability of somatostatin-expressing interneurons caused significant reduction in frequency-dependent disynaptic inhibition between neighboring layer V pyramidal neurons mediated by somatostatin-expressing Martinotti cells, which would lead to substantial disinhibition of the output of cortical circuits. In contrast to these deficits in interneurons, pyramidal cells showed no differences in excitability. These results reveal that the two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin-expressing, both have impaired excitability, resulting in disinhibition of the cortical network. These major functional deficits are likely to contribute synergistically to the pathophysiology of Dravet syndrome.

  9. Differential susceptibility of interneurons expressing neuropeptide Y or parvalbumin in the aged hippocampus to acute seizure activity.

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    Ramkumar Kuruba

    Full Text Available Acute seizure (AS activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE. Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY or the calcium binding protein parvalbumin (PV between young adult (5-months old and aged (22-months old F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity.

  10. Differential susceptibility of interneurons expressing neuropeptide Y or parvalbumin in the aged hippocampus to acute seizure activity.

    Science.gov (United States)

    Kuruba, Ramkumar; Hattiangady, Bharathi; Parihar, Vipan K; Shuai, Bing; Shetty, Ashok K

    2011-01-01

    Acute seizure (AS) activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE). Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY) or the calcium binding protein parvalbumin (PV) between young adult (5-months old) and aged (22-months old) F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA) induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity.

  11. Paradoxical proepileptic response to NMDA receptor blockade linked to cortical interneuron defect in stargazer mice

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    Atul eMaheshwari

    2013-09-01

    Full Text Available Paradoxical seizure exacerbation by antiepileptic medication is a well-known clinical phenomenon in epilepsy, but the cellular mechanisms remain unclear. One possibility is enhanced network disinhibition by unintended suppression of inhibitory interneurons. We investigated this hypothesis in the stargazer mouse model of absence epilepsy, which bears a mutation in stargazin, an AMPA receptor trafficking protein. If AMPA signaling onto inhibitory GABAergic neurons is impaired, their activation by glutamate depends critically upon NMDA receptors. Indeed, we find that stargazer seizures are exacerbated by NMDA receptor blockade with CPP and MK-801, whereas other genetic absence epilepsy models are sensitive to these antagonists. To determine how an AMPA receptor trafficking defect could lead to paradoxical network activation, we analyzed stargazin and AMPA receptor localization and found that stargazin is detected exclusively in parvalbumin-positive (PV+ fast-spiking interneurons in somatosensory cortex, where it is co-expressed with the AMPA receptor subunit GluA4. PV+ cortical interneurons in stargazer show a near two-fold decrease in the dendrite:soma GluA4 expression ratio compared to wild type littermates. We explored the functional consequence of this trafficking defect on network excitability in neocortical slices. Both NMDA receptor antagonists suppressed 0 Mg2+ induced network discharges in wild type but augmented bursting in stargazer cortex. Interneurons mediate this paradoxical response, since the difference between genotypes was masked by GABA receptor blockade. Our findings provide a cellular locus for AMPA receptor-dependent signaling defects in stargazer cortex and define an interneuron-dependent mechanism for paradoxical seizure exacerbation in absence epilepsy.

  12. Novel nootropic dipeptide Noopept increases inhibitory synaptic transmission in CA1 pyramidal cells.

    Science.gov (United States)

    Kondratenko, Rodion V; Derevyagin, Vladimir I; Skrebitsky, Vladimir G

    2010-05-31

    Effects of newly synthesized nootropic and anxiolytic dipeptide Noopept on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) significantly increased the frequency of spike-dependant spontaneous IPSCs whereas spike-independent mIPSCs remained unchanged. It was suggested that Noopept mediates its effect due to the activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion.

  13. Interneurons set the tune of developing networks.

    OpenAIRE

    Ben-Ari, Yehezkel; Khalilov, Ilgam; Represa, Alfonso; Gozlan, Henri

    2004-01-01

    International audience; Despite a rather long migratory journey, interneurons are functional before vertically migrating pyramidal neurons and they constitute the source and target of the first functional synapses in the developing hippocampus. Interneuron-driven network patterns are already present in utero while principal cells are mostly quiescent. At that early stage, GABAergic synapses--which are formed before glutamatergic ones--are excitatory, suggesting that GABA is a pioneer, much li...

  14. Fear Erasure Facilitated by Immature Inhibitory Neuron Transplantation.

    Science.gov (United States)

    Yang, Wu-Zhou; Liu, Ting-Ting; Cao, Jun-Wei; Chen, Xuan-Fu; Liu, Xiao; Wang, Min; Su, Xin; Zhang, Shu-Qing; Qiu, Bin-Long; Hu, Wen-Xiang; Liu, Lin-Yun; Ma, Lan; Yu, Yong-Chun

    2016-12-21

    Transplantation of embryonic γ-aminobutyric acid (GABA)ergic neurons has been shown to modify disease phenotypes in rodent models of neurologic and psychiatric disorders. However, whether transplanted interneurons modulate fear memory remains largely unclear. Here, we report that transplantation of embryonic interneurons into the amygdala does not alter host fear memory formation. Yet approximately 2 weeks after transplantation, but not earlier or later, extinction training produces a marked reduction in spontaneous recovery and renewal of fear response. Further analyses reveal that transplanted interneurons robustly form functional synapses with neurons of the host amygdala and exhibit similar developmental maturation in electrophysiological properties as native amygdala interneurons. Importantly, transplanted immature interneurons reduce the expression of perineuronal nets, promote long-term synaptic plasticity, and modulate both excitatory and inhibitory synaptic transmissions of the host circuits. Our findings demonstrate that transplanted immature interneurons modify amygdala circuitry and suggest a previously unknown strategy for the prevention of extinction-resistant pathological fear. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Altered distribution of hippocampal interneurons in the murine Down Syndrome model Ts65Dn.

    Science.gov (United States)

    Hernández-González, Samuel; Ballestín, Raúl; López-Hidalgo, Rosa; Gilabert-Juan, Javier; Blasco-Ibáñez, José Miguel; Crespo, Carlos; Nácher, Juan; Varea, Emilio

    2015-01-01

    Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration producing intellectual disability. We have used the Ts65Dn model, that mimics some of the alterations observed in Down Syndrome. This genetic alteration induces an imbalance between excitation and inhibition that has been suggested as responsible for the cognitive impairment present in this syndrome. The hippocampus has a crucial role in memory processing and is an important area to analyze this imbalance. In this report we have analysed, in the hippocampus of Ts65Dn mice, the expression of synaptic markers: synaptophysin, vesicular glutamate transporter-1 and isoform 67 of the glutamic acid decarboxylase; and of different subtypes of inhibitory neurons (Calbindin D-28k, parvalbumin, calretinin, NPY, CCK, VIP and somatostatin). We have observed alterations in the inhibitory neuropil in the hippocampus of Ts65Dn mice. There was an excess of inhibitory puncta and a reduction of the excitatory ones. In agreement with this observation, we have observed an increase in the number of inhibitory neurons in CA1 and CA3, mainly interneurons expressing calbindin, calretinin, NPY and VIP, whereas parvalbumin cell numbers were not affected. These alterations in the number of interneurons, but especially the alterations in the proportion of the different types, may influence the normal function of inhibitory circuits and underlie the cognitive deficits observed in DS.

  16. Soft-diet feeding impairs neural transmission between mitral cells and interneurons in the mouse olfactory bulb.

    Science.gov (United States)

    Noguchi, Tomohiro; Utsugi, Chizuru; Kashiwayanagi, Makoto

    2017-07-29

    (Objective) The subventricular zone in mice generates a lot of neuroblasts even during adulthood. These neuroblasts migrate to the olfactory bulb and differentiate into inhibitory interneurons such as granule cells and periglomerular cells. Olfactory sensory neurons receive information from various odorants and transmit it to the olfactory bulb. Our previous study showed that soft-diet feeding impairs neurogenesis in the subventricular zone, in turn leading to the reduction of odor-induced behaviors and Fos-immunoreactivities, the latter of which are markers of neural activity, at the olfactory bulb after exposure to odors. Release of GABA from inhibitory interneurons at the olfactory bulb induces inhibitory currents at the mitral cells, which are output neurons from the olfactory bulb. (Design) In the present study, we measured spontaneous inhibitory postsynaptic currents (sIPSCs) at the mitral cells of mice fed a soft diet in order to explore the effects of changes in texture of diets on neural function at the olfactory bulb. (Results) The soft-diet feeding extended the intervals between sIPSCs and reduced their peak amplitudes. (Conclusions) The present results suggest that soft-diet feeding in mice attenuates the neural functions of inhibitory interneurons at the olfactory bulb. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Unitary inhibitory field potentials in the CA3 region of rat hippocampus.

    Science.gov (United States)

    Bazelot, Michaël; Dinocourt, Céline; Cohen, Ivan; Miles, Richard

    2010-06-15

    Glickfeld and colleagues (2009) suggested that single hippocampal interneurones generate field potentials at monosynaptic latencies. We pursued this observation in simultaneous intracellular and multiple extracellular records from the CA3 region of rat hippocampal slices. We confirmed that interneurones evoked field potentials at monosynaptic latencies. Pyramidal cells initiated disynaptic inhibitory field potentials, but did not initiate detectable monosynaptic excitatory fields. We confirmed that inhibitory fields were GABAergic in nature and showed they were suppressed at low external Cl(-), suggesting they originate at postsynaptic sites. Field potentials generated by a single interneuron were detected at multiple sites over distances of more than 800 mum along the stratum pyramidale of the CA3 region. We used arrays of extracellular electrodes to examine amplitude distributions of spontaneous inhibitory fields recorded at sites orthogonal to or along the CA3 stratum pyramidale. Cluster analysis of spatially distributed inhibitory field events let us separate events generated by interneurones terminating on distinct zones of somato-dendritic axis. Events generated at dendritic sites had similar amplitudes but occurred less frequently and had somewhat slower kinetics than perisomatic events generated near the stratum pyramidale. In records from multiple sites in the CA3 stratum pyramidale, we distinguished inhibitory fields that seemed to be initiated by interneurones with spatially distinct axonal arborisations.

  18. Streptozotocin diabetic mice display depressive-like behavior and alterations in the structure, neurotransmission and plasticity of medial prefrontal cortex interneurons.

    Science.gov (United States)

    Castillo-Gómez, Esther; Coviello, Simona; Perez-Rando, Marta; Curto, Yasmina; Carceller, Héctor; Salvador, Alicia; Nacher, Juan

    2015-07-01

    Diabetes mellitus patients are at increased risk of developing depression, although the neurobiological bases of this comorbidity are not yet fully understood. These patients show CNS alterations, similar to those found in major depression, including changes in the structure and neurotransmission of excitatory neurons. However, although depressive patients and animal models also display alterations in inhibitory networks, little is known about the effects of diabetes on interneurons. Our main objective was to study the impact of diabetes on interneurons of the medial prefrontal cortex (mPFC), one of the regions most affected by major depression. For this purpose we have induced diabetes with high-dose streptozotozin in transgenic mice displaying fluorescent interneurons. These animals showed a depressive-like behavior (increased immobility time in tail suspension test) in parallel with reductions in interneuronal dendritic arborization and in the expression of GAD67, the enzyme that synthetizes the inhibitory neurotransmitter GABA. However, the levels of PSA-NCAM, a plasticity-related molecule exclusively expressed by interneurons in the mPFC, were unaltered in the different regions and layers of this cortical area. Interestingly, diabetic mice also showed increased levels of synaptophysin, a synaptic vesicle protein. These results indicate that the structure and neurotransmission of interneurons is altered in the mPFC of diabetic mice and suggest that these changes may play a key role in the depressive symptoms associated to diabetes.

  19. Plasticity in Single Axon Glutamatergic Connection to GABAergic Interneurons Regulates Complex Events in the Human Neocortex.

    Science.gov (United States)

    Szegedi, Viktor; Paizs, Melinda; Csakvari, Eszter; Molnar, Gabor; Barzo, Pal; Tamas, Gabor; Lamsa, Karri

    2016-11-01

    In the human neocortex, single excitatory pyramidal cells can elicit very large glutamatergic EPSPs (VLEs) in inhibitory GABAergic interneurons capable of triggering their firing with short (3-5 ms) delay. Similar strong excitatory connections between two individual neurons have not been found in nonhuman cortices, suggesting that these synapses are specific to human interneurons. The VLEs are crucial for generating neocortical complex events, observed as single pyramidal cell spike-evoked discharge of cell assemblies in the frontal and temporal cortices. However, long-term plasticity of the VLE connections and how the plasticity modulates neocortical complex events has not been studied. Using triple and dual whole-cell recordings from synaptically connected human neocortical layers 2-3 neurons, we show that VLEs in fast-spiking GABAergic interneurons exhibit robust activity-induced long-term depression (LTD). The LTD by single pyramidal cell 40 Hz spike bursts is specific to connections with VLEs, requires group I metabotropic glutamate receptors, and has a presynaptic mechanism. The LTD of VLE connections alters suprathreshold activation of interneurons in the complex events suppressing the discharge of fast-spiking GABAergic cells. The VLEs triggering the complex events may contribute to cognitive processes in the human neocortex, and their long-term plasticity can alter the discharging cortical cell assemblies by learning.

  20. VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons

    Science.gov (United States)

    Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Barker, David J.; Miranda-Barrientos, Jorge; Morales, Marisela

    2016-01-01

    The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens-glutamatergic pathway remains unknown. Here, we report that nAcc photoactivation of mesoaccumbens-glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens-glutamate-fibers lack GABA, the aversion evoked by their photoactivation depends on glutamate and GABA receptor signaling, and not on dopamine receptor signaling. We found that mesoaccumbens-glutamatergic-fibers establish multiple asymmetric synapses on single parvalbumin-GABAergic interneurons, and that nAcc photoactivation of these fibers drives AMPA-mediated cellular firing of parvalbumin-GABAergic interneurons. These parvalbumin-GABAergic-interneurons, in turn, inhibit nAcc medium spiny output neurons, as such, controlling inhibitory neurotransmission within nAcc. The mesoaccumbens-glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion, instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin-GABAergic interneurons. PMID:27019014

  1. Loss of calbindin-immunoreactivity in CA1 hippocampal stratum radiatum and stratum lacunosum-moleculare interneurons in the aged rat.

    Science.gov (United States)

    Potier, B; Krzywkowski, P; Lamour, Y; Dutar, P

    1994-10-24

    Alterations in hippocampal circuitry may underly age-related learning and memory impairment. We showed in a previous study that the GABAB-mediated slow inhibitory postsynaptic potential (IPSP) induced in CA1 pyramidal neurons by electrical stimulation of stratum radiatum, is depressed in the hippocampus of the aged rat. This could be due to alterations in GABAergic interneuron functions. We report in this study that the number of hippocampal calbindin-immunoreactive (CaBP-IR) GABAergic interneurons is decreased in the aged rat. The mean number of CaBP-IR interneurons per slice decreases by 50% in the aged rat. The most severe loss was observed in the stratum radiatum of CA1 (78%), with a less consistent loss of immunoreactivity in CA3 (35%). In contrast, the mean number of interneurons containing parvalbumin (PV), was not significantly decreased in the aged rat. Our results show a loss of CaBP immunoreactivity in a population of GABAergic interneurons, which might be related to an altered function of these interneurons and consequently of GABAergic synaptic transmission in the aged rat. In contrast, PV immunoreactivity in interneurons located close to the pyramidal layer does not decrease in the hippocampus of the aged rat.

  2. Are striatal tyrosine hydroxylase interneurons dopaminergic?

    Science.gov (United States)

    Xenias, Harry S; Ibáñez-Sandoval, Osvaldo; Koós, Tibor; Tepper, James M

    2015-04-22

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH-Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)-TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP-TH interneurons. Optogenetic activation of striatal EGFP-TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons.

  3. Control of neuronal excitability by calcium binding proteins : a new mathematical model for striatal fast-spiking interneurons.

    Directory of Open Access Journals (Sweden)

    Don Patrick eBischop

    2012-07-01

    Full Text Available Calcium binding proteins, such as parvalbumin, are abundantly expressed in very distinctive patterns in the central nervous system but their physiological function remains poorly understood. Notably, at the level of the striatum, parvalbumin is only expressed in the fast spiking (FS interneurons, which form a inhibitory network modulating the output of the striatum by synchronizing medium-sized spiny neurons (MSN. So far the existing conductance-based computational models for FS neurons did not allow the study of the the coupling between parvalbumin concentration and electrical activity. In the present paper, we propose a new mathematical model for the striatal FS interneurons that includes apamin-sensitive small conductance ca -dependent kk channels (SK and takes into account the presence of a calcium buffer. Our results demonstrate that a variation in the concentration of parvalbumin can modulate substantially the intrinsic excitability of the FS interneurons and therefore may be involved in the information processing at the striatal level.

  4. Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1G93A mouse model of ALS

    Science.gov (United States)

    Clark, Rosemary M.; Blizzard, Catherine A.; Young, Kaylene M.; King, Anna E.; Dickson, Tracey C.

    2017-01-01

    Increasing evidence indicates an excitatory/inhibitory imbalance may have a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Impaired inhibitory circuitry is consistently reported in the motor cortex of both familial and sporadic patients, closely associated with cortical hyperexcitability and ALS onset. Inhibitory network dysfunction is presumably mediated by intra-cortical inhibitory interneurons, however, the exact cell types responsible are yet to be identified. In this study we demonstrate dynamic changes in the number of calretinin- (CR) and neuropeptide Y-expressing (NPY) interneurons in the motor cortex of the familial hSOD1G93A ALS mouse model, suggesting their potential involvement in motor neuron circuitry defects. We show that the density of NPY-populations is significantly decreased by ~17% at symptom onset (8 weeks), and by end-stage disease (20 weeks) is significantly increased by ~30%. Conversely, the density of CR-populations is progressively reduced during later symptomatic stages (~31%) to end-stage (~36%), while CR-expressing interneurons also show alteration of neurite branching patterns at symptom onset. We conclude that a differential capacity for interneurons exists in the ALS motor cortex, which may not be a static phenomenon, but involves early dynamic changes throughout disease, implicating specific inhibitory circuitry. PMID:28294153

  5. Excitation-Transcription Coupling in Parvalbumin-Positive Interneurons Employs a Novel CaM Kinase-Dependent Pathway Distinct from Excitatory Neurons.

    Science.gov (United States)

    Cohen, Samuel M; Ma, Huan; Kuchibhotla, Kishore V; Watson, Brendon O; Buzsáki, György; Froemke, Robert C; Tsien, Richard W

    2016-04-20

    Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity, and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. We report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca(2+) influx through CaV1 channels triggers CaM nuclear translocation via local Ca(2+) signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca(2+) transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and they are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease.

  6. Elevated Expression of Acid-Sensing Ion Channel 3 Inhibits Epilepsy via Activation of Interneurons.

    Science.gov (United States)

    Cao, Qingqing; Wang, Wei; Gu, Juan; Jiang, Guohui; Bian, Xiling; Wang, Kewei; Xu, Zucai; Li, Jie; Chen, Guojun; Wang, Xuefeng

    2016-01-01

    Recent studies have indicated that acid-sensing ion channels may play a significant role in the termination of epilepsy. In particular, acid-sensing ion channel 3 (ASIC3) is expressed in the central nervous system and is most sensitive to extracellular pH. However, whether ASIC3 plays a role in epilepsy is unknown. In this study, qRT-PCR, Western blot, immunohistochemistry, double immunofluorescence labeling, and slice recordings were used. We first detected elevated ASIC3 expression patterns in the brains of temporal lobe epilepsy patients and epileptic rats. ASIC3 was expressed in neurons and glia in both humans and in an experimental model of epilepsy, and ASIC3 was colocalized with inhibitory GABAergic interneurons. By blocking ASIC3 with its antagonist APETx2, we observed that injected APETx2 shortened the latency to seizure and increased the incidence of generalized tonic clonic seizure compared to the control group in models of both pilocarpine- and pentylenetetrazole (PTZ)-induced seizures. Additionally, blocking ASIC3 significantly decreased the frequency of action potential (AP) firing in interneurons. Moreover, APETx2 significantly reduced the amplitudes and frequencies of miniature inhibitory postsynaptic currents (mIPSCs) while showed no differences with the APETx2 + bicuculline group and the bicuculline group. These findings suggest that elevated levels of ASIC3 may serve as an anti-epileptic mechanism via postsynaptic mechanisms in interneurons. It could represent a novel therapeutic strategy for epilepsy treatment.

  7. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy.

    Science.gov (United States)

    Yu, Frank H; Mantegazza, Massimo; Westenbroek, Ruth E; Robbins, Carol A; Kalume, Franck; Burton, Kimberly A; Spain, William J; McKnight, G Stanley; Scheuer, Todd; Catterall, William A

    2006-09-01

    Voltage-gated sodium channels (Na(V)) are critical for initiation of action potentials. Heterozygous loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy in infancy (SMEI). Homozygous null Scn1a-/- mice developed ataxia and died on postnatal day (P) 15 but could be sustained to P17.5 with manual feeding. Heterozygous Scn1a+/- mice had spontaneous seizures and sporadic deaths beginning after P21, with a notable dependence on genetic background. Loss of Na(V)1.1 did not change voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. The sodium current density was, however, substantially reduced in inhibitory interneurons of Scn1a+/- and Scn1a-/- mice but not in their excitatory pyramidal neurons. An immunocytochemical survey also showed a specific upregulation of Na(V)1.3 channels in a subset of hippocampal interneurons. Our results indicate that reduced sodium currents in GABAergic inhibitory interneurons in Scn1a+/- heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.

  8. The adhesion protein IgSF9b is coupled to neuroligin 2 via S-SCAM to promote inhibitory synapse development

    OpenAIRE

    Woo, Jooyeon; Kwon, Seok-Kyu; Nam, Jungyong; Choi, Seungwon; Takahashi, Hideto; Krueger, Dilja; Park, Joohyun; Lee, Yeunkum; Bae, Jin Young; Lee, Dongmin; Ko, Jaewon; Kim, Hyun; Kim, Myoung-Hwan; Bae, Yong Chul; Chang, Sunghoe

    2013-01-01

    Synaptic adhesion molecules regulate diverse aspects of synapse formation and maintenance. Many known synaptic adhesion molecules localize at excitatory synapses, whereas relatively little is known about inhibitory synaptic adhesion molecules. Here we report that IgSF9b is a novel, brain-specific, homophilic adhesion molecule that is strongly expressed in GABAergic interneurons. IgSF9b was preferentially localized at inhibitory synapses in cultured rat hippocampal and cortical interneurons an...

  9. Distinct Physiological Effects of Dopamine D4 Receptors on Prefrontal Cortical Pyramidal Neurons and Fast-Spiking Interneurons.

    Science.gov (United States)

    Zhong, Ping; Yan, Zhen

    2016-01-01

    Dopamine D4 receptor (D4R), which is strongly linked to neuropsychiatric disorders, such as attention-deficit hyperactivity disorder and schizophrenia, is highly expressed in pyramidal neurons and GABAergic interneurons in prefrontal cortex (PFC). In this study, we examined the impact of D4R on the excitability of these 2 neuronal populations. We found that D4R activation decreased the frequency of spontaneous action potentials (sAPs) in PFC pyramidal neurons, whereas it induced a transient increase followed by a decrease of sAP frequency in PFC parvalbumin-positive (PV+) interneurons. D4R activation also induced distinct effects in both types of PFC neurons on spontaneous excitatory and inhibitory postsynaptic currents, which drive the generation of sAP. Moreover, dopamine substantially decreased sAP frequency in PFC pyramidal neurons, but markedly increased sAP frequency in PV+ interneurons, and both effects were partially mediated by D4R activation. In the phencyclidine model of schizophrenia, the decreasing effect of D4R on sAP frequency in both types of PFC neurons was attenuated, whereas the increasing effect of D4R on sAP in PV+ interneurons was intact. These results suggest that D4R activation elicits distinct effects on synaptically driven excitability in PFC projection neurons versus fast-spiking interneurons, which are differentially altered in neuropsychiatric disorder-related conditions.

  10. Reduced densities of parvalbumin- and somatostatin-expressing interneurons in experimental cortical dysplasia and heterotopia in early postnatal development.

    Science.gov (United States)

    Akakin, Dilek; Martinez-Diaz, Hildabelis; Chen, Huan-Xin; Roper, Steven N

    2013-05-01

    Cortical dysplasia (CD) is strongly associated with intractable epilepsy, probably due to hyperexcitability of neuronal networks. However, the underlying mechanisms are not completely understood. GABAergic interneurons provide major inhibitory function in the CNS and have different subtypes, but it is not clear how each subtype is affected in CD during early post-natal development. We have examined the developmental alterations of the densities of two major subtypes of interneurons, parvalbumin (PV)- and somatostatin (SS)-expressing interneurons in an animal model of CD, in utero irradiation, using immunocytochemistry. We found that the density of PV- and SS-positive interneurons increases significantly in CD and controls during the first three weeks of postnatal life. However, compared to controls, the densities of both subtypes are significantly decreased in CD and heterotopia at all age groups although the time of onset for both PV and SS expression remained unchanged. Our results indicate that the densities of both PV- and SS-positive interneurons are significantly decreased in CD and heterotopia, which may be one important mechanism leading to hyperexcitability of CD.

  11. Decrease of a Current Mediated by Kv1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism

    Directory of Open Access Journals (Sweden)

    Cecilia Tubert

    2016-09-01

    Full Text Available The mechanism underlying a hypercholinergic state in Parkinson’s disease (PD remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by Kv1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on KCa channels.

  12. Long-term plasticity in interneurons of the dentate gyrus

    OpenAIRE

    Ross, Stephen T.; Soltesz, Ivan

    2001-01-01

    Single interneurons influence thousands of postsynaptic principal cells, and the control of interneuronal excitability is an important regulator of the computational properties of the hippocampus. However, the mechanisms underlying long-term alterations in the input–output functions of interneurons are not fully understood. We report a mechanism of interneuronal plasticity that leads to the functional enhancement of the gain of glutamatergic inputs in the absence of long-term potentiation of ...

  13. PGC-1α provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons.

    Science.gov (United States)

    Lucas, Elizabeth K; Dougherty, Sarah E; McMeekin, Laura J; Reid, Courtney S; Dobrunz, Lynn E; West, Andrew B; Hablitz, John J; Cowell, Rita M

    2014-10-22

    Accumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1α in the brain have remained enigmatic. Previous data demonstrate that PGC-1α is primarily concentrated in inhibitory neurons and that PGC-1α is required for the expression of the interneuron-specific Ca(2+)-binding protein parvalbumin (PV) throughout the cortex. To identify other possible transcriptional targets of PGC-1α in neural tissue, we conducted a microarray on neuroblastoma cells overexpressing PGC-1α, mined results for genes with physiological relevance to interneurons, and measured cortical gene and protein expression of these genes in mice with underexpression and overexpression of PGC-1α. We observed bidirectional regulation of novel PGC-1α-dependent transcripts spanning synaptic [synaptotagmin 2 (Syt2) and complexin 1 (Cplx1)], structural [neurofilament heavy chain (Nefh)], and metabolic [neutral cholesterol ester hydrolase 1 (Nceh1), adenylate kinase 1 (Ak1), inositol polyphosphate 5-phosphatase J (Inpp5j), ATP synthase mitochondrial F1 complex O subunit (Atp5o), phytanol-CoA-2hydroxylase (Phyh), and ATP synthase mitrochondrial F1 complex α subunit 1 (Atp5a1)] functions. The neuron-specific genes Syt2, Cplx1, and Nefh were developmentally upregulated in an expression pattern consistent with that of PGC-1α and were expressed in cortical interneurons. Conditional deletion of PGC-1α in PV-positive neurons significantly decreased cortical transcript expression of these genes, promoted asynchronous GABA release, and impaired long-term memory. Collectively, these data demonstrate that PGC-1α is required for normal PV-positive interneuron function and that loss of PGC-1α in this interneuron subpopulation could contribute to cortical dysfunction in disease states.

  14. Differential regulation of parvalbumin and calretinin interneurons in the prefrontal cortex during adolescence.

    Science.gov (United States)

    Caballero, Adriana; Flores-Barrera, Eden; Cass, Daryn K; Tseng, Kuei Y

    2014-01-01

    Determining the normal developmental trajectory of individual GABAergic components in the prefrontal cortex (PFC) during the adolescent transition period is critical because local GABAergic interneurons are thought to play an important role in the functional maturation of cognitive control that occurs in this developmental window. Based on the expression of calcium-binding proteins, three distinctive subtypes of interneurons have been identified in the PFC: parvalbumin (PV)-, calretinin (CR)-, and calbindin (CB)-positive cells. Using biochemical and histochemical measures, we found that the protein level of PV is lowest in juveniles [postnatal days (PD) 25-35] and increases during adolescence (PD 45-55) to levels similar to those observed in adulthood (PD 65-75). In contrast, the protein expression of CR is reduced in adults compared to juvenile and adolescent animals, whereas CB levels remain mostly unchanged across the developmental window studied here. Semi-quantitative immunostaining analyses revealed that the periadolescent upregulation of PV and the loss of the CR signal appear to be attributable to changes in PV- and CR-positive innervation, which are dissociable from the trajectory of PV- and CR-positive cell number. At the synaptic level, our electrophysiological data revealed that a developmental facilitation of spontaneous glutamatergic synaptic inputs onto PV-positive/fast-spiking interneurons parallels the increase in prefrontal PV signal during the periadolescent transition. In contrast, no age-dependent changes in glutamatergic transmission were observed in PV-negative/non fast-spiking interneurons. Together, these findings emphasize that GABAergic inhibitory interneurons in the PFC undergo a dynamic, cell type-specific remodeling during adolescence and provide a developmental framework for understanding alterations in GABAergic circuits that occur in psychiatric disorders.

  15. Synapse-specific compartmentalization of signaling cascades for LTP induction in CA3 interneurons.

    Science.gov (United States)

    Galván, E J; Pérez-Rosello, T; Gómez-Lira, G; Lara, E; Gutiérrez, R; Barrionuevo, G

    2015-04-02

    Inhibitory interneurons with somata in strata radiatum and lacunosum-molecular (SR/L-M) of hippocampal area CA3 receive excitatory input from pyramidal cells via the recurrent collaterals (RCs), and the dentate gyrus granule cells via the mossy fibers (MFs). Here we demonstrate that Hebbian long-term potentiation (LTP) at RC synapses on SR/L-M interneurons requires the concomitant activation of calcium-impermeable AMPARs (CI-AMPARs) and N-methyl-d-aspartate receptors (NMDARs). RC LTP was prevented by voltage clamping the postsynaptic cell during high-frequency stimulation (HFS; 3 trains of 100 pulses delivered at 100 Hz every 10s), with intracellular injections of the Ca(2+) chelator BAPTA (20mM), and with the NMDAR antagonist D-AP5. In separate experiments, RC and MF inputs converging onto the same interneuron were sequentially activated. We found that RC LTP induction was blocked by inhibitors of the calcium/calmodulin-dependent protein kinase II (CaMKII; KN-62, 10 μM or KN-93, 10 μM) but MF LTP was CaMKII independent. Conversely, the application of the protein kinase A (PKA) activators forskolin/IBMX (50 μM/25 μM) potentiated MF EPSPs but not RC EPSPs. Together these data indicate that the aspiny dendrites of SR/L-M interneurons compartmentalize synapse-specific Ca(2+) signaling required for LTP induction at RC and MF synapses. We also show that the two signal transduction cascades converge to activate a common effector, protein kinase C (PKC). Specifically, LTP at RC and MF synapses on the same SR/LM interneuron was blocked by postsynaptic injections of chelerythrine (10 μM). These data indicate that both forms of LTP share a common mechanism involving PKC-dependent signaling modulation.

  16. Distribution of interneurons in the CA2 region of the rat hippocampus.

    Science.gov (United States)

    Botcher, Nicola A; Falck, Joanne E; Thomson, Alex M; Mercer, Audrey

    2014-01-01

    The CA2 region of the mammalian hippocampus is a unique region with its own distinctive properties, inputs and pathologies. Disruption of inhibitory circuits in this region appears to be linked with the pathology of specific psychiatric disorders, promoting interest in its local circuitry, its role in hippocampal function and its dysfunction in disease. In previous studies, CA2 interneurons, including a novel subclass of CA2 dendrite-preferring interneurons that has not been identified in other CA regions, have been shown to display physiological, synaptic and morphological properties unique to this sub-field and may therefore play a crucial role in the hippocampal circuitry. The distributions of immuno-labeled interneurons in dorsal CA2 were studied and compared with those of interneurons in CA1 and CA3. Like those in CA1 and CA3, the somata of CA2 parvalbumin-immunoperoxidase-labeled interneurons were located primarily in Stratum Pyramidale (SP) and Stratum Oriens (SO), with very few cells in Stratum Radiatum (SR) and none in Stratum Lacunosum Moleculare (SLM). There was, however, a greater proportion of GAD-positive cells were immunopositive for PV in SP in CA2 than in CA1 or CA3. CA2 SP also contained a larger density of somatostatin-, calbindin-, and VIP-immunopositive somata than CA1 and/or CA3. Like those in CA1 and CA3, CCK-immunopositive somata in CA2 were mostly located in SR. Reelin- and NPY- immunolabeled cell bodies were located in all layers of the three CA regions. However, a higher density of Reelin-positive somata was found in SP and SR of CA2 than in CA1 or CA3.

  17. Interneuron progenitor transplantation to treat CNS dysfunction

    Directory of Open Access Journals (Sweden)

    Muhammad O Chohan

    2016-08-01

    Full Text Available Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field.

  18. Control of response reliability by parvalbumin-expressing interneurons in visual cortex.

    Science.gov (United States)

    Zhu, Yingjie; Qiao, Wenhui; Liu, Kefei; Zhong, Huiyuan; Yao, Haishan

    2015-04-14

    The responses of visual cortical neurons to natural stimuli are both reliable and sparse. These properties require inhibition, yet the contribution of specific types of inhibitory neurons is not well understood. Here we demonstrate that optogenetic suppression of parvalbumin (PV)- but not somatostatin (SOM)-expressing interneurons reduces response reliability in the primary visual cortex of anaesthetized and awake mice. PV suppression leads to increases in the low firing rates and decreases in the high firing rates of cortical neurons, resulting in an overall reduction of the signal-to-noise ratio (SNR). In contrast, SOM suppression generally increases the overall firing rate for most neurons, without affecting the SNR. Further analysis reveals that PV, but not SOM, suppression impairs neural discrimination of natural stimuli. Together, these results reveal a critical role for PV interneurons in the formation of reliable visual cortical representations of natural stimuli.

  19. Excitatory and Inhibitory Neurons in the Hippocampus Exhibit Molecularly Distinct Large Dense Core Vesicles

    Directory of Open Access Journals (Sweden)

    Jose Jorge Ramirez-Franco

    2016-08-01

    Full Text Available Hippocampal interneurons comprise a diverse family of inhibitory neurons which function is critical for fine information processing. Along with gamma-aminobutyric acid (GABA, interneurons secrete a myriad of neuroactive substances via secretory vesicles which molecular composition and regulatory mechanisms remain unknown. In this study, we have carried out an immunohistofluorescence analysis to describe the molecular content of vesicles in distinct populations of hippocampal neurons. Our results indicate that phogrin, an integral protein of secretory vesicles in neuroendocrine cells, is highly enriched in parvalbumin-positive interneurons. Consistently, immunoelectron microscopy revealed phogrin staining in axon terminals of symmetrical synapses establishing inhibitory contacts with cell bodies of CA1 pyramidal neurons. Furthermore, phogrin is highly expressed in CA3 and dentate gyrus interneurons which are both positive for PV and neuropeptide Y. Surprisingly, chromogranin B a canonical large dense core vesicle marker, is excluded from inhibitory cells in the hippocampus but highly expressed in excitatory CA3 pyramidal neurons and dentate gyrus granule cells. Our results provide the first evidence of phogrin expression in hippocampal interneurons and suggest the existence of molecularly distinct populations of secretory vesicles in different types of inhibitory neurons.

  20. Neural - glial circuits : Can Interneurons stop seizures

    Science.gov (United States)

    Nadkarni, Suhita; Jung, Peter

    2004-03-01

    Recent progress in neurobiology suggests that astrocytes - through calcium excitability - are active partners to the neurons by integrating their activity and, in turn, regulating synaptic transmission. In a similar fashion neurons and interneurons are the 'Yin and Yang' of the hippocampus. The dichotomy of excitation and inhibition between pyramidal neurons and interneurons plays a crucial role in the function of the neuronal circuit.We consider a model of a pyramidal cell in contact with one synaptic astrocytes. It has been shown that such a circuit - triggered by transient stimulation - can exhibit sustained oscillations ("seizures") for strong coupling. The question we are considering is, under what conditions synaptic inhibition can stop these seizures?

  1. Inhibitory noise

    Directory of Open Access Journals (Sweden)

    Alain Destexhe

    2010-03-01

    Full Text Available Cortical neurons in vivo may operate in high-conductance states, in which the major part of the neuron's input conductance is due to synaptic activity, sometimes several-fold larger than the resting conductance. We examine here the contribution of inhibition in such high-conductance states. At the level of the absolute conductance values, several studies have shown that cortical neurons in vivo are characterized by strong inhibitory conductances. However, conductances are balanced and spiking activity is mostly determined by fluctuations, but not much is known about excitatory and inhibitory contributions to these fluctuations. Models and dynamic-clamp experiments show that, during high-conductance states, spikes are mainly determined by fluctuations of inhibition, or by inhibitory noise. This stands in contrast to low-conductance states, in which excitatory conductances determine spiking activity. To determine these contributions from experimental data, maximum likelihood methods can be designed and applied to intracellular recordings in vivo. Such methods indicate that action potentials are indeed mostly correlated with inhibitory fluctuations in awake animals. These results argue for a determinant role for inhibitory fluctuations in evoking spikes, and do not support feed-forward modes of processing, for which opposite patterns are predicted.

  2. Cortical interneuron dysfunction in epilepsy associated with autism spectrum disorders.

    Science.gov (United States)

    Jacob, John

    2016-02-01

    Autism and epilepsy are two associated disorders that are highly prevalent, share common developmental origins, and demonstrate substantial heritability. In this review, cross-disciplinary data in a rapidly evolving field that bridges neurology and psychiatry are synthesized to identify shared biologic mechanisms. The relationship between these debilitating, lifelong conditions is examined at the clinical, genetic, and neurophysiologic levels in humans and in animal models. Scopus and PubMed searches were used to identify relevant literature. Clinical observations have prompted speculation about the interdependence of autism and epilepsy, but causal relationships have proved difficult to determine. Despite their heritability, the genetic basis of autism spectrum disorder (ASD) and epilepsy has remained largely elusive until the advent of next-generation sequencing. This approach has revealed that mutations that are either causal or confer an increased disease risk are found in numerous different genes, any one of which accounts for only a small percentage of cases. Conversely, even cases with identical clinical phenotypes can be genetically heterogeneous. Candidate gene identification has facilitated the development of mouse genetic models, which in parallel with human studies have implicated shared brain regions and circuits that mediate disease expression. Diverse genetic causes of ASD and epilepsy converge on cortical interneuron circuits as one important mediator of both disorders. Cortical interneurons are among the most diverse cell types in the brain and their unique chemical and electrical coupling exert a powerful inhibitory influence on excitatory neurons via the release of the neurotransmitter, γ-aminobutyric acid (GABA). These multifaceted approaches have validated theories derived from the field of developmental neurobiology, which propose that the neurologic and neuropsychiatric manifestations are caused by an altered ratio of excitation to

  3. Synaptic potentials of primary afferent fibers and motoneurons evoked by single intermediate nucleus interneurons in the cat spinal cord.

    Science.gov (United States)

    Rudomin, P; Solodkin, M; Jiménez, I

    1987-05-01

    Spike-triggered averaging of dorsal and ventral root potentials was used in anesthetized cats to disclose possible synaptic connections of spinal interneurons in the intermediate nucleus with afferent fibers and/or motoneurons. With this method we have been able to document the existence of a distinct group of interneurons whose activity was associated with the recording of inhibitory potentials in the ventral roots (iVRPs), but not with negative dorsal root potentials (nDRPs). The iVRPs had mean durations of 60.8 +/- 22.1 ms and latencies between 1.7 and 5.1 ms relative to the onset of the interneuronal spikes. Within this group of neurons it was possible to characterize two categories depending on their responses to segmental inputs. Most type A interneurons were mono- or disynaptically activated by group I muscle afferents and polysynaptically by low threshold (1.08-1.69 X T) cutaneous fibers. Type B interneurons were instead polysynaptically activated by group II muscle and by cutaneous fibers with thresholds ranging from 1.02 to 3.1 X T. Whenever tested, both type A and B interneurons could be antidromically activated from Clarke's columns. There was a second group of interneurons whose activity was associated with the generation of both iVRPs and nDRPs. These potentials had mean durations of 107.5 +/- 35.6 and 131.5 +/- 32 ms, respectively, and onset latencies between 1.7 and 6.1 ms. The interneurons belonging to this group, which appear not to send axonal projections to Clarke's column, could be classified in three categories depending on their responses to peripheral inputs. Type C interneurons responded mono- or disynaptically to group I muscle volleys and polysynaptically to intermediate threshold (1.22-2.7 X T) cutaneous afferents. Type D interneurons were polysynaptically activated by group II muscle afferents (2.3-8.5 X T) and by intermediate threshold (1.4-3 X T) cutaneous fibers and type E interneurons only by group I muscle afferents with mono- or

  4. HCN4 subunit expression in fast-spiking interneurons of the rat spinal cord and hippocampus

    Science.gov (United States)

    Hughes, D.I.; Boyle, K.A.; Kinnon, C.M.; Bilsland, C.; Quayle, J.A.; Callister, R.J.; Graham, B.A.

    2013-01-01

    Hyperpolarisation-activated (Ih) currents are considered important for dendritic integration, synaptic transmission, setting membrane potential and rhythmic action potential (AP) discharge in neurons of the central nervous system. Hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels underlie these currents and are composed of homo- and hetero-tetramers of HCN channel subunits (HCN1–4), which confer distinct biophysical properties on the channel. Despite understanding the structure–function relationships of HCN channels with different subunit stoichiometry, our knowledge of their expression in defined neuronal populations remains limited. Recently, we have shown that HCN subunit expression is a feature of a specific population of dorsal horn interneurons that exhibit high-frequency AP discharge. Here we expand on this observation and use neuroanatomical markers to first identify well-characterised neuronal populations in the lumbar spinal cord and hippocampus and subsequently determine whether HCN4 expression correlates with high-frequency AP discharge in these populations. In the spinal cord, HCN4 is expressed in several putative inhibitory interneuron populations including parvalbumin (PV)-expressing islet cells (84.1%; SD: ±2.87), in addition to all putative Renshaw cells and Ia inhibitory interneurons. Similarly, virtually all PV-expressing cells in the hippocampal CA1 subfield (93.5%; ±3.40) and the dentate gyrus (90.9%; ±6.38) also express HCN4. This HCN4 expression profile in inhibitory interneurons mirrors both the prevalence of Ih sub-threshold currents and high-frequency AP discharge. Our findings indicate that HCN4 subunits are expressed in several populations of spinal and hippocampal interneurons, which are known to express both Ih sub-threshold currents and exhibit high-frequency AP discharge. As HCN channel function plays a critical role in pain perception, learning and memory, and sleep as well as the pathogenesis of several

  5. HCN4 subunit expression in fast-spiking interneurons of the rat spinal cord and hippocampus.

    Science.gov (United States)

    Hughes, D I; Boyle, K A; Kinnon, C M; Bilsland, C; Quayle, J A; Callister, R J; Graham, B A

    2013-05-01

    Hyperpolarisation-activated (Ih) currents are considered important for dendritic integration, synaptic transmission, setting membrane potential and rhythmic action potential (AP) discharge in neurons of the central nervous system. Hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels underlie these currents and are composed of homo- and hetero-tetramers of HCN channel subunits (HCN1-4), which confer distinct biophysical properties on the channel. Despite understanding the structure-function relationships of HCN channels with different subunit stoichiometry, our knowledge of their expression in defined neuronal populations remains limited. Recently, we have shown that HCN subunit expression is a feature of a specific population of dorsal horn interneurons that exhibit high-frequency AP discharge. Here we expand on this observation and use neuroanatomical markers to first identify well-characterised neuronal populations in the lumbar spinal cord and hippocampus and subsequently determine whether HCN4 expression correlates with high-frequency AP discharge in these populations. In the spinal cord, HCN4 is expressed in several putative inhibitory interneuron populations including parvalbumin (PV)-expressing islet cells (84.1%; SD: ±2.87), in addition to all putative Renshaw cells and Ia inhibitory interneurons. Similarly, virtually all PV-expressing cells in the hippocampal CA1 subfield (93.5%; ±3.40) and the dentate gyrus (90.9%; ±6.38) also express HCN4. This HCN4 expression profile in inhibitory interneurons mirrors both the prevalence of Ih sub-threshold currents and high-frequency AP discharge. Our findings indicate that HCN4 subunits are expressed in several populations of spinal and hippocampal interneurons, which are known to express both Ih sub-threshold currents and exhibit high-frequency AP discharge. As HCN channel function plays a critical role in pain perception, learning and memory, and sleep as well as the pathogenesis of several

  6. An inhibitory gate for state transition in cortex

    Science.gov (United States)

    Zucca, Stefano; D’Urso, Giulia; Pasquale, Valentina; Vecchia, Dania; Pica, Giuseppe; Bovetti, Serena; Moretti, Claudio; Varani, Stefano; Molano-Mazón, Manuel; Chiappalone, Michela; Panzeri, Stefano; Fellin, Tommaso

    2017-01-01

    Large scale transitions between active (up) and silent (down) states during quiet wakefulness or NREM sleep regulate fundamental cortical functions and are known to involve both excitatory and inhibitory cells. However, if and how inhibition regulates these activity transitions is unclear. Using fluorescence-targeted electrophysiological recording and cell-specific optogenetic manipulation in both anesthetized and non-anesthetized mice, we found that two major classes of interneurons, the parvalbumin and the somatostatin positive cells, tightly control both up-to-down and down-to-up state transitions. Inhibitory regulation of state transition was observed under both natural and optogenetically-evoked conditions. Moreover, perturbative optogenetic experiments revealed that the inhibitory control of state transition was interneuron-type specific. Finally, local manipulation of small ensembles of interneurons affected cortical populations millimetres away from the modulated region. Together, these results demonstrate that inhibition potently gates transitions between cortical activity states, and reveal the cellular mechanisms by which local inhibitory microcircuits regulate state transitions at the mesoscale. DOI: http://dx.doi.org/10.7554/eLife.26177.001 PMID:28509666

  7. Interneurons. Fast-spiking, parvalbumin⁺ GABAergic interneurons: from cellular design to microcircuit function.

    Science.gov (United States)

    Hu, Hua; Gan, Jian; Jonas, Peter

    2014-08-01

    The success story of fast-spiking, parvalbumin-positive (PV(+)) GABAergic interneurons (GABA, γ-aminobutyric acid) in the mammalian central nervous system is noteworthy. In 1995, the properties of these interneurons were completely unknown. Twenty years later, thanks to the massive use of subcellular patch-clamp techniques, simultaneous multiple-cell recording, optogenetics, in vivo measurements, and computational approaches, our knowledge about PV(+) interneurons became more extensive than for several types of pyramidal neurons. These findings have implications beyond the "small world" of basic research on GABAergic cells. For example, the results provide a first proof of principle that neuroscientists might be able to close the gaps between the molecular, cellular, network, and behavioral levels, representing one of the main challenges at the present time. Furthermore, the results may form the basis for PV(+) interneurons as therapeutic targets for brain disease in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will be able to use PV(+) interneurons for therapeutic purposes.

  8. Parvalbumin Interneurons of Hippocampus Tune Population Activity at Theta Frequency.

    Science.gov (United States)

    Amilhon, Bénédicte; Huh, Carey Y L; Manseau, Frédéric; Ducharme, Guillaume; Nichol, Heather; Adamantidis, Antoine; Williams, Sylvain

    2015-06-03

    Hippocampal theta rhythm arises from a combination of recently described intrinsic theta oscillators and inputs from multiple brain areas. Interneurons expressing the markers parvalbumin (PV) and somatostatin (SOM) are leading candidates to participate in intrinsic rhythm generation and principal cell (PC) coordination in distal CA1 and subiculum. We tested their involvement by optogenetically activating and silencing PV or SOM interneurons in an intact hippocampus preparation that preserves intrinsic connections and oscillates spontaneously at theta frequencies. Despite evidence suggesting that SOM interneurons are crucial for theta, optogenetic manipulation of these interneurons modestly influenced theta rhythm. However, SOM interneurons were able to strongly modulate temporoammonic inputs. In contrast, activation of PV interneurons powerfully controlled PC network and rhythm generation optimally at 8 Hz, while continuously silencing them disrupted theta. Our results thus demonstrate a pivotal role of PV but not SOM interneurons for PC synchronization and the emergence of intrinsic hippocampal theta.

  9. Identification of mRNA for endocannabinoid biosynthetic enzymes within hippocampal pyramidal cells and CA1 stratum radiatum interneuron subtypes using quantitative real-time polymerase chain reaction.

    Science.gov (United States)

    Merrill, C B; McNeil, M; Williamson, R C; Poole, B R; Nelson, B; Sudweeks, S; Edwards, J G

    2012-08-30

    The hippocampus is required for short-term memory and contains both excitatory pyramidal cells and inhibitory interneurons. These cells exhibit various forms of synaptic plasticity, the mechanism underlying learning and memory. More recently, endocannabinoids were identified to be involved in synaptic plasticity. Our goal was to describe the distribution of endocannabinoid biosynthetic enzymes within CA1 stratum radiatum interneurons and CA3/CA1 pyramidal cells. We extracted mRNA from single interneurons and pyramidal cells and used real-time quantitative polymerase chain reaction (RT-PCR) to detect the presence of 12-lipoxygenase, N-acyl-phosphatidylethanolamine-specific phospholipase D, diacylglycerol lipase α, and type I metabotropic glutamate receptors, all known to be involved in endocannabinoid production and plasticity. We observed that the expression of endocannabinoid biosynthetic enzyme mRNA does occur within interneurons and that it is coexpressed with type I metabotropic glutamate receptors, suggesting interneurons have the potential to produce endocannabinoids. We also identified that CA3 and CA1 pyramidal cells express endocannabinoid biosynthetic enzyme mRNA. Our data provide the first molecular biological evidence for putative endocannabinoid production in interneurons, suggesting their potential ability to regulate endocannabinoid-mediated processes, such as synaptic plasticity.

  10. Brain-derived neurotrophic factor mediates activity-dependent dendritic growth in nonpyramidal neocortical interneurons in developing organotypic cultures.

    Science.gov (United States)

    Jin, Xiaoming; Hu, Hang; Mathers, Peter H; Agmon, Ariel

    2003-07-02

    Brain-derived neurotrophic factor (BDNF) promotes postnatal maturation of GABAergic inhibition in the cerebral and cerebellar cortices, and its expression and release are enhanced by neuronal activity, suggesting that it acts in a feedback manner to maintain a balance between excitation and inhibition during development. BDNF promotes differentiation of cerebellar, hippocampal, and neostriatal inhibitory neurons, but its effects on the dendritic development of neocortical inhibitory interneurons remain unknown. Here, we show that BDNF mediates depolarization-induced dendritic growth and branching in neocortical interneurons. To visualize inhibitory interneurons, we biolistically transfected organotypic cortical slice cultures from neonatal mice with green fluorescent protein (GFP) driven by the glutamic acid decarboxylase (GAD)67 promoter. Nearly all GAD67-GFP-expressing neurons were nonpyramidal, many contained GABA, and some expressed markers of neurochemically defined GABAergic subtypes, indicating that GAD67-GFP-expressing neurons were GABAergic. We traced dendritic trees from confocal images of the same GAD67-GFP-expressing neurons before and after a 5 d growth period, and quantified the change in total dendritic length (TDL) and total dendritic branch points (TDBPs) for each neuron. GAD67-GFP-expressing neurons growing in control medium exhibited a 20% increase in TDL, but in 200 ng/ml BDNF or 10 mm KCl, this increase nearly doubled and was accompanied by a significant increase in TDBPs. Blocking action potentials with TTX did not prevent the BDNF-induced growth, but antibodies against BDNF blocked the growth-promoting effect of KCl. We conclude that BDNF, released by neocortical pyramidal neurons in response to depolarization, enhances dendritic growth and branching in nearby inhibitory interneurons.

  11. Cholinergic modulation of local pyramid-interneuron synapses exhibiting divergent short-term dynamics in rat sensory cortex

    OpenAIRE

    Levy, Robert B.; Reyes, Alex D.; Aoki, Chiye

    2008-01-01

    Acetylcholine (ACh) influences attention, short-term memory, and sleep/waking transitions, through its modulatory influence on cortical neurons. It has been proposed that behavioral state changes mediated by ACh result from its selective effects on the intrinsic membrane properties of diverse cortical inhibitory interneuron classes. ACh has been widely shown to reduce the strength of excitatory (glutamatergic) synapses. But past studies using extracellular stimulation have not been able to ex...

  12. Quantitative Morphometry of Electrophysiologically Identified CA3b Interneurons Reveals Robust Local Geometry and Distinct Cell Classes

    OpenAIRE

    Ascoli, Giorgio A.; Brown, Kerry M.; Calixto, Eduardo; Card, J. Patrick; Galvan, E. J.; Perez-Rosello, T.; Barrionuevo, Germán

    2009-01-01

    The morphological and electrophysiological diversity of inhibitory cells in hippocampal area CA3 may underlie specific computational roles and is not yet fully elucidated. In particular, interneurons with somata in strata radiatum (R) and lacunosum-moleculare (L-M) receive converging stimulation from the dentate gyrus and entorhinal cortex as well as within CA3. Although these cells express different forms of synaptic plasticity, their axonal trees and connectivity are still largely unknown. ...

  13. Mice lacking the transcriptional coactivator PGC-1α exhibit alterations in inhibitory synaptic transmission in the motor cortex.

    Science.gov (United States)

    Dougherty, S E; Bartley, A F; Lucas, E K; Hablitz, J J; Dobrunz, L E; Cowell, R M

    2014-06-20

    Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator known to regulate gene programs in a cell-specific manner in energy-demanding tissues, and its dysfunction has been implicated in numerous neurological and psychiatric disorders. Previous work from the Cowell laboratory indicates that PGC-1α is concentrated in inhibitory interneurons and is required for the expression of the calcium buffer parvalbumin (PV) in the cortex; however, the impact of PGC-1α deficiency on inhibitory neurotransmission in the motor cortex is not known. Here, we show that mice lacking PGC-1α exhibit increased amplitudes and decreased frequency of spontaneous inhibitory postsynaptic currents in layer V pyramidal neurons. Upon repetitive train stimulation at the gamma frequency, decreased GABA release is observed. Furthermore, PV-positive interneurons in PGC-1α -/- mice display reductions in intrinsic excitability and excitatory input without changes in gross interneuron morphology. Taken together, these data show that PGC-1α is required for normal inhibitory neurotransmission and cortical PV-positive interneuron function. Given the pronounced motor dysfunction in PGC-1α -/- mice and the essential role of PV-positive interneurons in maintenance of cortical excitatory:inhibitory balance, it is possible that deficiencies in PGC-1α expression could contribute to cortical hyperexcitability and motor abnormalities in multiple neurological disorders.

  14. 3D Clustering of GABAergic Neurons Enhances Inhibitory Actions on Excitatory Neurons in the Mouse Visual Cortex

    Directory of Open Access Journals (Sweden)

    Teppei Ebina

    2014-12-01

    Full Text Available Neocortical neurons with similar functional properties assemble into spatially coherent circuits, but it remains unclear how inhibitory interneurons are organized. We applied in vivo two-photon functional Ca2+ imaging and whole-cell recording of synaptic currents to record visual responses of cortical neurons and analyzed their spatial arrangements. GABAergic interneurons were clustered in the 3D space of the mouse visual cortex, and excitatory neurons located within the clusters (insiders had a lower amplitude and sharper orientation tuning of visual responses than outsiders. Inhibitory synaptic currents recorded from the insiders were larger than those of the outsiders. Single, isolated interneurons did not show such a location-tuning/amplitude relationship. The two principal subtypes of interneurons, parvalbumin- and somatostatin-expressing neurons, also formed clusters with only slightly overlapping each other and exhibited a different location-tuning relationship. These findings suggest that GABAergic interneurons and their subgroups form clusters to make their inhibitory function more effective than isolated interneurons.

  15. HDAC2 expression in parvalbumin interneurons regulates synaptic plasticity in the mouse visual cortex

    Directory of Open Access Journals (Sweden)

    Alexi Nott

    2015-01-01

    Full Text Available An experience-dependent postnatal increase in GABAergic inhibition in the visual cortex is important for the closure of a critical period of enhanced synaptic plasticity. Although maturation of the subclass of parvalbumin (Pv–expressing GABAergic interneurons is known to contribute to critical period closure, the role of epigenetics on cortical inhibition and synaptic plasticity has not been explored. The transcription regulator, histone deacetylase 2 (HDAC2, has been shown to modulate synaptic plasticity and learning processes in hippocampal excitatory neurons. We found that genetic deletion of HDAC2 specifically from Pv interneurons reduces inhibitory input in the visual cortex of adult mice and coincides with enhanced long-term depression that is more typical of young mice. These findings show that HDAC2 loss in Pv interneurons leads to a delayed closure of the critical period in the visual cortex and supports the hypothesis that HDAC2 is a key negative regulator of synaptic plasticity in the adult brain.

  16. Distinct and synergistic feedforward inhibition of pyramidal cells by basket and bistratified interneurons

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    Michele eFerrante

    2015-11-01

    Full Text Available Feedforward inhibition (FFI enables pyramidal cells in area CA1 of the hippocampus (CA1PCs to remain easily excitable while faithfully representing a broad range of excitatory inputs without quickly saturating. Despite the cortical ubiquity of FFI, its specific function is not completely understood. FFI in CA1PCs is mediated by two physiologically and morphologically distinct GABAergic interneurons: fast-spiking, perisomatic-targeting basket cells and regular-spiking, dendritic-targeting bistratified cells. These two FFI pathways might create layer-specific computational sub-domains within the same CA1PC, but teasing apart their specific contributions remains experimentally challenging. We implemented a biophysically realistic model of CA1PCs using 40 digitally reconstructed morphologies and constraining synaptic numbers, locations, amplitude, and kinetics with available experimental data. First, we validated the model by reproducing the known combined basket and bistratified FFI of CA1PCs at the population level. We then analyzed how the two interneuron types independently affected the CA1PC spike probability and timing as a function of inhibitory strength. Separate FFI by basket and bistratified respectively modulated CA1PC threshold and gain. Concomitant FFI by both interneuron types synergistically extended the dynamic range of CA1PCs by buffering their spiking response to excitatory stimulation. These results suggest testable hypotheses on the precise effects of GABAergic diversity on cortical computation.

  17. Cortical GABAergic Interneurons in Cross-Modal Plasticity following Early Blindness

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    Sébastien Desgent

    2012-01-01

    Full Text Available Early loss of a given sensory input in mammals causes anatomical and functional modifications in the brain via a process called cross-modal plasticity. In the past four decades, several animal models have illuminated our understanding of the biological substrates involved in cross-modal plasticity. Progressively, studies are now starting to emphasise on cell-specific mechanisms that may be responsible for this intermodal sensory plasticity. Inhibitory interneurons expressing γ-aminobutyric acid (GABA play an important role in maintaining the appropriate dynamic range of cortical excitation, in critical periods of developmental plasticity, in receptive field refinement, and in treatment of sensory information reaching the cerebral cortex. The diverse interneuron population is very sensitive to sensory experience during development. GABAergic neurons are therefore well suited to act as a gate for mediating cross-modal plasticity. This paper attempts to highlight the links between early sensory deprivation, cortical GABAergic interneuron alterations, and cross-modal plasticity, discuss its implications, and further provide insights for future research in the field.

  18. GABAergic Projections from the Medial Septum Selectively Inhibit Interneurons in the Medial Entorhinal Cortex

    Science.gov (United States)

    Gonzalez-Sulser, Alfredo; Parthier, Daniel; Candela, Antonio; McClure, Christina; Pastoll, Hugh; Garden, Derek; Sürmeli, Gülşen

    2014-01-01

    The medial septum (MS) is required for theta rhythmic oscillations and grid cell firing in the medial entorhinal cortex (MEC). While GABAergic, glutamatergic, and cholinergic neurons project from the MS to the MEC, their synaptic targets are unknown. To investigate whether MS neurons innervate specific layers and cell types in the MEC, we expressed channelrhodopsin-2 in mouse MS neurons and used patch-clamp recording in brain slices to determine the response to light activation of identified cells in the MEC. Following activation of MS axons, we observed fast monosynaptic GABAergic IPSPs in the majority (>60%) of fast-spiking (FS) and low-threshold-spiking (LTS) interneurons in all layers of the MEC, but in only 1.5% of nonstellate principal cells (NSPCs) and in no stellate cells. We also observed fast glutamatergic responses to MS activation in a minority (<5%) of NSPCs, FS, and LTS interneurons. During stimulation of MS inputs at theta frequency (10 Hz), the amplitude of GABAergic IPSPs was maintained, and spike output from LTS and FS interneurons was entrained at low (25–60 Hz) and high (60–180 Hz) gamma frequencies, respectively. By demonstrating cell type-specific targeting of the GABAergic projection from the MS to the MEC, our results support the idea that the MS controls theta frequency activity in the MEC through coordination of inhibitory circuits. PMID:25505326

  19. Expression of neuronal nicotinic acetylcholine receptor subunit mRNAs in rat hippocampal GABAergic interneurons.

    Science.gov (United States)

    Son, Jong-Hyun; Winzer-Serhan, Ursula H

    2008-11-10

    Hippocampal inhibitory interneurons are a diverse population of cells widely scattered in the hippocampus, where they regulate hippocampal circuit activity. The hippocampus receives cholinergic projections from the basal forebrain, and functional studies have suggested the presence of different subtypes of nicotinic acetylcholine receptors (AChRs) on gamma-aminobutyric acid (GABA)ergic interneurons. Single-cell polymerase chain reaction analysis had confirmed that several nAChR subunit mRNAs are co-expressed with glutamate decarboxylase 67 (GAD67), the marker for GABAergic interneurons. In this anatomical study, we systematically investigated the co-expression of GAD67 with different nAChR subunits by using double in situ hybridization with a digoxigenin-labeled GAD67 probe and (35)S-labeled probes for nAChR subunits (alpha2, alpha3, alpha4, alpha5, alpha6, alpha7, beta2, beta3, and beta4). The results revealed that most GAD67-positive interneurons expressed beta2, and 67 % also expressed alpha7 mRNA. In contrast, mRNA expression of other subunits was limited; only 13 % of GAD67-positive neurons co-expressed alpha4, and less than 10% expressed transcripts for alpha2, alpha3, alpha5, or beta4. Most GAD67/alpha2 co-expression was located in CA1/CA3 stratum oriens, and GAD67/alpha5 co-expression was predominantly detected in CA1/CA3 stratum radiatum/lacunosum moleculare and the dentate gyrus. Expression of alpha6 and beta3 mRNAs was rarely detected in the hippocampus, and mRNAs were not co-expressed with GAD67. These findings suggest that the majority of nicotinic responses in GABAergic interneurons should be mediated by a homomeric alpha7 or heteromeric alpha7*-containing nAChRs. Other possible combinations such as alpha2beta2*, alpha4beta2*, or alpha5beta2* heteromeric nAChRs could contribute to functional nicotinic response in subsets of GABAergic interneurons but overall would have a minor role.

  20. Presynaptic miniature GABAergic currents in developing interneurons.

    Science.gov (United States)

    Trigo, Federico F; Bouhours, Brice; Rostaing, Philippe; Papageorgiou, George; Corrie, John E T; Triller, Antoine; Ogden, David; Marty, Alain

    2010-04-29

    Miniature synaptic currents have long been known to represent random transmitter release under resting conditions, but much remains to be learned about their nature and function in central synapses. In this work, we describe a new class of miniature currents ("preminis") that arise by the autocrine activation of axonal receptors following random vesicular release. Preminis are prominent in gabaergic synapses made by cerebellar interneurons during the development of the molecular layer. Unlike ordinary miniature postsynaptic currents in the same cells, premini frequencies are strongly enhanced by subthreshold depolarization, suggesting that the membrane depolarization they produce belongs to a feedback loop regulating neurotransmitter release. Thus, preminis could guide the formation of the interneuron network by enhancing neurotransmitter release at recently formed synaptic contacts.

  1. Lineage-specific laminar organization of cortical GABAergic interneurons.

    Science.gov (United States)

    Ciceri, Gabriele; Dehorter, Nathalie; Sols, Ignasi; Huang, Z Josh; Maravall, Miguel; Marín, Oscar

    2013-09-01

    In the cerebral cortex, pyramidal cells and interneurons are generated in distant germinal zones, and so the mechanisms that control their precise assembly into specific microcircuits remain an enigma. Here we report that cortical interneurons labeled at the clonal level do not distribute randomly but rather have a strong tendency to cluster in the mouse neocortex. This behavior is common to different classes of interneurons, independently of their origin. Interneuron clusters are typically contained within one or two adjacent cortical layers, are largely formed by isochronically generated neurons and populate specific layers, as revealed by unbiased hierarchical clustering methods. Our results suggest that different progenitor cells give rise to interneurons populating infra- and supragranular cortical layers, which challenges current views of cortical neurogenesis. Thus, specific lineages of cortical interneurons seem to be produced to primarily mirror the laminar structure of the cerebral cortex, rather than its columnar organization.

  2. Striatal fast-spiking interneurons: from firing patterns to postsynaptic impact

    Directory of Open Access Journals (Sweden)

    Andreas eKlaus

    2011-07-01

    Full Text Available In the striatal microcircuit, fast-spiking (FS interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization, do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity.

  3. Morphology and physiology of auditory and vibratory ascending interneurones in bushcrickets.

    Science.gov (United States)

    Nebeling, B

    2000-02-15

    Auditory/vibratory interneurones of the bushcricket species Decticus albifrons and Decticus verrucivorus were studied with intracellular dye injection and electrophysiology. The morphologies of five physiologically characterised auditory/vibratory interneurones are shown in the brain, subesophageal and prothoracic ganglia. Based on their physiology, these five interneurones fall into three groups, the purely auditory or sound neurones: S-neurones, the purely vibratory V-neurones, and the bimodal vibrosensitive VS-neurones. The S1-neurones respond phasically to airborne sound whereas the S4-neurones exhibit a tonic spike pattern. Their somata are located in the prothoracic ganglion and they show an ascending axon with dendrites located in the prothoracic, subesophageal ganglia, and the brain. The VS3-neurone, responding to both auditory and vibratory stimuli in a tonic manner, has its axon traversing the brain, the suboesophageal ganglion and the prothoracic ganglion although with dendrites only in the brain. The V1- and V2-neurones respond to vibratory stimulation of the fore- and midlegs with a tonic discharge pattern, and our data show that they receive inhibitory input suppressing their spontaneous activity. Their axon transverses the prothoracic ganglion, subesophageal ganglion and terminate in the brain with dendritic branching. Thus the auditory S-neurones have dendritic arborizations in all three ganglia (prothoracic, subesophageal, and brain) compared to the vibratory (V) and vibrosensitive (VS) neurones, which have dendrites almost only in the brain. The dendrites of the S-neurones are also more extensive than those of the V-, VS-neurones. V- and VS-neurones terminate more laterally in the brain. Due to an interspecific comparison of the identified auditory interneurones the S1-neurone is found to be homologous to the TN1 of crickets and other bushcrickets, and the S4-neurone also can be called AN2. J. Exp. Zool. 286:219-230, 2000.

  4. Bidirectional Hebbian plasticity at hippocampal mossy fiber synapses on CA3 interneurons.

    Science.gov (United States)

    Galván, Emilio J; Calixto, Eduardo; Barrionuevo, Germán

    2008-12-24

    Hippocampal area CA3 is critically involved in the formation of nonoverlapping neuronal subpopulations ("pattern separation") to store memory representations as distinct events. Efficient pattern separation relies on the strong and sparse excitatory input from the mossy fibers (MFs) to pyramidal cells and feedforward inhibitory interneurons. However, MF synapses on CA3 pyramidal cells undergo long-term potentiation (LTP), which, if unopposed, will degrade pattern separation because MF activation will now recruit additional CA3 pyramidal cells. Here, we demonstrate MF LTP in stratum lacunosum-moleculare (L-M) interneurons induced by the same stimulation protocol that induces MF LTP in pyramidal cells. This LTP was NMDA receptor (NMDAR) independent and occurred at MF Ca(2+)-impermeable AMPA receptor synapses. LTP was prevented by with voltage clamping the postsynaptic cell soma during high-frequency stimulation (HFS), intracellular injections of the Ca(2+) chelator BAPTA (20 mm), or bath applications of the L-type Ca(2+) channel blocker nimodipine (10 microm). We propose that MF LTP in L-M interneurons preserves the sparsity of pyramidal cell activation, thus allowing CA3 to maintain its role in pattern separation. In the presence of the mGluR1alpha antagonist LY367385 [(S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid] (100 microm), the same HFS that induces MF LTP in naive slices triggered NMDAR-independent MF LTD. This LTD, like LTP, required activation of the L-type Ca(2+) channel and also was induced after blockade of IP(3) receptors with heparin (4 mg/ml) or the selective depletion of receptor-gated Ca(2+) stores with ryanodine (10 or 100 microm). We conclude that L-M interneurons are endowed with Ca(2+) signaling cascades suitable for controlling the polarity of MF long-term plasticity induced by joint presynaptic and postsynaptic activities.

  5. Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

    OpenAIRE

    Xenias, Harry S.; Ibáñez-Sandoval, Osvaldo; Koós, Tibor; Tepper, James M.

    2015-01-01

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH–Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow...

  6. Desynchronization of neocortical networks by asynchronous release of GABA at autaptic and synaptic contacts from fast-spiking interneurons.

    Directory of Open Access Journals (Sweden)

    Frédéric Manseau

    Full Text Available Networks of specific inhibitory interneurons regulate principal cell firing in several forms of neocortical activity. Fast-spiking (FS interneurons are potently self-inhibited by GABAergic autaptic transmission, allowing them to precisely control their own firing dynamics and timing. Here we show that in FS interneurons, high-frequency trains of action potentials can generate a delayed and prolonged GABAergic self-inhibition due to sustained asynchronous release at FS-cell autapses. Asynchronous release of GABA is simultaneously recorded in connected pyramidal (P neurons. Asynchronous and synchronous autaptic release show differential presynaptic Ca(2+ sensitivity, suggesting that they rely on different Ca(2+ sensors and/or involve distinct pools of vesicles. In addition, asynchronous release is modulated by the endogenous Ca(2+ buffer parvalbumin. Functionally, asynchronous release decreases FS-cell spike reliability and reduces the ability of P neurons to integrate incoming stimuli into precise firing. Since each FS cell contacts many P neurons, asynchronous release from a single interneuron may desynchronize a large portion of the local network and disrupt cortical information processing.

  7. Hippocampal CA3 pyramidal cells selectively innervate aspiny interneurons.

    Science.gov (United States)

    Wittner, Lucia; Henze, Darrell A; Záborszky, László; Buzsáki, György

    2006-09-01

    The specific connectivity among principal cells and interneurons determines the flow of activity in neuronal networks. To elucidate the connections between hippocampal principal cells and various classes of interneurons, CA3 pyramidal cells were intracellularly labelled with biocytin in anaesthetized rats and the three-dimensional distribution of their axon collaterals was reconstructed. The sections were double-stained for substance P receptor (SPR)- or metabotropic glutamate receptor 1alpha (mGluR-1alpha)-immunoreactivity to investigate interneuron targets of the CA3 pyramidal cells. SPR-containing interneurons represent a large portion of the GABAergic population, including spiny and aspiny classes. Axon terminals of CA3 pyramidal cells contacted SPR-positive interneuron dendrites in the hilus and in all hippocampal strata in both CA3 and CA1 regions (7.16% of all boutons). The majority of axons formed single contacts (87.5%), but multiple contacts (up to six) on single target neurons were also found. CA3 pyramidal cell axon collaterals innervated several types of morphologically different aspiny SPR-positive interneurons. In contrast, spiny SPR-interneurons or mGluR-1alpha-positive interneurons in the hilus, CA3 and CA1 regions were rarely contacted by the filled pyramidal cells. These findings indicate a strong target selection of CA3 pyramidal cells favouring the activation of aspiny classes of interneurons.

  8. Bulbar microcircuit model predicts connectivity and roles of interneurons in odor coding.

    Directory of Open Access Journals (Sweden)

    Aditya Gilra

    Full Text Available Stimulus encoding by primary sensory brain areas provides a data-rich context for understanding their circuit mechanisms. The vertebrate olfactory bulb is an input area having unusual two-layer dendro-dendritic connections whose roles in odor coding are unclear. To clarify these roles, we built a detailed compartmental model of the rat olfactory bulb that synthesizes a much wider range of experimental observations on bulbar physiology and response dynamics than has hitherto been modeled. We predict that superficial-layer inhibitory interneurons (periglomerular cells linearize the input-output transformation of the principal neurons (mitral cells, unlike previous models of contrast enhancement. The linearization is required to replicate observed linear summation of mitral odor responses. Further, in our model, action-potentials back-propagate along lateral dendrites of mitral cells and activate deep-layer inhibitory interneurons (granule cells. Using this, we propose sparse, long-range inhibition between mitral cells, mediated by granule cells, to explain how the respiratory phases of odor responses of sister mitral cells can be sometimes decorrelated as observed, despite receiving similar receptor input. We also rule out some alternative mechanisms. In our mechanism, we predict that a few distant mitral cells receiving input from different receptors, inhibit sister mitral cells differentially, by activating disjoint subsets of granule cells. This differential inhibition is strong enough to decorrelate their firing rate phases, and not merely modulate their spike timing. Thus our well-constrained model suggests novel computational roles for the two most numerous classes of interneurons in the bulb.

  9. Bulbar microcircuit model predicts connectivity and roles of interneurons in odor coding.

    Science.gov (United States)

    Gilra, Aditya; Bhalla, Upinder S

    2015-01-01

    Stimulus encoding by primary sensory brain areas provides a data-rich context for understanding their circuit mechanisms. The vertebrate olfactory bulb is an input area having unusual two-layer dendro-dendritic connections whose roles in odor coding are unclear. To clarify these roles, we built a detailed compartmental model of the rat olfactory bulb that synthesizes a much wider range of experimental observations on bulbar physiology and response dynamics than has hitherto been modeled. We predict that superficial-layer inhibitory interneurons (periglomerular cells) linearize the input-output transformation of the principal neurons (mitral cells), unlike previous models of contrast enhancement. The linearization is required to replicate observed linear summation of mitral odor responses. Further, in our model, action-potentials back-propagate along lateral dendrites of mitral cells and activate deep-layer inhibitory interneurons (granule cells). Using this, we propose sparse, long-range inhibition between mitral cells, mediated by granule cells, to explain how the respiratory phases of odor responses of sister mitral cells can be sometimes decorrelated as observed, despite receiving similar receptor input. We also rule out some alternative mechanisms. In our mechanism, we predict that a few distant mitral cells receiving input from different receptors, inhibit sister mitral cells differentially, by activating disjoint subsets of granule cells. This differential inhibition is strong enough to decorrelate their firing rate phases, and not merely modulate their spike timing. Thus our well-constrained model suggests novel computational roles for the two most numerous classes of interneurons in the bulb.

  10. Gate control of mechanical itch by a subpopulation of spinal cord interneurons

    Science.gov (United States)

    Bourane, Steeve; Duan, Bo; Koch, Stephanie C.; Dalet, Antoine; Britz, Olivier; Garcia-Campmany, Lidia; Kim, Euiseok; Cheng, Longzhen; Ghosh, Anirvan; Ma, Qiufu; Goulding, Martyn

    2015-01-01

    Light mechanical stimulation of the hairy skin can induce a form of itch known as mechanical itch. This itch sensation is normally suppressed by inputs from mechanoreceptors, however, in many forms of chronic itch, including alloknesis, this gating mechanism is lost. Here we demonstrate that a population of spinal inhibitory interneurons (INs) that are defined by the expression of neuropeptide Y::Cre (NPY::Cre) act to gate mechanical itch. Mice in which dorsal NPY::Cre-derived neurons are selectively ablated or silenced develop mechanical itch without an increase in sensitivity to chemical itch or pain. This chronic itch state is histamine-independent and is transmitted independently of the GRP-GRPR signaling pathway. Our studies thereby reveal a dedicated spinal cord inhibitory pathway that gates the transmission of mechanical itch PMID:26516282

  11. CREB-Dependent Regulation of GAD65 Transcription by BDNF/TrkB in Cortical Interneurons.

    Science.gov (United States)

    Sánchez-Huertas, Carlos; Rico, Beatriz

    2011-04-01

    In the cerebral cortex, the functional output of projection neurons is fine-tuned by inhibitory neurons present in the network, which use γ-aminobutyric acid (GABA) as their main neurotransmitter. Previous studies have suggested that the expression levels of the rate-limiting GABA synthetic enzyme, GAD65, depend on brain derived neurotrophic factor (BDNF)/TrkB activation. However, the molecular mechanisms by which this neurotrophic factor and its receptor controls GABA synthesis are still unknown. Here, we show a direct regulation of the GAD65 gene by BDNF-TrkB signaling via CREB in cortical interneurons. Conditional ablation of TrkB in cortical interneurons causes a cell-autonomous decrease in the synaptically enriched GAD65 protein and its transcripts levels, suggesting that transcriptional regulation of the GAD65 gene is altered. Dissection of the intracellular pathway that underlies this process revealed that BDNF/TrkB signaling controls the transcription of GAD65 in a Ras-ERK-CREB-dependent manner. Our study reveals a novel molecular mechanism through which BDNF/TrkB signaling may modulate the maturation and function of cortical inhibitory circuits.

  12. Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia

    Science.gov (United States)

    Steullet, P; Cabungcal, J-H; Coyle, J; Didriksen, M; Gill, K; Grace, A A; Hensch, T K; LaMantia, A-S; Lindemann, L; Maynard, T M; Meyer, U; Morishita, H; O'Donnell, P; Puhl, M; Cuenod, M; Do, K Q

    2017-01-01

    Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress. PMID:28322275

  13. Response features of parvalbumin-expressing interneurons suggest precise roles for subtypes of inhibition in visual cortex.

    Science.gov (United States)

    Runyan, Caroline A; Schummers, James; Van Wart, Audra; Kuhlman, Sandra J; Wilson, Nathan R; Huang, Z Josh; Sur, Mriganka

    2010-09-09

    Inhibitory interneurons in the cerebral cortex include a vast array of subtypes, varying in their molecular signatures, electrophysiological properties, and connectivity patterns. This diversity suggests that individual inhibitory classes have unique roles in cortical circuits; however, their characterization to date has been limited to broad classifications including many subtypes. We used the Cre/LoxP system, specifically labeling parvalbumin(PV)-expressing interneurons in visual cortex of PV-Cre mice with red fluorescent protein (RFP), followed by targeted loose-patch recordings and two-photon imaging of calcium responses in vivo to characterize the visual receptive field properties of these cells. Despite their relative molecular and morphological homogeneity, we find that PV+ neurons have a diversity of feature-specific visual responses that include sharp orientation and direction-selectivity, small receptive fields, and band-pass spatial frequency tuning. These results suggest that subsets of parvalbumin interneurons are components of specific cortical networks and that perisomatic inhibition contributes to the generation of precise response properties.

  14. Synapse-specific mGluR1-dependent long-term potentiation in interneurones regulates mouse hippocampal inhibition

    Science.gov (United States)

    Lapointe, Valérie; Morin, France; Ratté, Stéphanie; Croce, Ariane; Conquet, François; Lacaille, Jean-Claude

    2004-01-01

    Hippocampal CA1 inhibitory interneurones control the excitability and synchronization of pyramidal cells, and participate in hippocampal synaptic plasticity. Pairing theta-burst stimulation (TBS) with postsynaptic depolarization, we induced long-term potentiation (LTP) of putative single-fibre excitatory postsynaptic currents (EPSCs) in stratum oriens/alveus (O/A) interneurones of mouse hippocampal slices. LTP induction was absent in metabotropic glutamate receptor 1 (mGluR1) knockout mice, was correlated with the postsynaptic presence of mGluR1a, and required a postsynaptic Ca2+ rise. Changes in paired-pulse facilitation and coefficient of variation indicated that LTP expression involved presynaptic mechanisms. LTP was synapse specific, occurring selectively at synapses modulated by presynaptic group II, but not group III, mGluRs. Furthermore, the TBS protocol applied in O/A induced a long-term increase of polysynaptic inhibitory responses in CA1 pyramidal cells, that was absent in mGluR1 knockout mice. These results uncover the mechanisms of a novel form of interneurone synaptic plasticity that can adaptively regulate inhibition of hippocampal pyramidal cells. PMID:14673190

  15. Age-dependent loss of parvalbumin-expressing hippocampal interneurons in mice deficient in CHL1, a mental retardation and schizophrenia susceptibility gene.

    Science.gov (United States)

    Schmalbach, Barbara; Lepsveridze, Eka; Djogo, Nevena; Papashvili, Giorgi; Kuang, Fang; Leshchyns'ka, Iryna; Sytnyk, Vladimir; Nikonenko, Alexander G; Dityatev, Alexander; Jakovcevski, Igor; Schachner, Melitta

    2015-11-01

    In humans, deletions/mutations in the CHL1/CALL gene are associated with mental retardation and schizophrenia. Juvenile CHL1-deficient (CHL1(-/-) ) mice have been shown to display abnormally high numbers of parvalbumin-expressing (PV(+) ) hippocampal interneurons and, as adults, display behavioral traits observed in neuropsychiatric disorders. Here, we addressed the question whether inhibitory interneurons and synaptic plasticity in the CHL1(-/-) mouse are affected during brain maturation and in adulthood. We found that hippocampal, but not neocortical, PV(+) interneurons were reduced with age in CHL1(-/-) mice, from a surplus of +27% at 1 month to a deficit of -20% in adulthood compared with wild-type littermates. This loss occurred during brain maturation, correlating with microgliosis and enhanced interleukin-6 expression. In parallel with the loss of PV(+) interneurons, the inhibitory input to adult CA1 pyramidal cells was reduced and a deficit in short- and long-term potentiation developed at CA3-CA1 excitatory synapses between 2 and 9 months of age in CHL1(-/-) mice. This deficit could be abrogated by a GABAA receptor agonist. We propose that region-specific aberrant GABAergic synaptic connectivity resulting from the mutation and a subsequently enhanced synaptic elimination during brain maturation lead to microgliosis, increase in pro-inflammatory cytokine levels, loss of interneurons, and impaired synaptic plasticity. Close homolog of L1-deficient (CHL1(-/-) ) mice have abnormally high numbers of parvalbumin (PV)-expressing hippocampal interneurons in juvenile animals, but in adult animals a loss of these cells is observed. This loss correlates with an increased density of microglia (M), enhanced interleukin-6 (IL6) production and a deficit in short- and long-term potentiation at CA3-CA1 excitatory synapses. Furthermore, adult CHL1(-/-) mice display behavioral traits similar to those observed in neuropsychiatric disorders of humans.

  16. Anatomically heterogeneous populations of CB1 cannabinoid receptor-expressing interneurons in the CA3 region of the hippocampus show homogeneous input-output characteristics.

    Science.gov (United States)

    Szabó, Gergely G; Papp, Orsolya I; Máté, Zoltán; Szabó, Gábor; Hájos, Norbert

    2014-12-01

    A subpopulation of GABAergic cells in cortical structures expresses CB1 cannabinoid receptors (CB1 ) on their axon terminals. To understand the function of these interneurons in information processing, it is necessary to uncover how they are embedded into neuronal circuits. Therefore, the proportion of GABAergic terminals expressing CB1 and the morphological and electrophysiological properties of CB1 -immunoreactive interneurons should be revealed. We investigated the ratio and the origin of CB1 -expressing inhibitory boutons in the CA3 region of the hippocampus. Using immunocytochemical techniques, we estimated that ∼40% of GABAergic axon terminals in different layers of CA3 also expressed CB1 . To identify the inhibitory cell types expressing CB1 in this region, we recorded and intracellularly labeled interneurons in hippocampal slices. CB1 -expressing interneurons showed distinct axonal arborization, and were classified as basket cells, mossy-fiber-associated cells, dendritic-layer-innervating cells or perforant-path-associated cells. In each morphological category, a substantial variability in axonal projection was observed. In contrast to the diverse morphology, the active and passive membrane properties were found to be rather similar. Using paired recordings, we found that pyramidal cells displayed large and fast unitary postsynaptic currents in response to activating basket and mossy-fiber-associated cells, while they showed slower and smaller synaptic events in pairs originating from interneurons that innervate the dendritic layer, which may be due to dendritic filtering. In addition, CB1 activation significantly reduced the amplitude of the postsynaptic currents in each cell pair tested. Our data suggest that CB1 -expressing interneurons with different axonal projections have comparable physiological characteristics, contributing to a similar proportion of GABAergic inputs along the somato-dendritic axis of CA3 pyramidal cells.

  17. mGluR1/5 subtype-specific calcium signalling and induction of long-term potentiation in rat hippocampal oriens/alveus interneurones

    Science.gov (United States)

    Topolnik, Lisa; Azzi, Mounia; Morin, France; Kougioumoutzakis, André; Lacaille, Jean-Claude

    2006-01-01

    Hippocampal inhibitory interneurones demonstrate pathway- and synapse-specific rules of transmission and plasticity, which are key determinants of their role in controlling pyramidal cell excitability. Mechanisms underlying long-term changes at interneurone excitatory synapses, despite their importance, remain largely unknown. We use two-photon calcium imaging and whole-cell recordings to determine the Ca2+ signalling mechanisms linked specifically to group I metabotropic glutamate receptors (mGluR1α and mGluR5) and their role in hebbian long-term potentiation (LTP) in oriens/alveus (O/A) interneurones. We demonstrate that mGluR1α activation elicits dendritic Ca2+ signals resulting from Ca2+ influx via transient receptor potential (TRP) channels and Ca2+ release from intracellular stores. By contrast, mGluR5 activation produces dendritic Ca2+ transients mediated exclusively by intracellular Ca2+ release. Using Western blot analysis and immunocytochemistry, we show mGluR1α-specific extracellular signal-regulated kinase (ERK1/2) activation via Src in CA1 hippocampus and, in particular, in O/A interneurones. Moreover, we find that mGluR1α/TRP Ca2+ signals in interneurone dendrites are dependent on activation of the Src/ERK cascade. Finally, this mGluR1α-specific Ca2+ signalling controls LTP at interneurone synapses since blocking either TRP channels or Src/ERK and intracellular Ca2+ release prevents LTP induction. Thus, our findings uncover a novel molecular mechanism of interneurone-specific Ca2+ signalling, critical in regulating synaptic excitability in hippocampal networks. PMID:16740609

  18. Adenosine A1 Receptor Suppresses Tonic GABAA Receptor Currents in Hippocampal Pyramidal Cells and in a Defined Subpopulation of Interneurons.

    Science.gov (United States)

    Rombo, Diogo M; Dias, Raquel B; Duarte, Sofia T; Ribeiro, Joaquim A; Lamsa, Karri P; Sebastião, Ana M

    2016-03-01

    Adenosine is an endogenous neuromodulator that decreases excitability of hippocampal circuits activating membrane-bound metabotropic A1 receptor (A1R). The presynaptic inhibitory action of adenosine A1R in glutamatergic synapses is well documented, but its influence on inhibitory GABAergic transmission is poorly known. We report that GABAA receptor (GABAAR)-mediated tonic, but not phasic, transmission is suppressed by A1R in hippocampal neurons. Adenosine A1R activation strongly inhibits GABAAR agonist (muscimol)-evoked currents in Cornu Ammonis 1 (CA1) pyramidal neurons and in a specific subpopulation of interneurons expressing axonal cannabinoid receptor type 1. In addition, A1R suppresses tonic GABAAR currents measured in the presence of elevated ambient GABA as well as in naïve slices. The inhibition of GABAergic currents involves both protein kinase A (PKA) and protein kinase C (PKC) signaling pathways and decreases GABAAR δ-subunit expression. On the contrary, no A1R-mediated modulation was detected in phasic inhibitory postsynaptic currents evoked either by afferent electrical stimulation or by spontaneous quantal release. The results show that A1R modulates extrasynaptic rather than synaptic GABAAR-mediated signaling, and that this modulation selectively occurs in hippocampal pyramidal neurons and in a specific subpopulation of inhibitory interneurons. We conclude that modulation of tonic GABAAR signaling by adenosine A1R in specific neuron types may regulate neuronal gain and excitability in the hippocampus.

  19. Functional and molecular differences between voltage-gated K+ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus.

    Science.gov (United States)

    Martina, M; Schultz, J H; Ehmke, H; Monyer, H; Jonas, P

    1998-10-15

    We have examined gating and pharmacological characteristics of somatic K+ channels in fast-spiking interneurons and regularly spiking principal neurons of hippocampal slices. In nucleated patches isolated from basket cells of the dentate gyrus, a fast delayed rectifier K+ current component that was highly sensitive to tetraethylammonium (TEA) and 4-aminopyridine (4-AP) (half-maximal inhibitory concentrations Kv3 (Kv3.1, Kv3.2) subunit transcripts were expressed in almost all (89%) of the interneurons but only in 17% of the pyramidal neurons. In contrast, Kv4 (Kv4.2, Kv4.3) subunit mRNAs were present in 87% of pyramidal neurons but only in 55% of interneurons. Selective block of fast delayed rectifier K+ channels, presumably assembled from Kv3 subunits, by 4-AP reduced substantially the action potential frequency in interneurons. These results indicate that the differential expression of Kv3 and Kv4 subunits shapes the action potential phenotypes of principal neurons and interneurons in the cortex.

  20. Interneurons spark seizure-like activity in the entorhinal cortex.

    Science.gov (United States)

    Lévesque, Maxime; Herrington, Rochelle; Hamidi, Shabnam; Avoli, Massimo

    2016-03-01

    Excessive neuronal synchronization is presumably involved in epileptiform synchronization. However, the respective roles played by interneurons (GABAergic) and principal (glutamatergic) cells during interictal and ictal discharges remain unclear. Here, we employed tetrode wire recordings to establish the involvement of these two cell types in 4-aminopyridine-induced interictal- and low-voltage fast (LVF) onset ictal-like discharges in the rat entorhinal cortex in an in vitro slice preparation. We recorded a total of 90 single units (69 putative interneurons, 17 putative principal and 4 unclassified cells) from 36 slices, and found that: (i) interneurons (66.7%) were more likely to fire during interictal discharges than principal cells (35.3%); (ii) interneuron activity increased shortly before LVF ictal onset, whereas principal cell activity did not change; (iii) interneurons and principal cells fired at high rates throughout the tonic phase of the ictal discharge; however, (iv) only interneurons showed phase-locked relationship with LVF activity at 5-15Hz during the tonic phase. Finally, the association of interneuron firing with interictal discharges was maintained during blockade of ionotropic glutamatergic transmission. Our findings demonstrate the prominent involvement of interneurons in interictal discharge generation and in the transition to LVF ictal activity in this in vitro model of epileptiform synchronization.

  1. Characterization of voltage-gated K+ currents contributing to subthreshold membrane potential oscillations in hippocampal CA1 interneurons.

    Science.gov (United States)

    Morin, France; Haufler, Darrell; Skinner, Frances K; Lacaille, Jean-Claude

    2010-06-01

    CA1 inhibitory interneurons at the stratum lacunosum-moleculare and radiatum junction (LM/RAD-INs) display subthreshold membrane potential oscillations (MPOs) involving voltage-dependent Na(+) and A-type K(+) currents. LM/RAD-INs also express other voltage-gated K(+) currents, although their properties and role in MPOs remain unclear. Here, we characterized these voltage-gated K(+) currents and investigated their role in MPOs. Using outside-out patch recordings from LM/RAD-IN somata, we distinguished four voltage-gated K(+) currents based on their pharmacology and activation/inactivation properties: a fast delayed rectifier current (I(Kfast)), a slow delayed rectifier current (I(Kslow)), a rapidly inactivating A-type current (I(A)), and a slowly inactivating current (I(D)). Their relative contribution to the total K(+) current was I(A) > I(Kfast) > I(Kslow) = I(D). The presence of I(D) and the relative contributions of K(+) currents in LM/RAD-INs are different from those of other CA1 interneurons, suggesting the presence of differential complement of K(+) currents in subgroups of interneurons. We next determined whether these K(+) currents were sufficient for MPO generation using a single-compartment model of LM/RAD-INs. The model captured the subthreshold voltage dependence of MPOs. Moreover, all K(+) currents were active at subthreshold potentials but I(D), I(A), and the persistent sodium current (I(NaP)) were most active near threshold. Using impedance analysis, we found that I(A) and I(NaP) contribute to MPO generation by modulating peak spectral frequency during MPOs and governing the voltage range over which MPOs occur. Our findings uncover a differential expression of a complement of K(+) channels that underlies intrinsic rhythmic activity in inhibitory interneurons.

  2. Immunofluorescent visualization of mouse interneuron subtypes [v3; ref status: indexed, http://f1000r.es/5hn

    Directory of Open Access Journals (Sweden)

    Simon Molgaard

    2015-06-01

    Full Text Available The activity of excitatory neurons is controlled by a highly diverse population of inhibitory interneurons. These cells show a high level of physiological, morphological and neurochemical heterogeneity, and play highly specific roles in neuronal circuits. In the mammalian hippocampus, these are divided into 21 different subtypes of GABAergic interneurons based on their expression of different markers, morphology and their electrophysiological properties. Ideally, all can be marked using an antibody directed against the inhibitory neurotransmitter GABA, but parvalbumin, calbindin, somatostatin, and calretinin are also commonly used as markers to narrow down the specific interneuron subtype. Here, we describe a journey to find the necessary immunological reagents for studying GABAergic interneurons of the mouse hippocampus. Based on web searches there are several hundreds of different antibodies on the market directed against these four markers. Searches in the literature databases allowed us to narrow it down to a subset of antibodies most commonly used in publications. However, in our hands the most cited ones did not work for immunofluorescence stainings of formaldehyde fixed tissue sections and cultured hippocampal neurons, and we had to immunostain our way through thirteen different commercial antibodies before finally finding a suitable antibody for each of the four markers. The antibodies were evaluated based on signal-to-noise ratios as well as if positive cells were found in layers of the hippocampus where they have previously been described. Additionally, the antibodies were also tested on sections from mouse spinal cord with similar criteria for specificity of the antibodies. Using the antibodies with a high rating on pAbmAbs, an antibody review database, stainings with high signal-to-noise ratios and location of the immunostained cells in accordance with the literature could be obtained, making these antibodies suitable choices for

  3. Immunofluorescent visualization of mouse interneuron subtypes [v2; ref status: indexed, http://f1000r.es/4qq

    Directory of Open Access Journals (Sweden)

    Simon Molgaard

    2014-11-01

    Full Text Available The activity of excitatory neurons is controlled by a highly diverse population of inhibitory interneurons. These cells show a high level of physiological, morphological and neurochemical heterogeneity, and play highly specific roles in neuronal circuits. In the mammalian hippocampus, these are divided into 21 different subtypes of GABAergic interneurons based on their expression of different markers, morphology and their electrophysiological properties. Ideally, all can be marked using an antibody directed against the inhibitory neurotransmitter GABA, but parvalbumin, calbindin, somatostatin, and calretinin are also commonly used as markers to narrow down the specific interneuron subtype. Here, we describe a journey to find the necessary immunological reagents for studying GABAergic interneurons of the mouse hippocampus. Based on web searches there are several hundreds of different antibodies on the market directed against these four markers. Searches in the literature databases allowed us to narrow it down to a subset of antibodies most commonly used in publications. However, in our hands the most cited ones did not work for immunofluorescence stainings of formaldehyde fixed tissue sections and cultured hippocampal neurons, and we had to immunostain our way through thirteen different commercial antibodies before finally finding a suitable antibody for each of the four markers. The antibodies were evaluated based on signal-to-noise ratios as well as if positive cells were found in layers of the hippocampus where they have previously been described. Additionally, the antibodies were also tested on sections from mouse spinal cord with similar criteria for specificity of the antibodies. Using the antibodies with a high rating on pAbmAbs, an antibody review database, stainings with high signal-to-noise ratios and location of the immunostained cells in accordance with the literature could be obtained, making these antibodies suitable choices for

  4. Quantitative morphometry of electrophysiologically identified CA3b interneurons reveals robust local geometry and distinct cell classes.

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    Ascoli, Giorgio A; Brown, Kerry M; Calixto, Eduardo; Card, J Patrick; Galván, E J; Perez-Rosello, T; Barrionuevo, Germán

    2009-08-20

    The morphological and electrophysiological diversity of inhibitory cells in hippocampal area CA3 may underlie specific computational roles and is not yet fully elucidated. In particular, interneurons with somata in strata radiatum (R) and lacunosum-moleculare (L-M) receive converging stimulation from the dentate gyrus and entorhinal cortex as well as within CA3. Although these cells express different forms of synaptic plasticity, their axonal trees and connectivity are still largely unknown. We investigated the branching and spatial patterns, plus the membrane and synaptic properties, of rat CA3b R and L-M interneurons digitally reconstructed after intracellular labeling. We found considerable variability within but no difference between the two layers, and no correlation between morphological and biophysical properties. Nevertheless, two cell types were identified based on the number of dendritic bifurcations, with significantly different anatomical and electrophysiological features. Axons generally branched an order of magnitude more than dendrites. However, interneurons on both sides of the R/L-M boundary revealed surprisingly modular axodendritic arborizations with consistently uniform local branch geometry. Both axons and dendrites followed a lamellar organization, and axons displayed a spatial preference toward the fissure. Moreover, only a small fraction of the axonal arbor extended to the outer portion of the invaded volume, and tended to return toward the proximal region. In contrast, dendritic trees demonstrated more limited but isotropic volume occupancy. These results suggest a role of predominantly local feedforward and lateral inhibitory control for both R and L-M interneurons. Such a role may be essential to balance the extensive recurrent excitation of area CA3 underlying hippocampal autoassociative memory function.

  5. Immunohistochemical visualization of mouse interneuron subtypes [v1; ref status: indexed, http://f1000r.es/4em

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    Simon Molgaard

    2014-10-01

    Full Text Available The activity of excitatory neurons is controlled by a small, but highly diverse population of inhibitory interneurons. These cells show a high level of physiological, morphological and neurochemical heterogeneity, and play highly specific roles in neuronal circuits. In the mammalian hippocampus, these are divided into 21 different subtypes of GABAergic interneurons based on their expression of different markers, morphology and their electrophysiological properties. Ideally, all can be marked using an antibody directed against the inhibitory neurotransmitter GABA, but parvalbumin, calbindin, somatostatin, and calretinin are also commonly used as markers to narrow down the specific interneuron subtype. Here, we describe a journey to find the necessary immunological reagents for studying GABAergic interneurons of the mouse hippocampus. Based on web searches there are several hundreds of different antibodies on the market directed against these four markers. Searches in the literature databases allowed us to narrow it down to a subset of antibodies most commonly used in publications. However, in our hands the most cited ones did not work for immunofluorescence stainings of formaldehyde fixed tissue sections and cultured hippocampal neurons, and we had to immunostain our way through thirteen different commercial antibodies before finally finding a suitable antibody for each of the four markers. The antibodies were evaluated based on signal-to-noise ratios as well as if positive cells were found in layers of the hippocampus where they have previously been described. Additionally, the antibodies were also tested on sections from mouse spinal cord with similar criteria for specificity of the antibodies. Using the antibodies with a high rating on pAbmAbs, stainings with high signal-to-noise ratios and location of the immunostained cells in accordance with the literature could be obtained, making these antibodies suitable choices for studying the

  6. Classification of neocortical interneurons using affinity propagation

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    Roberto eSantana

    2013-12-01

    Full Text Available In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. Neuronal classification has been a difficult problem because it is unclear what a neuronal cell class actually is and what are the best characteristics are to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological or molecular characteristics, when applied to selected datasets, have provided quantitative and unbiased identification of distinct neuronal subtypes. However, better and more robust classification methods are needed for increasingly complex and larger datasets. We explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. In fact, using a combined anatomical/physiological dataset, our algorithm differentiated parvalbumin from somatostatin interneurons in 49 out of 50 cases. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits.

  7. The Stochastic Search Dynamics of Interneuron Migration

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    Britto, Joanne M.; Johnston, Leigh A.; Tan, Seong-Seng

    2009-01-01

    Abstract Migration is a dynamic process in which a cell searches the environment and translates acquired information into somal advancement. In particular, interneuron migration during development is accomplished by two distinct processes: the extension of neurites tipped with growth cones; and nucleus translocation, termed nucleokinesis. The primary purpose of our study is to investigate neurite branching and nucleokinesis using high-resolution time-lapse confocal microscopy and computational modeling. We demonstrate that nucleokinesis is accurately modeled by a spring-dashpot system and that neurite branching is independent of the nucleokinesis event, and displays the dynamics of a stochastic birth-death process. This is in contrast to traditional biological descriptions, which suggest a closer relationship between the two migratory mechanisms. Our models are validated on independent data sets acquired using two different imaging protocols, and are shown to be robust to alterations in guidance cues and cellular migratory mechanisms, through treatment with brain-derived neurotrophic factor, neurotrophin-4, and blebbistatin. We postulate that the stochastic branch dynamics exhibited by interneurons undergoing guidance-directed migration permit efficient exploration of the environment. PMID:19651028

  8. Parvalbumin Interneurons: All Forest, No Trees.

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    Trachtenberg, Joshua T

    2015-07-15

    There has been a surge of interest in how inhibitory neurons influence the output of local circuits in the brain. In this issue of Neuron, Scholl et al. (2015) provide a compelling argument for what one class of inhibitory neurons actually does.

  9. Role of cortical feedback in regulating inhibitory microcircuits.

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    Strowbridge, Ben W

    2009-07-01

    The olfactory bulb contains an impressive array of specialized inhibitory local circuits. The most frequent inhibitory microcircuit in this brain region is the reciprocal dendrodendritic synapse formed between the lateral dendrites of mitral cells and distal dendritic spines of GABAergic granule cells. Recent work discussed in this review suggests that release of GABA from granule cell spines may reflect near-coincident activation of both mitral cell-to-granule cell synapses and proximal excitatory synapses on granule cells that originate from pyramidal cells in piriform cortex. Recent work using two-photon guided microstimulation demonstrated that proximal and distal excitatory synapses onto granule cells exhibit different forms of short-term plasticity, with feedback inputs from piriform cortex facilitating when tested with brief ( approximately 50 ms) interstimulus intervals. One consequence of this synaptic plasticity is that short duration, gamma-frequency, oscillatory discharges in piriform cortical cells evoke summating excitatory postsynaptic potentials (EPSPs) in granule cells that effectively trigger action potentials. Piriform cortex stimulation can gate dendrodendritic inhibition onto mitral cells, presumably through the ability of EPSP-driven action potentials in granule cells to temporarily relieve the tonic blockade of NMDA receptors by extracellular Mg(2+) ions. Feedback projections in other CNS systems also may target inhibitory neurons, such as the backprojection from CA3 pyramidal neurons to GABAergic hilar interneurons. The ability of downstream processing areas to rapidly and selectively activate inhibitory interneurons in other brain regions may provide an important mechanism to dynamically modulate biological information processing.

  10. Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state.

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    Fuchs, T; Jefferson, S J; Hooper, A; Yee, P-Hp; Maguire, J; Luscher, B

    2016-11-08

    Major depressive disorder (MDD) is associated with reduced concentrations of γ-aminobutyric acid (GABA) that are normalized by antidepressant therapies. Moreover, depressive-like phenotypes of GABAA receptor mutant mice can be reversed by treatment with conventional antidepressants drugs, as well as by subanesthetic doses of ketamine. Thus GABAergic deficits may causally contribute to depressive disorders, while antidepressant therapies may enhance GABAergic synaptic transmission. Here we tested the hypothesis that sustained enhancement of GABAergic transmission alone is sufficient to elicit antidepressant-like behavior, using disinhibition of GABAergic interneurons. We focused on somatostatin-positive (SST(+)) GABAergic interneurons because of evidence that their function is compromised in MDD. To disinhibit SST(+) interneurons, we inactivated the γ2 subunit gene of GABAA receptors selectively in these neurons (SSTCre:γ2(f/f) mice). Loss of inhibitory synaptic input resulted in increased excitability of SST(+) interneurons. In turn, pyramidal cell targets of SST(+) neurons showed an increased frequency of spontaneous inhibitory postsynaptic currents. The behavior of SSTCre:γ2(f/f) mice mimicked the effects of anxiolytic and antidepressant drugs in a number of behavioral tests, without affecting performance in a spatial learning- and memory-dependent task. Finally, brain extracts of SSTCre:γ2(f/f) mice showed decreased phosphorylation of the eukaryotic elongation factor eEF2, reminiscent of the effects of ketamine. Importantly, these effects occurred without altered activity of the mammalian target of rapamycin pathway nor did they involve altered expression of SST. However, they were associated with reduced Ca(2+)/calmodulin-dependent auto-phosphorylation of eEF2 kinase, which controls the activity of eEF2 as its single target. Thus enhancing GABAergic inhibitory synaptic inputs from SST(+) interneurons to pyramidal cells and corresponding chronic reductions

  11. Inhibitory Gating of Input Comparison in the CA1 Microcircuit.

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    Milstein, Aaron D; Bloss, Erik B; Apostolides, Pierre F; Vaidya, Sachin P; Dilly, Geoffrey A; Zemelman, Boris V; Magee, Jeffrey C

    2015-09-23

    Spatial and temporal features of synaptic inputs engage integration mechanisms on multiple scales, including presynaptic release sites, postsynaptic dendrites, and networks of inhibitory interneurons. Here we investigate how these mechanisms cooperate to filter synaptic input in hippocampal area CA1. Dendritic recordings from CA1 pyramidal neurons reveal that proximal inputs from CA3 as well as distal inputs from entorhinal cortex layer III (ECIII) sum sublinearly or linearly at low firing rates due to feedforward inhibition, but sum supralinearly at high firing rates due to synaptic facilitation, producing a high-pass filter. However, during ECIII and CA3 input comparison, supralinear dendritic integration is dynamically balanced by feedforward and feedback inhibition, resulting in suppression of dendritic complex spiking. We find that a particular subpopulation of CA1 interneurons expressing neuropeptide Y (NPY) contributes prominently to this dynamic filter by integrating both ECIII and CA3 input pathways and potently inhibiting CA1 pyramidal neuron dendrites.

  12. Molecular mechanisms controlling the migration of striatal interneurons.

    Science.gov (United States)

    Villar-Cerviño, Verona; Kappeler, Caroline; Nóbrega-Pereira, Sandrina; Henkemeyer, Mark; Rago, Luciano; Nieto, M Angela; Marín, Oscar

    2015-06-10

    In the developing telencephalon, the medial ganglionic eminence (MGE) generates many cortical and virtually all striatal interneurons. While the molecular mechanisms controlling the migration of interneurons to the cortex have been extensively studied, very little is known about the nature of the signals that guide interneurons to the striatum. Here we report that the allocation of MGE-derived interneurons in the developing striatum of the mouse relies on a combination of chemoattractive and chemorepulsive activities. Specifically, interneurons migrate toward the striatum in response to Nrg1/ErbB4 chemoattraction, and avoid migrating into the adjacent cortical territories by a repulsive activity mediated by EphB/ephrinB signaling. Our results also suggest that the responsiveness of MGE-derived striatal interneurons to these cues is at least in part controlled by the postmitotic activity of the transcription factor Nkx2-1. This study therefore reveals parallel mechanisms for the migration of MGE-derived interneurons to the striatum and the cerebral cortex.

  13. Local interneurons define functionally distinct regions within lobster olfactory glomeruli

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    Wachowiak; Diebel; Ache

    1997-01-01

    Whole-cell recording coupled with biocytin injection revealed four types of interneurons intrinsic to the olfactory lobe (OL) of the spiny lobster Panulirus argus. Each type of neuron had a distinct pattern of arborization within the three anatomically defined regions of OL glomeruli (cap, subcap and base). Type I interneurons innervated all three regions, while types II, III and IV branched only in the cap, subcap and base, respectively. Type I interneurons responded to electrical stimulation of the antennular (olfactory) nerve with a burst of 1­20 action potentials and a 1­10 s depolarization. Type II (cap) interneurons responded to the same input with a burst of 1­3 action potentials followed by a shorter hyperpolarization. Type III (subcap) interneurons responded with a burst of 1­6 action potentials followed by a delayed, 0.5­4 s depolarization. Type IV (base) interneurons responded with a brief depolarization or a burst of 1­3 action potentials followed by a 1 s hyperpolarization. The regionalized arborization and the different response properties of the type II, III and IV interneurons strongly imply that lobster olfactory glomeruli contain functionally distinct regions, a feature that should be useful in understanding the multiple synaptic pathways involved in processing olfactory input.

  14. Cbln1 downregulates the formation and function of inhibitory synapses in mouse cerebellar Purkinje cells.

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    Ito-Ishida, Aya; Kakegawa, Wataru; Kohda, Kazuhisa; Miura, Eriko; Okabe, Shigeo; Yuzaki, Michisuke

    2014-04-01

    The formation of excitatory and inhibitory synapses must be tightly coordinated to establish functional neuronal circuitry during development. In the cerebellum, the formation of excitatory synapses between parallel fibers and Purkinje cells is strongly induced by Cbln1, which is released from parallel fibers and binds to the postsynaptic δ2 glutamate receptor (GluD2). However, Cbln1's role, if any, in inhibitory synapse formation has been unknown. Here, we show that Cbln1 downregulates the formation and function of inhibitory synapses between Purkinje cells and interneurons. Immunohistochemical analyses with an anti-vesicular GABA transporter antibody revealed an increased density of interneuron-Purkinje cell synapses in the cbln1-null cerebellum. Whole-cell patch-clamp recordings from Purkinje cells showed that both the amplitude and frequency of miniature inhibitory postsynaptic currents were increased in cbln1-null cerebellar slices. A 3-h incubation with recombinant Cbln1 reversed the increased amplitude of inhibitory currents in Purkinje cells in acutely prepared cbln1-null slices. Furthermore, an 8-day incubation with recombinant Cbln1 reversed the increased interneuron-Purkinje cell synapse density in cultured cbln1-null slices. In contrast, recombinant Cbln1 did not affect cerebellar slices from mice lacking both Cbln1 and GluD2. Finally, we found that tyrosine phosphorylation was upregulated in the cbln1-null cerebellum, and acute inhibition of Src-family kinases suppressed the increased inhibitory postsynaptic currents in cbln1-null Purkinje cells. These findings indicate that Cbln1-GluD2 signaling inhibits the number and function of inhibitory synapses, and shifts the excitatory-inhibitory balance towards excitation in Purkinje cells. Cbln1's effect on inhibitory synaptic transmission is probably mediated by a tyrosine kinase pathway.

  15. Hippocampal CA1 lacunosum-moleculare interneurons: modulation of monosynaptic GABAergic IPSCs by presynaptic GABAB receptors.

    Science.gov (United States)

    Khazipov, R; Congar, P; Ben-Ari, Y

    1995-11-01

    1. Whole cell patch-clamp recordings were employed to characterize monosynaptic inhibitory postsynaptic currents (IPSCs) in morphologically and electrophysiologically identified interneurons located in the stratum lacunosum moleculare, or near the border of the stratum radiatum (LM interneurons), in the CA1 region of hippocampal slices taken from 3- to 4-wk-old rats. Monosynaptic IPSCs, evoked in the presence of glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20 microM) and D-2-amino-5-phosphopentanoate (APV; 50 microM) were biphasic. The gamma-aminobutyric acid-A (GABAA) receptor antagonist, bicuculline (20 microM), blocked the fast IPSC, and the slow IPSC was blocked by the GABAB receptor antagonist CGP35348 (500 microM). 2. Monosynaptic IPSCs were evoked by electrical stimulation in several distant regions including the stratum radiatum, the stratum oriens, the stratum lacunosum-moleculare, and the molecular layer of dentate gyrus, suggesting an extensive network of inhibitory interneurons in the hippocampus. In paired recordings of CA1 interneurons and pyramidal cells, IPSCs were evoked by electrical stimulation of most of these distal regions with the exception of the molecular layer of dentate gyrus, which evoked an IPSC only in LM interneurons. 3. Frequent (> 0.1 Hz) stimulation depressed the evoked IPSCs. With a paired-pulse protocol, the second IPSC was depressed and the maximal depression (40-50%) was observed with an interstimulus interval of 100-200 ms. 4. The GABAB receptor agonist baclofen (1 microM) reduced the amplitude of evoked IPSCs and the paired-pulse depression of the second IPSC. The GABAB receptor antagonist CGP35348 (0.5-1 mM) had no significant effect on the amplitude of isolated IPSCs. However, CGP35348 reduced but did not fully block paired-pulse depression, suggesting that this depression is partly due to the activation of presynaptic GABAB receptors. 5. The paired-pulse depression depended on the level of

  16. Genetics and Function of Neocortical GABAergic Interneurons in Neurodevelopmental Disorders

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    E. Rossignol

    2011-01-01

    Full Text Available A dysfunction of cortical and limbic GABAergic circuits has been postulated to contribute to multiple neurodevelopmental disorders in humans, including schizophrenia, autism, and epilepsy. In the current paper, I summarize the characteristics that underlie the great diversity of cortical GABAergic interneurons and explore how the multiple roles of these cells in developing and mature circuits might contribute to the aforementioned disorders. Furthermore, I review the tightly controlled genetic cascades that determine the fate of cortical interneurons and summarize how the dysfunction of genes important for the generation, specification, maturation, and function of cortical interneurons might contribute to these disorders.

  17. Hippocampal CA1 Ripples as Inhibitory Transients.

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    Paola Malerba

    2016-04-01

    Full Text Available Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network.

  18. Hippocampal CA1 Ripples as Inhibitory Transients.

    Science.gov (United States)

    Malerba, Paola; Krishnan, Giri P; Fellous, Jean-Marc; Bazhenov, Maxim

    2016-04-01

    Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network.

  19. Ethanol affects striatal interneurons directly and projection neurons through a reduction in cholinergic tone.

    Science.gov (United States)

    Blomeley, Craig P; Cains, Sarah; Smith, Richard; Bracci, Enrico

    2011-04-01

    The acute effects of ethanol on the neurons of the striatum, a basal ganglia nucleus crucially involved in motor control and action selection, were investigated using whole-cell recordings. An intoxicating concentration of ethanol (50 mM) produced inhibitory effects on striatal large aspiny cholinergic interneurons (LAIs) and low-threshold spike interneurons (LTSIs). These effects persisted in the presence of tetrodotoxin and were because of an increase in potassium currents, including those responsible for medium and slow afterhyperpolarizations. In contrast, fast-spiking interneurons (FSIs) were directly excited by ethanol, which depolarized these neurons through the suppression of potassium currents. Medium spiny neurons (MSNs) became hyperpolarized in the presence of ethanol, but this effect did not persist in the presence of tetrodotoxin and was mimicked and occluded by application of the M1 muscarinic receptor antagonist telenzepine. Ethanol effects on MSNs were also abolished by 100 μM barium. This showed that the hyperpolarizations observed in MSNs were because of decreased tonic activation of M1 muscarinic receptors, resulting in an increase in Kir2 conductances. Evoked GABAergic responses of MSNs were reversibly decreased by ethanol with no change in paired-pulse ratio. Furthermore, ethanol impaired the ability of thalamostriatal inputs to inhibit a subsequent corticostriatal glutamatergic response in MSNs. These results offer the first comprehensive description of the highly cell type-specific effects of ethanol on striatal neurons and provide a cellular basis for the interpretation of ethanol influence on a brain area crucially involved in the motor and decisional impairment caused by this drug.

  20. Temporal organization of GABAergic interneurons in the intermediate CA1 hippocampus during network oscillations.

    Science.gov (United States)

    Forro, Thomas; Valenti, Ornella; Lasztoczi, Balint; Klausberger, Thomas

    2015-05-01

    Travelling theta oscillations and sharp wave-associated ripples (SWRs) provide temporal structures to neural activity in the CA1 hippocampus. The contribution of rhythm-generating GABAergic interneurons to network timing across the septotemporal CA1 axis remains unknown. We recorded the spike-timing of identified parvalbumin (PV)-expressing basket, axo-axonic, oriens-lacunosum moleculare (O-LM) interneurons, and pyramidal cells in the intermediate CA1 (iCA1) of anesthetized rats in relation to simultaneously detected network oscillations in iCA1 and dorsal CA1 (dCA1). Distinct interneuron types were coupled differentially to SWR, and the majority of iCA1 SWR events occurred simultaneously with dCA1 SWR events. In contrast, iCA1 theta oscillations were shifted in time relative to dCA1 theta oscillations. During theta cycles, the highest firing of iCA1 axo-axonic cells was followed by PV-expressing basket cells and subsequently by O-LM together with pyramidal cells, similar to the firing sequence of dCA1 cell types reported previously. However, we observed that this temporal organization of cell types is shifted in time between dCA1 and iCA1, together with the respective shift in theta oscillations. We show that GABAergic activity can be synchronized during SWR but is shifted in time from dCA1 to iCA1 during theta oscillations, highlighting the flexible inhibitory control of excitatory activity across a brain structure.

  1. Different populations of vasoactive intestinal polypeptide-immunoreactive interneurons are specialized to control pyramidal cells or interneurons in the hippocampus.

    Science.gov (United States)

    Acsády, L; Görcs, T J; Freund, T F

    1996-07-01

    The postsynaptic targets of three vasoactive intestinal polypeptide-containing GABAergic interneuron types were examined in the rat hippocampus. Two of them showed remarkable target selectivity for other GABAergic neurons, while the third contacted the somata and proximal dendrites of pyramidal cells. Vasoactive intestinal polypeptide-positive interneurons innervating the stratum oriens/alveus border in the CA1 region were shown to establish multiple contacts with horizontal GABAergic interneurons immunoreactive for type 1 metabotropic glutamate receptor. Similarly, identified axons of vasoactive intestinal polypeptide-positive interneurons projecting to stratum radiatum were found to establish symmetrical synapses largely on GABAergic dendrites. The majority of these postsynaptic GABAergic neurons were shown to contain calbindin or vasoactive intestinal polypeptide. In contrast to the first two vasoactive intestinal polypeptide-containing cell populations, vasoactive intestinal polypeptide-positive interneurons arborizing in stratum pyramidale formed baskets around pyramidal cells. These results revealed a new element in cortical microcircuits, interneurons which are specialized to innervate other GABAergic interneurons. The role of this new component may be the synchronization of dendritic inhibition, or an input-specific disinhibition of pyramidal cells in various dendritic domains. In contrast, vasoactive intestinal polypeptide-containing basket cells are likely to be involved in perisomatic inhibition of pyramidal neurons, and represents a new basket cell type different from that containing parvalbumin.

  2. Experience-Dependent Plasticity in Accessory Olfactory Bulb Interneurons following Male-Male Social Interaction.

    Science.gov (United States)

    Cansler, Hillary L; Maksimova, Marina A; Meeks, Julian P

    2017-07-26

    Chemosensory information processing in the mouse accessory olfactory system guides the expression of social behavior. After salient chemosensory encounters, the accessory olfactory bulb (AOB) experiences changes in the balance of excitation and inhibition at reciprocal synapses between mitral cells (MCs) and local interneurons. The mechanisms underlying these changes remain controversial. Moreover, it remains unclear whether MC-interneuron plasticity is unique to specific behaviors, such as mating, or whether it is a more general feature of the AOB circuit. Here, we describe targeted electrophysiological studies of AOB inhibitory internal granule cells (IGCs), many of which upregulate the immediate-early gene Arc after male-male social experience. Following the resident-intruder paradigm, Arc-expressing IGCs in acute AOB slices from resident males displayed stronger excitation than nonexpressing neighbors when sensory inputs were stimulated. The increased excitability of Arc-expressing IGCs was not correlated with changes in the strength or number of excitatory synapses with MCs but was instead associated with increased intrinsic excitability and decreased HCN channel-mediated IH currents. Consistent with increased inhibition by IGCs, MCs responded to sensory input stimulation with decreased depolarization and spiking following resident-intruder encounters. These results reveal that nonmating behaviors drive AOB inhibitory plasticity and indicate that increased MC inhibition involves intrinsic excitability changes in Arc-expressing interneurons.SIGNIFICANCE STATEMENT The accessory olfactory bulb (AOB) is a site of experience-dependent plasticity between excitatory mitral cells (MCs) and inhibitory internal granule cells (IGCs), but the physiological mechanisms and behavioral conditions driving this plasticity remain unclear. Here, we report studies of AOB neuronal plasticity following male-male social chemosensory encounters. We show that the plasticity

  3. Synaptic plasticity in inhibitory neurons of the auditory brainstem.

    Science.gov (United States)

    Bender, Kevin J; Trussell, Laurence O

    2011-04-01

    There is a growing appreciation of synaptic plasticity in the early levels of auditory processing, and particularly of its role in inhibitory circuits. Synaptic strength in auditory brainstem and midbrain is sensitive to standard protocols for induction of long-term depression, potentiation, and spike-timing-dependent plasticity. Differential forms of plasticity are operative at synapses onto inhibitory versus excitatory neurons within a circuit, and together these could serve to tune circuits involved in sound localization or multisensory integration. Such activity-dependent control of synaptic function in inhibitory neurons may also be expressed after hearing loss and could underlie persistent neuronal activity in patients with tinnitus. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'.

  4. Expression and distribution of Kv4 potassium channel subunits and potassium channel interacting proteins in subpopulations of interneurons in the basolateral amygdala.

    Science.gov (United States)

    Dabrowska, J; Rainnie, D G

    2010-12-15

    The Kv4 potassium channel α subunits, Kv4.1, Kv4.2, and Kv4.3, determine some of the fundamental physiological properties of neurons in the CNS. Kv4 subunits are associated with auxiliary β-subunits, such as the potassium channel interacting proteins (KChIP1 - 4), which are thought to regulate the trafficking and gating of native Kv4 potassium channels. Intriguingly, KChIP1 is thought to show cell type-selective expression in GABA-ergic inhibitory interneurons, while other β-subunits (KChIP2-4) are associated with principal glutamatergic neurons. However, nothing is known about the expression of Kv4 family α- and β-subunits in specific interneurons populations in the BLA. Here, we have used immunofluorescence, co-immunoprecipitation, and Western Blotting to determine the relative expression of KChIP1 in the different interneuron subtypes within the BLA, and its co-localization with one or more of the Kv4 α subunits. We show that all three α-subunits of Kv4 potassium channel are found in rat BLA neurons, and that the immunoreactivity of KChIP1 closely resembles that of Kv4.3. Indeed, Kv4.3 showed almost complete co-localization with KChIP1 in the soma and dendrites of a distinct subpopulation of BLA neurons. Dual-immunofluorescence studies revealed this to be in BLA interneurons immunoreactive for parvalbumin, cholecystokin-8, and somatostatin. Finally, co-immunoprecipitation studies showed that KChIP1 was associated with all three Kv4 α subunits. Together our results suggest that KChIP1 is selectively expressed in BLA interneurons where it may function to regulate the activity of A-type potassium channels. Hence, KChIP1 might be considered as a cell type-specific regulator of GABAergic inhibitory circuits in the BLA.

  5. Activation of prefrontal cortical parvalbumin interneurons facilitates extinction of reward-seeking behavior.

    Science.gov (United States)

    Sparta, Dennis R; Hovelsø, Nanna; Mason, Alex O; Kantak, Pranish A; Ung, Randall L; Decot, Heather K; Stuber, Garret D

    2014-03-05

    Forming and breaking associations between emotionally salient environmental stimuli and rewarding or aversive outcomes is an essential component of learned adaptive behavior. Importantly, when cue-reward contingencies degrade, animals must exhibit behavioral flexibility to extinguish prior learned associations. Understanding the specific neural circuit mechanisms that operate during the formation and extinction of conditioned behaviors is critical because dysregulation of these neural processes is hypothesized to underlie many of the maladaptive and pathological behaviors observed in various neuropsychiatric disorders in humans. The medial prefrontal cortex (mPFC) participates in the behavioral adaptations seen in both appetitive and aversive-cue-mediated responding, but the precise cell types and circuit mechanisms sufficient for driving these complex behavioral states remain largely unspecified. Here, we recorded and manipulated the activity of parvalbumin-positive fast spiking interneurons (PV+ FSIs) in the prelimbic area (PrL) of the mPFC in mice. In vivo photostimulation of PV+ FSIs resulted in a net inhibition of PrL neurons, providing a circuit blueprint for behavioral manipulations. Photostimulation of mPFC PV+ cells did not alter anticipatory or consummatory licking behavior during reinforced training sessions. However, optical activation of these inhibitory interneurons to cues associated with reward significantly accelerated the extinction of behavior during non-reinforced test sessions. These data suggest that suppression of excitatory mPFC networks via increased activity of PV+ FSIs may enhance reward-related behavioral flexibility.

  6. Dynamics and diversity in interneurons: a model exploration with slowly inactivating potassium currents.

    Science.gov (United States)

    Saraga, F; Skinner, F K

    2002-01-01

    Recent experimental and model work indicates that slowly inactivating potassium currents might play critical roles in generating population rhythms. In particular, slow (hippocampus correlate with oscillatory behaviors in interneurons in this frequency range. Limiting the ion channels to the traditional Hodgkin-Huxley sodium and potassium currents, a persistent sodium current, and a slowly inactivating potassium current, we explore the role of slowly inactivating conductances in a multi-compartmental interneuronal model. We find a rich repertoire of tonic and bursting behaviors depending on the distribution, density and kinetics of this conductance. Specifically, burst frequencies of appropriate frequencies could be obtained for certain distributions and kinetics of this conductance. Robust (with respect to injected currents) regimes of tonic firing and bursting behaviors are uncovered. In addition, we find a bistable tonic firing pattern that depends on the slowly inactivating potassium current. Therefore, this work shows ways in which different channel distributions and heterogeneities could produce variable signal outputs. We suggest that an understanding of the dynamical profiles of inhibitory neurons based on the density and distribution of their currents is helpful in dissecting out the complex roles played by this heterogeneous group of cells.

  7. Repeated cocaine exposure increases fast-spiking interneuron excitability in the rat medial prefrontal cortex.

    Science.gov (United States)

    Campanac, Emilie; Hoffman, Dax A

    2013-06-01

    The medial prefrontal cortex plays a key role in cocaine addiction. However, how chronic cocaine exposure affects cortical networks remains unclear. Most studies have focused on layer 5 pyramidal neurons (the circuit output), while the response of local GABAergic interneurons to cocaine remains poorly understood. Here, we recorded from fast-spiking interneurons (FS-IN) after repeated cocaine exposure and found altered membrane excitability. After cocaine withdrawal, FS-IN showed an increase in the number of spikes evoked by positive current injection, increased input resistance, and decreased hyperpolarization-activated current. We also observed a reduction in miniature excitatory postsynaptic currents, whereas miniature inhibitory postsynaptic current activity was unaffected. We show that, in animals with cocaine history, dopamine receptor D(2) activation is less effective in increasing FS-IN intrinsic excitability. Interestingly, these alterations are only observed 1 wk or more after the last cocaine exposure. This suggests that the dampening of D(2)-receptor-mediated response may be a compensatory mechanism to rein down the excitability of FS-IN.

  8. Evidence for the existence of non-GABAergic, cholinergic interneurons in the rodent hippocampus.

    Science.gov (United States)

    Frotscher, M; Vida, I; Bender, R

    2000-01-01

    Previous studies have revealed a small number of hippocampal interneurons immunoreactive for choline acetyltransferase, the acetylcholine-synthesizing enzyme. It remained an open question, however, whether these neurons represented a subgroup of inhibitory GABAergic neurons co-localizing acetylcholine. In this study, we have combined immunocytochemistry for choline acetyltransferase and in situ hybridization for glutamate decarboxylase messenger RNA, the GABA-synthesizing enzyme. None of the choline acetyltransferase-immunoreactive neurons in the various layers of the hippocampus proper and fascia dentata were found to co-localize glutamate decarboxylase messenger RNA. The lack of an in situ hybridization signal in these neurons is unlikely to result from the combination of the two labeling techniques. When combining in situ hybridization for glutamate decarboxylase messenger RNA with immunostaining for parvalbumin, a calcium-binding protein expressed by many GABAergic hippocampal interneurons, numerous double-labeled cells were observed. These data provide neurochemical evidence for the existence of non-GABAergic, supposedly cholinergic non-principal cells in the hippocampus.

  9. Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons.

    Science.gov (United States)

    Tan, Guo-He; Liu, Yuan-Yuan; Hu, Xiao-Ling; Yin, Dong-Min; Mei, Lin; Xiong, Zhi-Qi

    2011-12-11

    Epilepsy is a common and refractory neurological disorder, but the neuronal regulatory mechanisms of epileptogenesis remain largely unclear. Activity-dependent transcription of genes for neurotrophins such as brain-derived neurotrophic factor (BDNF) has been shown to promote epileptogenesis; however, little is known about factors that may act as intrinsic, homeostatic or counterbalancing mechanisms. Using rodent models, here we show that limbic seizure activity upregulated NRG1-ErbB4 signaling and that epileptogenesis was inhibited by infusing NRG1 intracerebrally but exacerbated by neutralizing endogenous NRG1 with soluble ErbB4 extracellular domain, by inhibiting ErbB4 activation or by deleting the Erbb4 gene. Furthermore, specific depletion of ErbB4 in parvalbumin-expressing interneurons abolished NRG1-mediated inhibition of epileptogenesis and promoted kindling progression, resulting in increased spontaneous seizures and exuberant mossy fiber sprouting. In contrast, depleting ErbB4 in CaMKIIα-positive pyramidal neurons had no effect. Thus, NRG1-induced activation of ErbB4 in parvalbumin-expressing inhibitory interneurons may serve as a critical endogenous negative-feedback mechanism to suppress limbic epileptogenesis.

  10. Early establishment of multiple release site connectivity between interneurons and pyramidal neurons in the developing hippocampus.

    Science.gov (United States)

    Groc, Laurent; Gustafsson, Bengt; Hanse, Eric

    2003-05-01

    The strength of the synaptic transmission between two neurons critically depends on the number of release sites connecting the neurons. Here we examine the development of connectivity between gamma-aminobutyric acid (GABA)ergic interneurons and CA1 pyramidal neurons in the hippocampus. GABAergic postsynaptic currents (PSCs) were recorded in whole-cell voltage-clamped CA1 pyramidal neurons. By comparing spontaneous and miniature (action potential-independent) GABAergic PSCs, we found that multiple release site connectivity is established already at the first postnatal day and that the degree of connectivity remains unaltered into adulthood. During the same time there is a dramatic increase in the number of GABAergic synapses on each pyramidal neuron as indicated by the increase in frequency of miniature GABAergic PSCs. These results indicate that during development a given interneuron contacts an increasing number of target pyramidal neurons but with the same multiple release site connectivity. It has been shown previously that the connectivity between CA3 and CA1 pyramidal neurons is initially restricted to one release site, and develops gradually. The present result thus suggests different mechanisms to govern the maturation of excitatory and inhibitory synaptic transmissions.

  11. Two Loci of expression for long-term depression at hippocampal mossy fiber-interneuron synapses.

    Science.gov (United States)

    Lei, Saobo; McBain, Chris J

    2004-03-03

    Two distinct forms of long-term depression (LTD) exist at mossy fiber synapses between dentate gyrus granule cells and hippocampal CA3 stratum lucidum interneurons. Although induction of each form of LTD requires an elevation of postsynaptic intracellular Ca2+, at Ca2+-impermeable AMPA receptor (CI-AMPAR) synapses, induction is NMDA receptor (NMDAR) dependent, whereas LTD at Ca2+-permeable AMPA receptor (CP-AMPAR) synapses is NMDAR independent. However, the expression locus of either form of LTD is not known. Using a number of criteria, including the coefficient of variation, paired-pulse ratio, AMPA-NMDA receptor activity, and the low-affinity AMPAR antagonist gamma-D-glutamyl-glycine, we demonstrate that LTD expression at CP-AMPAR synapses is presynaptic and results from reduced transmitter release, whereas LTD expression at CI-AMPAR synapses is postsynaptic. The N-ethylmaleimide-sensitive fusion protein-AP2-clathrin adaptor protein 2 inhibitory peptide pep2m occluded LTD expression at CI-AMPAR synapses but not at CP-AMPAR synapses, confirming that CI-AMPAR LTD involves postsynaptic AMPAR trafficking. Thus, mossy fiber innervation of CA3 stratum lucidum interneurons occurs via two parallel systems targeted to either Ca2+-permeable or Ca2+-impermeable AMPA receptors, each with a distinct expression locus for long-term synaptic plasticity.

  12. Apical versus Basal Neurogenesis Directs Cortical Interneuron Subclass Fate

    Directory of Open Access Journals (Sweden)

    Timothy J. Petros

    2015-11-01

    Full Text Available Fate determination in the mammalian telencephalon, with its diversity of neuronal subtypes and relevance to neuropsychiatric disease, remains a critical area of study in neuroscience. Most studies investigating this topic focus on the diversity of neural progenitors within spatial and temporal domains along the lateral ventricles. Often overlooked is whether the location of neurogenesis within a fate-restricted domain is associated with, or instructive for, distinct neuronal fates. Here, we use in vivo fate mapping and the manipulation of neurogenic location to demonstrate that apical versus basal neurogenesis influences the fate determination of major subgroups of cortical interneurons derived from the subcortical telencephalon. Somatostatin-expressing interneurons arise mainly from apical divisions along the ventricular surface, whereas parvalbumin-expressing interneurons originate predominantly from basal divisions in the subventricular zone. As manipulations that shift neurogenic location alter interneuron subclass fate, these results add an additional dimension to the spatial-temporal determinants of neuronal fate determination.

  13. Disruption of mGluR5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders.

    Science.gov (United States)

    Barnes, S A; Pinto-Duarte, A; Kappe, A; Zembrzycki, A; Metzler, A; Mukamel, E A; Lucero, J; Wang, X; Sejnowski, T J; Markou, A; Behrens, M M

    2015-10-01

    Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv(+)) fast-spiking interneurons, have been proposed as underlying causes of several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv(+) GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv(+) interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv(+) interneurons resulted in reduced numbers of Pv(+) neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv(+) neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders.

  14. Delta-opioid receptors mediate unique plasticity onto parvalbumin-expressing interneurons in area CA2 of the hippocampus.

    Science.gov (United States)

    Piskorowski, Rebecca A; Chevaleyre, Vivien

    2013-09-04

    Inhibition is critical for controlling information transfer in the brain. However, the understanding of the plasticity and particular function of different interneuron subtypes is just emerging. Using acute hippocampal slices prepared from adult mice, we report that in area CA2 of the hippocampus, a powerful inhibitory transmission is acting as a gate to prevent CA3 inputs from driving CA2 neurons. Furthermore, this inhibition is highly plastic, and undergoes a long-term depression following high-frequency 10 Hz or theta-burst induction protocols. We describe a novel form of long-term depression at parvalbumin-expressing (PV+) interneuron synapses that is dependent on delta-opioid receptor (DOR) activation. Additionally, PV+ interneuron transmission is persistently depressed by DOR activation in area CA2 but only transiently depressed in area CA1. These results provide evidence for a differential temporal modulation of PV+ synapses between two adjacent cortical circuits, and highlight a new function of PV+ cells in controlling information transfer.

  15. Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons.

    Science.gov (United States)

    Wulff, Peer; Ponomarenko, Alexey A; Bartos, Marlene; Korotkova, Tatiana M; Fuchs, Elke C; Bähner, Florian; Both, Martin; Tort, Adriano B L; Kopell, Nancy J; Wisden, William; Monyer, Hannah

    2009-03-03

    Hippocampal theta (5-10 Hz) and gamma (35-85 Hz) oscillations depend on an inhibitory network of GABAergic interneurons. However, the lack of methods for direct and cell-type-specific interference with inhibition has prevented better insights that help link synaptic and cellular properties with network function. Here, we generated genetically modified mice (PV-Deltagamma(2)) in which synaptic inhibition was ablated in parvalbumin-positive (PV+) interneurons. Hippocampal local field potential and unit recordings in the CA1 area of freely behaving mice revealed that theta rhythm was strongly reduced in these mice. The characteristic coupling of theta and gamma oscillations was strongly altered in PV-Deltagamma(2) mice more than could be accounted for by the reduction in theta rhythm only. Surprisingly, gamma oscillations were not altered. These data indicate that synaptic inhibition onto PV+ interneurons is indispensable for theta- and its coupling to gamma oscillations but not for rhythmic gamma-activity in the hippocampus. Similar alterations in rhythmic activity were obtained in a computational hippocampal network model mimicking the genetic modification, suggesting that intrahippocampal networks might contribute to these effects.

  16. Hyperactive Somatostatin Interneurons Contribute to Excitotoxicity in Neurodegenerative Disorders

    Science.gov (United States)

    Liang, Bo; Schroeder, David; Zhang, Zhong-wei; Cox, Gregory A.; Li, Yun; Lin, Da-Ting

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders whose pathogenesis remains largely unknown. Here using TDP-43A315T mice, an ALS and FTD model with profound cortical pathology, we demonstrated that hyperactive somatostatin interneurons disinhibited layer 5 pyramidal neurons (L5-PN) and contributed to their excitotoxicity. Focal ablation of somatostatin interneurons efficiently restored normal excitability of L5-PN and alleviated neurodegeneration, suggesting a novel therapeutic target for ALS and FTD. PMID:26900927

  17. Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties

    OpenAIRE

    Casale, Amanda E.; Foust, Amanda J.; Bal, Thierry; McCormick, David A.

    2015-01-01

    The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two o...

  18. A NOVEL FUNCTIONALLY DISTINCT SUBTYPE OF STRIATAL NPY INTERNEURON

    OpenAIRE

    Ibáñez-Sandoval, Osvaldo; Tecuapetla, Fatuel; Unal, Bengi; Shah, Fulva; Koós, Tibor; Tepper, James M.

    2011-01-01

    We investigated the properties of neostriatal neuropeptide Y (NPY)-expressing interneurons in transgenic green fluorescent protein (GFP)-NPY reporter mice. In vitro whole cell recordings and biocytin staining demonstrated the existence of a novel class of neostriatal NPY-expressing GABAergic interneurons that exhibit electrophysiological, neurochemical and morphological properties strikingly different from those of previously described NPY-containing, plateau-depolarization low-threshold spik...

  19. Dopaminergic and Cholinergic Modulation of Striatal Tyrosine Hydroxylase Interneurons

    OpenAIRE

    Ibáñez-Sandoval, Osvaldo; Xenias, Harry S.; Tepper, James M.; Koós, Tibor

    2015-01-01

    The recent electrophysiological characterization of TH-expressing GABAergic interneurons (THINs) in the neostriatum revealed an unexpected degree of diversity of interneurons in this brain area (Ibáñez-Sandoval et al., 2010, Unal et al., 2011, 2013). Despite being relatively few in number, THINs may play a significant role in transmitting and distributing extra- and intrastriatal neuromodulatory signals in the striatal circuitry. Here we investigated the dopaminergic and cholinergic regulatio...

  20. Neuregulin 1/ErbB4 enhances synchronized oscillations of prefrontal cortex neurons via inhibitory synapses.

    Science.gov (United States)

    Hou, X-J; Ni, K-M; Yang, J-M; Li, X-M

    2014-03-07

    Both neuregulin 1 (NRG1) and its receptor ErbB4 are susceptibility genes for schizophrenia. Reduced synchronization of evoked oscillations in several cortical regions, especially in the prefrontal cortex, is associated with the core symptoms of schizophrenia. Recent studies have reported that NRG1 may affect the hippocampal oscillations. However, the role of NRG1/ErbB4 signaling in the synchronization of neurons in the prefrontal cortex is unclear. Here, we found that NRG1 enhanced the synchrony of pyramidal neurons via presynaptic interneurons. Meanwhile, NRG1 also increased the synchrony between pairs of fast-spiking interneurons and pairs of fast-spiking and non-fast-spiking interneurons in the prefrontal cortex, and this effect was mediated by ErbB4 receptors. Moreover, the NRG1-enhanced synchrony of interneurons was through their mutually-inhibitory synapses but not electrical coupling. Furthermore, kainate-induced gamma oscillations in vivo were enhanced by NRG1 and did not change in Dlx5/6-ErbB4(-/-) mice in which the ErbB4 receptors were specifically knocked out in interneurons of the frontal brain. Overall, our findings suggested that NRG1/ErbB4 signaling plays an important role in the synchronized oscillations of the whole network in the prefrontal cortex that are impaired in schizophrenia.

  1. IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase.

    Directory of Open Access Journals (Sweden)

    Laura L Dugan

    imply that IL-6 levels may predict adverse CNS effects in older patients exposed to these compounds through specific derangements in inhibitory interneurons, and that therapies directed at lowering IL-6 may have cognitive benefits clinically.

  2. Interneuron diversity series: containing the detonation--feedforward inhibition in the CA3 hippocampus.

    Science.gov (United States)

    Lawrence, J Josh; McBain, Chris J

    2003-11-01

    Feedforward inhibitory circuits are involved both in the suppression of excitability and timing of action potential generation in principal cells. In the CA3 hippocampus, a single mossy fiber from a dentate gyrus granule cell forms giant boutons with multiple release sites, which are capable of detonating CA3 principal cells. By contrast, mossy fiber terminals form a larger number of Lilliputian-sized synapses with few release sites onto local circuit interneurons, with distinct presynaptic and postsynaptic properties. This dichotomy between the two synapse types endows the circuit with exquisite control over pyramidal cell discharge. Under pathological conditions where feedforward inhibition is compromised, focal excitation is no longer contained, rendering the circuit susceptible to hyperexcitability.

  3. A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons.

    Science.gov (United States)

    Rosato-Siri, Marcelo D; Zambello, Erika; Mutinelli, Chiara; Garbati, Nicoletta; Benedetti, Roberto; Aldegheri, Laura; Graziani, Francesca; Virginio, Caterina; Alvaro, Giuseppe; Large, Charles H

    2015-09-01

    Kv3.1 and Kv3.2 high voltage-activated potassium channels, which display fast activation and deactivation kinetics, are known to make a crucial contribution to the fast-spiking phenotype of certain neurons. Pharmacological experiments show that the blockade of native Kv3 currents with low concentrations of tetraethylammonium or 4-aminopyridine impairs the expression of this firing phenotype. In particular, Kv3 channels are highly expressed by fast-spiking, parvalbumin-positive interneurons in corticolimbic brain circuits, which modulate the synchronization of cortical circuits and the generation of brain rhythms. Here, we describe a novel small molecule, (5R)-5-ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione (AUT1), which modulates Kv3.1 and Kv3.2 channels in human recombinant and rodent native neurons. AUT1 increased whole currents mediated by human Kv3.1b and Kv3.2a channels, with a concomitant leftward shift in the voltage dependence of activation. A less potent effect was observed on hKv3.3 currents. In mouse somatosensory cortex slices in vitro, AUT1 rescued the fast-spiking phenotype of parvalbumin-positive-fast-spiking interneurons following an impairment of their firing capacity by blocking a proportion of Kv3 channels with a low concentration of tetraethylammonium. Notably, AUT1 had no effect on interneuron firing when applied alone. Together, these data confirm the role played by Kv3 channels in the regulation of the firing phenotype of somatosensory interneurons and suggest that AUT1 and other Kv3 modulators could represent a new and promising therapeutic approach to the treatment of disorders associated with dysfunction of inhibitory feedback in corticolimbic circuits, such as schizophrenia.

  4. Sleep Impairment and Reduced Interneuron Excitability in a Mouse Model of Dravet Syndrome

    Science.gov (United States)

    Kalume, Franck; Oakley, John C.; Westenbroek, Ruth E.; Gile, Jennifer; de la Iglesia, Horacio O.; Scheuer, Todd; Catterall, William A.

    2015-01-01

    Dravet Syndrome (DS) is caused by heterozygous loss-of-function mutations in voltage-gated sodium channel NaV1.1. Our genetic mouse model of DS recapitulates its severe seizures and premature death. Sleep disturbance is common in DS, but its mechanism is unknown. Electroencephalographic studies revealed abnormal sleep in DS mice, including reduced delta wave power, reduced sleep spindles, increased brief wakes, and numerous interictal spikes in Non-Rapid-Eye-Movement sleep. Theta power was reduced in Rapid-Eye-Movement sleep. Mice with NaV1.1 deleted specifically in forebrain interneurons exhibited similar sleep pathology to DS mice, but without changes in circadian rhythm. Sleep architecture depends on oscillatory activity in the thalamocortical network generated by excitatory neurons in the ventrobasal nucleus (VBN) of the thalamus and inhibitory GABAergic neurons in the reticular nucleus of the thalamus (RNT). Whole-cell NaV current was reduced in GABAergic RNT neurons but not in VBN neurons. Rebound firing of action potentials following hyperpolarization, the signature firing pattern of RNT neurons during sleep, was also reduced. These results demonstrate imbalance of excitatory vs. inhibitory neurons in this circuit. As predicted from this functional impairment, we found substantial deficit in homeostatic rebound of slow wave activity following sleep deprivation. Although sleep disorders in epilepsies have been attributed to anti-epileptic drugs, our results show that sleep disorder in DS mice arises from loss of NaV1.1 channels in forebrain GABAergic interneurons without drug treatment. Impairment of NaV currents and excitability of GABAergic RNT neurons are correlated with impaired sleep quality and homeostasis in these mice. PMID:25766678

  5. Human prefrontal layer II interneurons in areas 46, 10 and 24.

    Science.gov (United States)

    Arteaga, Gabriel; Buritica, Efrain; Escobar, Martha Isabel; Pimienta, Hernan

    2015-01-01

    Prefrontal cortex (PFC) represents the highest level of integration and control of psychic and behavioral states. Several dysfunctions such as autism, hyperactivity disorders, depression, and schizophrenia have been related with alterations in the prefrontal cortex (PFC). Among the cortical layers of the PFC, layer II shows a particular vertical pattern of organization, the highest cell density and the biggest non-pyramidal/pyramidal neuronal ratio. We currently characterized the layer II cytoarchitecture in human areas 10, 24, and 46. We focused particularly on the inhibitory neurons taking into account that these cells are involved in sustained firing (SF) after stimuli disappearance. Postmortem samples from five subjects who died by causes different to central nervous system diseases were studied. Immunohistochemistry for the neuronal markers, NeuN, parvalbumin (PV), calbindin (CB), and calretinin (CR) were used. NeuN targeted the total neuronal population while the rest of the markers specifically the interneurons. Cell density and soma size were statically different between areas 10, 46, 24 when using NeuN. Layer II of area 46 showed the highest cell density. Regarding interneurons, PV+-cells of area 46 showed the highest density and size, in accordance to the proposal of a dual origin of the cerebral cortex. Interhemispheric asymmetries were not identified between homologue areas. First, our findings suggest that layer II of area 46 exhibits the most powerful inhibitory system compared to the other prefrontal areas analyzed. This feature is not only characteristic of the PFC but also supports a particular role of layer II of area 46 in SF. Additionally, known functional asymmetries between hemispheres might not be supported by morphological asymmetries.

  6. Physiological and morphological diversity of immunocytochemically defined parvalbumin- and cholecystokinin-positive interneurones in CA1 of the adult rat hippocampus.

    Science.gov (United States)

    Pawelzik, Hannelore; Hughes, David I; Thomson, Alex M

    2002-02-18

    To investigate the electrophysiological properties, synaptic connections, and anatomy of individual parvalbumin-immunoreactive (PV-IR) and cholecystokinin-immunoreactive (CCK-IR) interneurones in CA1, dual intracellular recordings using biocytin-filled microelectrodes in slices of adult rat hippocampus were combined with fluorescence labelling of PV- and CCK-containing cells. Of 36 PV-IR cells, 29 were basket cells, with most of their axonal arbours in the stratum pyramidale (SP). Six were bistratified cells with axons ramifying throughout stratum oriens (SO) and stratum radiatum (SR). One was a putative axo-axonic cell with an axonal arbour confined to half of the SP and a narrow adjacent region of the SO. Of 27 CCK-IR neurones, 13 were basket cells, with most of their axonal arbours in the SP, and included basket cells with somata in the SP (6), SO (3), and SR (2) and at the border between the stratum lacunosum-moleculare (SLM) and the SR (2). In addition, several dendrite-targeting cell classes expressed CCK-IR: 4 of 9 bistratified cells with axons ramifying in the SO and SR; all five Schaffer-associated cells whose axons ramified extensively in the SR; both cells classified as quadrilaminar because their axons ramified in the SO, SP, SR, and SLM; one SO-SO cell whose dendritic and axonal arbours were contained within the SO; and one perforant path-associated cell with axonal and dendritic arbours within the distal SR and SLM. The majority (31 of 36) of PV-IR neurones recorded were fast-spiking, and most fast-spiking cells tested (25 of 29 basket, 1 axo-axonic, and 5 of 6 bistratified cells) were PV-IR. However, 1 of 6 regular-spiking basket, 1 of 4 regular-spiking bistratified, and 3 of 5 burst-firing basket cells were also PV-IR. In contrast, the majority (17 of 27) of the CCK-IR neurones recorded were regular-spiking, 3 were burst-firing, and 7 were fast-spiking. These data confirm that the majority of PV-IR and CCK-IR axon terminals innervate proximal

  7. In Vivo Effect of a 5-HT7 Receptor Agonist on 5-HT Neurons and GABA Interneurons in the Dorsal Raphe Nuclei of Sham and PD Rats.

    Science.gov (United States)

    Wang, Shuang; Zhao, Yan; Gao, Jie; Guo, Yufang; Wang, Xiang; Huo, Jian; Wei, Ping; Cao, Jian

    2017-03-01

    The 5-hydroxytryptamine (5-HT; serotonin) neurotransmission is severely affected by the degeneration of nigrostriatal dopaminergic neurons. Here, we report the effects of the systemic administration of the 5-HT7 receptor agonist AS-19. In sham rats, the mean response of the 5-HT neurons in the dorsal raphe nucleus (DRN) to systemic AS-19 was excitatory and the mean response of the γ-aminobutyric acid (GABA) interneurons was inhibitory. In Parkinson disease (PD) rats, the same dose did not affect the 5-HT neurons and only high doses (640 μg/kg intravenous) were able to the increase GABA interneuron activity. These results indicate that DRN 5-HT neurons and GABA interneurons are regulated by the activation of 5-HT7 receptors and that the degeneration of the nigrostriatal pathway leads to decreased responses of these neurons to AS-19, which in turn suggests that the 5-HT7 receptors on 5-HT neurons and GABA interneurons in PD rats are dysfunctional and downregulated.

  8. Loss of COUP-TFI alters the balance between caudal ganglionic eminence- and medial ganglionic eminence-derived cortical interneurons and results in resistance to epilepsy.

    Science.gov (United States)

    Lodato, Simona; Tomassy, Giulio Srubek; De Leonibus, Elvira; Uzcategui, Yoryani G; Andolfi, Gennaro; Armentano, Maria; Touzot, Audrey; Gaztelu, Jose M; Arlotta, Paola; Menendez de la Prida, Liset; Studer, Michèle

    2011-03-23

    In rodents, cortical interneurons originate from the medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) according to precise temporal schedules. The mechanisms controlling the specification of CGE-derived interneurons and their role in cortical circuitry are still unknown. Here, we show that COUP-TFI expression becomes restricted to the dorsal MGE and CGE at embryonic day 13.5 in the basal telencephalon. Conditional loss of function of COUP-TFI in subventricular precursors and postmitotic cells leads to a decrease of late-born, CGE-derived, VIP (vasoactive intestinal peptide)- and CR (calretinin)-expressing bipolar cortical neurons, compensated by the concurrent increase of early-born MGE-derived, PV (parvalbumin)-expressing interneurons. Strikingly, COUP-TFI mutants are more resistant to pharmacologically induced seizures, a phenotype that is dependent on GABAergic signaling. Together, our data indicate that COUP-TFI controls the delicate balance between MGE- and CGE-derived cortical interneurons by regulating intermediate progenitor divisions and ultimately affecting the activity of the cortical inhibitory circuitry.

  9. Interneurons containing calretinin are specialized to control other interneurons in the rat hippocampus.

    Science.gov (United States)

    Gulyás, A I; Hájos, N; Freund, T F

    1996-05-15

    Spine-free calretinin-immunoreactive (CR-IR) interneurons form a subpopulation of GABAergic cells in the rat hippocampus. A characteristic feature of these cells--located in all areas and layers--is the frequent dendro-dendritic and axo-dendritic contacts they form with each other. In this study we examined in detail the connectivity of these neurons by reconstructing their dendritic and axonal arbor and by identifying their postsynaptic targets. Radially running dendrites of CR-IR cells, located in different layers, intermingled into long braids. An average cell was in contact with dendrites of three to seven other CR-IR cells. Reconstruction of the dendritic trees from six consecutive sections demonstrated that at least 15 cells may participate in a dendro-dendritically connected cluster. Electron microscopical examination revealed that regularly spaced zonula adherentia connect the touching dendrites. The postsynaptic targets of CR-IR neurons have been examined using postembedding immunogold staining for GABA. CR-containing GABA-immunoreactive axons of local origin formed multiple symmetrical synaptic contacts (two to five) exclusively on GABAergic dendrites (CR-negative as well as CR-positive). Two to 10 CR-IR axons may converge onto a single CR-IR neuron, often from cells belonging to the same dendro-dendritically connected cluster. Using double immunocytochemistry, CR-IR cells were shown to heavily innervate calbindin D28k-containing interneurons and VIP-containing basket cells but avoided the parvalbumin-containing basket and axo-axonic cells. The unique connectivity of CR-IR cells may enable them to play a crucial role in the generation of synchronous, rhythmic hippocampal activity by controlling other interneurons terminating on different dendritic and somatic compartments of principal cells.

  10. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice.

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    Laura Leung

    Full Text Available Apolipoprotein (apo E4 is the major genetic risk factor for Alzheimer's disease (AD. ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive--but not NPY- or parvalbumin-positive-interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype.

  11. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice.

    Science.gov (United States)

    Leung, Laura; Andrews-Zwilling, Yaisa; Yoon, Seo Yeon; Jain, Sachi; Ring, Karen; Dai, Jessica; Wang, Max Mu; Tong, Leslie; Walker, David; Huang, Yadong

    2012-01-01

    Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive--but not NPY- or parvalbumin-positive-interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype.

  12. Hippocampal CA1 interneurons: an in vivo intracellular labeling study.

    Science.gov (United States)

    Sik, A; Penttonen, M; Ylinen, A; Buzsáki, G

    1995-10-01

    Fast spiking interneurons in the CA1 area of the dorsal hippocampus were recorded from and filled with biocytin in anesthetized rats. The full extent of their dendrites and axonal arborizations as well as their calcium binding protein content were examined. Based on the spatial extent of axon collaterals, local circuit cells (basket and O-LM neurons) and long-range cells (bistratified, trilaminar, and backprojection neurons) could be distinguished. Basket cells were immunoreactive for parvalbumin and their axon collaterals were confined to the pyramidal layer. A single basket cell contacted more than 1500 pyramidal neurons and 60 other parvalbumin-positive interneurons. Commissural stimulation directly discharged basket cells, followed by an early and late IPSPs, indicating interneuronal inhibition of basket cells. The dendrites of another local circuit neuron (O-LM) were confined to stratum oriens and it had a small but high-density axonal terminal field in stratum lacunosum-moleculare. The fastest firing cell of all interneurons was a calbindin-immunoreactive bistratified neuron with axonal targets in stratum oriens and radiatum. Two neurons with their cell bodies in the alveus innervated the CA3 region (backprojection cells), in addition to rich axon collaterals in the CA1 region. The trilaminar interneuron had axon collaterals in strata radiatum, oriens and pyramidale with its dendrites confined to stratum oriens. Commissural stimulation evoked an early EPSP-IPSP-late depolarizing potential sequence in this cell. All interneurons formed symmetric synapses with their targets at the electron microscopic level. These findings indicate that interneurons with distinct axonal targets have differential functions in shaping the physiological patterns of the CA1 network.

  13. Revisiting the enigmatic cortical calretinin-expressing interneurons

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    Bruno eCauli

    2014-06-01

    Full Text Available Cortical calretinin (CR-expressing interneurons represent a heterogeneous subpopulation of about 10-30% of GABAergic interneurons, which altogether total ca. 12-20% of all cortical neurons. In the rodent neocortex, CR cells display different somatodendritic morphologies ranging from bipolar to multipolar but the bipolar cells and their variations dominate. They are also diverse at the molecular level as they were shown to express numerous neuropeptides in different combinations including vasoactive intestinal polypeptide (VIP, cholecystokinin (CCK, neurokinin B (NKB corticotrophin releasing factor (CRF, enkephalin (Enk but also neuropeptide Y (NPY and somatostatin (SOM to a lesser extent. CR-expressing interneurons exhibit different firing behaviors such as adapting, bursting or irregular. They mainly originate from the caudal ganglionic eminence (CGE but a subpopulation also derives from the dorsal part of the medial ganglionic eminence (MGE. Cortical GABAergic CR-expressing interneurons can be divided in two main populations: VIP-bipolar interneurons deriving from the CGE and SOM-Martinotti-like interneurons originating in the dorsal MGE. Although bipolar cells account for the majority of CR-expressing interneurons, the roles they play in cortical neuronal circuits and in the more general metabolic physiology of the brain remain elusive and enigmatic. The aim of this review is, firstly, to provide a comprehensive view of the morphological, molecular and electrophysiological features defining this cell type. We will, secondly, also summarize what is known about their place in the cortical circuit, their modulation by subcortical afferents and the functional roles they might play in neuronal processing and energy metabolism.

  14. Striatal cholinergic interneuron regulation and circuit effects

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    Sean Austin Lim

    2014-10-01

    Full Text Available The striatum plays a central role in motor control and motor learning. Appropriate responses to environmental stimuli, including pursuit of reward or avoidance of aversive experience all require functional striatal circuits. These pathways integrate synaptic inputs from limbic and cortical regions including sensory, motor and motivational information to ultimately connect intention to action. Although many neurotransmitters participate in striatal circuitry, one critically important player is acetylcholine (ACh. Relative to other brain areas, the striatum contains exceptionally high levels of ACh, the enzymes that catalyze its synthesis and breakdown, as well as both nicotinic and muscarinic receptor types that mediate its postsynaptic effects. The principal source of striatal ACh is the cholinergic interneuron (ChI, which comprises only about 1-2% of all striatal cells yet sends dense arbors of projections throughout the striatum. This review summarizes recent advances in our understanding of the factors affecting the excitability of these neurons through acute effects and long term changes in their synaptic inputs. In addition, we discuss the physiological effects of ACh in the striatum, and how changes in ACh levels may contribute to disease states during striatal dysfunction.

  15. Classification of neocortical interneurons using affinity propagation

    Science.gov (United States)

    Santana, Roberto; McGarry, Laura M.; Bielza, Concha; Larrañaga, Pedro; Yuste, Rafael

    2013-01-01

    In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. In fact, neuronal classification is a difficult problem because it is unclear how to designate a neuronal cell class and what are the best characteristics to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological, or molecular characteristics, have provided quantitative and unbiased identification of distinct neuronal subtypes, when applied to selected datasets. However, better and more robust classification methods are needed for increasingly complex and larger datasets. Here, we explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. Affinity propagation outperformed Ward's method, a current standard clustering approach, in classifying the neurons into 4 subtypes. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits. PMID:24348339

  16. Classification of neocortical interneurons using affinity propagation.

    Science.gov (United States)

    Santana, Roberto; McGarry, Laura M; Bielza, Concha; Larrañaga, Pedro; Yuste, Rafael

    2013-01-01

    In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. In fact, neuronal classification is a difficult problem because it is unclear how to designate a neuronal cell class and what are the best characteristics to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological, or molecular characteristics, have provided quantitative and unbiased identification of distinct neuronal subtypes, when applied to selected datasets. However, better and more robust classification methods are needed for increasingly complex and larger datasets. Here, we explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. Affinity propagation outperformed Ward's method, a current standard clustering approach, in classifying the neurons into 4 subtypes. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits.

  17. Loss of cholecystokinin-containing terminals in temporal lobe epilepsy.

    Science.gov (United States)

    Sun, Chengsan; Sun, Jianli; Erisir, Alev; Kapur, Jaideep

    2014-02-01

    Altered GABA-mediated inhibition is proposed to play a role in the pathogenesis of epilepsy. Previous studies have demonstrated a loss of somatostatin-containing GABAergic interneurons innervating granule cells in epileptic animals. However, the reorganization of synapses between interneurons and granule cells has not been investigated. We studied synapse organization in an animal model of temporal lobe epilepsy (TLE) using continuous hippocampal stimulation. The distribution of axon terminals and inhibitory synapses on granule cell dendrites was studied using a combination of immunohistochemistry and pre-embedding electron microscopy techniques. A whole-cell patch-clamp technique was applied to study the functional changes in GABAergic input from different interneurons. In epileptic animals, the density of cholecystokinin (CCK)-immunoreactive (IR) fibers and α2 subunit containing GABAA receptors in the inner molecular layer of the dentate gyrus was reduced. Quantitative immuno-electron microscopy study revealed that the ratio of CCK-containing symmetric synapses to the total symmetric synapses was reduced. The frequency of GABAergic synaptic currents (sIPSC) was decreased and their amplitude was increased. The inhibitory effect of the activation of cannabinoid 1 (CB1) receptors was also reduced in epileptic animals. Isolation of CCK- and parvalbumin (PV)-containing GABAergic inputs by N- and P/Q-type calcium channel blockers respectively suggested that GABA release from CCK-containing interneurons was selectively reduced in epileptic rats. This study found that there was a loss of CCK-containing GABAergic synapses to granule cells both morphologically and functionally. These studies add to our understanding of the mechanisms that contribute to altering GABAergic inhibition of granule cells in TLE.

  18. Role of Somatostatin-Positive Cortical Interneurons in the Generation of Sleep Slow Waves.

    Science.gov (United States)

    Funk, Chadd M; Peelman, Kayla; Bellesi, Michele; Marshall, William; Cirelli, Chiara; Tononi, Giulio

    2017-09-20

    During non-rapid eye-movement (NREM) sleep, cortical and thalamic neurons oscillate every second or so between ON periods, characterized by membrane depolarization and wake-like tonic firing, and OFF periods, characterized by membrane hyperpolarization and neuronal silence. Cortical slow waves, the hallmark of NREM sleep, reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because ∼70% of them are Martinotti cells that target diffusely layer I and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving male mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation during ON periods of NREM sleep triggers long OFF periods. Next, we show that chemogenetic activation of SOM+ cells increases slow-wave activity (SWA), slope of individual slow waves, and NREM sleep duration; whereas their chemogenetic inhibition decreases SWA and slow-wave incidence without changing time spent in NREM sleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing, triggers short OFF periods in NREM sleep, and increases NREM sleep duration. Thus SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated.SIGNIFICANCE STATEMENT Cortical slow waves are a defining feature of non-rapid eye-movement (NREM) sleep and are thought to be important for many of its restorative benefits. Yet, the mechanism by which cortical neurons abruptly and synchronously cease firing, the

  19. Interplay of intrinsic and synaptic conductances in the generation of high-frequency oscillations in interneuronal networks with irregular spiking.

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    Fabiano Baroni

    2014-05-01

    Full Text Available High-frequency oscillations (above 30 Hz have been observed in sensory and higher-order brain areas, and are believed to constitute a general hallmark of functional neuronal activation. Fast inhibition in interneuronal networks has been suggested as a general mechanism for the generation of high-frequency oscillations. Certain classes of interneurons exhibit subthreshold oscillations, but the effect of this intrinsic neuronal property on the population rhythm is not completely understood. We study the influence of intrinsic damped subthreshold oscillations in the emergence of collective high-frequency oscillations, and elucidate the dynamical mechanisms that underlie this phenomenon. We simulate neuronal networks composed of either Integrate-and-Fire (IF or Generalized Integrate-and-Fire (GIF neurons. The IF model displays purely passive subthreshold dynamics, while the GIF model exhibits subthreshold damped oscillations. Individual neurons receive inhibitory synaptic currents mediated by spiking activity in their neighbors as well as noisy synaptic bombardment, and fire irregularly at a lower rate than population frequency. We identify three factors that affect the influence of single-neuron properties on synchronization mediated by inhibition: i the firing rate response to the noisy background input, ii the membrane potential distribution, and iii the shape of Inhibitory Post-Synaptic Potentials (IPSPs. For hyperpolarizing inhibition, the GIF IPSP profile (factor iii exhibits post-inhibitory rebound, which induces a coherent spike-mediated depolarization across cells that greatly facilitates synchronous oscillations. This effect dominates the network dynamics, hence GIF networks display stronger oscillations than IF networks. However, the restorative current in the GIF neuron lowers firing rates and narrows the membrane potential distribution (factors i and ii, respectively, which tend to decrease synchrony. If inhibition is shunting instead

  20. Inhibitory interneuron classes express complementary AMPA-receptor patterns in macaque primary visual cortex

    NARCIS (Netherlands)

    Kooijmans, Roxana N; Self, Matthew W; Wouterlood, Floris G; Beliën, Jeroen A M; Roelfsema, Pieter R

    2014-01-01

    Glutamate receptors mediate excitatory neurotransmission. A very prevalent type of glutamate receptor in the neocortex is the AMPA receptor (AMPAR). AMPARs mediate fast synaptic transmission and their functionality depends on the subunit composition. In primary visual cortex (area V1), the density a

  1. VIP enhances both pre- and postsynaptic GABAergic transmission to hippocampal interneurones leading to increased excitatory synaptic transmission to CA1 pyramidal cells.

    Science.gov (United States)

    Cunha-Reis, Diana; Sebastião, Ana M; Wirkner, Kerstin; Illes, Peter; Ribeiro, Joaquim Alexandre

    2004-11-01

    Vasoactive intestinal peptide (VIP) is present in the hippocampus in three subtypes of GABAergic interneurones, two of which innervate preferentially other interneurones, responsible for pyramidal cell inhibition. We investigated how pre- and postsynaptic modulation of GABAergic transmission (to both pyramidal cells and interneurones) by VIP could influence excitatory synaptic transmission in the CA1 area of the hippocampus. VIP (0.1-100 nM) increased [(3)H]GABA release from hippocampal synaptosomes (maximum effect at 1 nM VIP; 63.8 +/- 4.0%) but did not change [(3)H]glutamate release. VIP (0.3-30 nM) enhanced synaptic transmission in hippocampal slices (maximum effect at 1 nM VIP; field excitatory postsynaptic potentials (epsp) slope: 23.7 +/- 1.1%; population spike amplitude: 20.3 +/- 1.7%). The action on field epsp slope was fully dependent on GABAergic transmission since it was absent in the presence of picrotoxin (50 microM) plus CGP55845 (1 microM). VIP (1 nM) did not change paired-pulse facilitation but increased paired-pulse inhibition in CA1 pyramidal cells (16.0 +/- 0.9%), reinforcing the involvement of GABAergic transmission in the action of VIP. VIP (1 nM) increased muscimol-evoked inhibitory currents by 36.4 +/- 8.7% in eight out of ten CA1 interneurones in the stratum radiatum. This suggests that VIP promotes increased inhibition of interneurones that control pyramidal cells, leading to disinhibition of synaptic transmission to pyramidal cell dendrites. In conclusion, concerted pre- and postsynaptic actions of VIP lead to disinhibition of pyramidal cell dendrites causing an enhancement of synaptic transmission.

  2. Glycine Receptor α2 Subunit Activation Promotes Cortical Interneuron Migration

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    Ariel Avila

    2013-08-01

    Full Text Available Glycine receptors (GlyRs are detected in the developing CNS before synaptogenesis, but their function remains elusive. This study demonstrates that functional GlyRs are expressed by embryonic cortical interneurons in vivo. Furthermore, genetic disruption of these receptors leads to interneuron migration defects. We discovered that extrasynaptic activation of GlyRs containing the α2 subunit in cortical interneurons by endogenous glycine activates voltage-gated calcium channels and promotes calcium influx, which further modulates actomyosin contractility to fine-tune nuclear translocation during migration. Taken together, our data highlight the molecular events triggered by GlyR α2 activation that control cortical tangential migration during embryogenesis.

  3. Generation of v2a interneurons from mouse embryonic stem cells.

    Science.gov (United States)

    Brown, Chelsea R; Butts, Jessica C; McCreedy, Dylan A; Sakiyama-Elbert, Shelly E

    2014-08-01

    V2a interneurons of the ventral spinal cord and hindbrain play an important role in the central pattern generators (CPGs) involved in locomotion, skilled reaching, and respiration. However, sources of V2a interneurons for in vitro studies are limited. In this study, we developed a differentiation protocol for V2a interneurons from mouse embryonic stem cells (mESCs). Cells were induced in a 2(-)/4(+) induction protocol with varying concentrations of retinoic acid (RA) and the mild sonic hedgehog (Shh) agonist purmorphamine (Pur) in order to increase the expression of V2a interneuron transcription factors (eg, Chx10). Notch signaling, which influences the commitment of p2 progenitor cells to V2a or V2b interneurons, was inhibited in cell cultures to increase the percentage of V2a interneurons. At the end of the induction period, cell commitment was assessed using quantitative real-time polymerase chain reaction, immunocytochemistry, and flow cytometry to quantify expression of transcription factors specific to V2a interneurons and the adjacent ventral spinal cord regions. Low concentrations of RA and high concentrations of Pur led to greater expression of transcription factors specific for V2a interneurons. Notch inhibition favored V2a interneuron over V2b interneuron differentiation. The protocol established in this study can be used to further elucidate the pathways involved in V2a interneuron differentiation and help produce sources of V2a interneurons for developmental neurobiology, electrophysiology, and transplantation studies.

  4. Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory

    OpenAIRE

    Murray, Andrew J.; Sauer, Jonas-Frederic; Riedel, Gernot; McClure, Christina; Ansel, Laura; Cheyne, Lesley; Bartos, Marlene; Wisden, William; Wulff, Peer

    2011-01-01

    Parvalbumin-positive GABAergic interneurons in cortical circuits are hypothesized to control cognitive function. To test this idea directly, we functionally removed parvalbumin-positive interneurons selectively from hippocampal CA1 in mice. We found that parvalbumin-positive interneurons are dispensable for spatial reference, but are essential for spatial working memory.

  5. Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory.

    Science.gov (United States)

    Murray, Andrew J; Sauer, Jonas-Frederic; Riedel, Gernot; McClure, Christina; Ansel, Laura; Cheyne, Lesley; Bartos, Marlene; Wisden, William; Wulff, Peer

    2011-03-01

    Parvalbumin-positive GABAergic interneurons in cortical circuits are hypothesized to control cognitive function. To test this idea directly, we functionally removed parvalbumin-positive interneurons selectively from hippocampal CA1 in mice. We found that parvalbumin-positive interneurons are dispensable for spatial reference, but are essential for spatial working memory.

  6. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus.

    OpenAIRE

    Song, J; Sun, J.; Moss, J.; Z. Wen; G. J. Sun; D Hsu; Zhong, C.; Davoudi, H.; Christian, K.M.; Toni, N.; Ming, G.L.; Song, H.

    2013-01-01

    Using immunohistology, electron microscopy, electrophysiology and optogenetics, we found that proliferating adult mouse hippocampal neural precursors received immature GABAergic synaptic inputs from parvalbumin-expressing interneurons. Recently shown to suppress adult quiescent neural stem cell activation, parvalbumin interneuron activation promoted newborn neuronal progeny survival and development. Our results suggest a niche mechanism involving parvalbumin interneurons that couples local ci...

  7. Transmission to interneurons is via slow excitatory synaptic potentials mediated by P2Y(1 receptors during descending inhibition in guinea-pig ileum.

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    Peter D J Thornton

    Full Text Available BACKGROUND: The nature of synaptic transmission at functionally distinct synapses in intestinal reflex pathways has not been fully identified. In this study, we investigated whether transmission between interneurons in the descending inhibitory pathway is mediated by a purine acting at P2Y receptors to produce slow excitatory synaptic potentials (EPSPs. METHODOLOGY/PRINCIPAL FINDINGS: Myenteric neurons from guinea-pig ileum in vitro were impaled with intracellular microelectrodes. Responses to distension 15 mm oral to the recording site, in a separately perfused stimulation chamber and to electrical stimulation of local nerve trunks were recorded. A subset of neurons, previously identified as nitric oxide synthase immunoreactive descending interneurons, responded to both stimuli with slow EPSPs that were reversibly abolished by a high concentration of PPADS (30 μM, P2 receptor antagonist. When added to the central chamber of a three chambered organ bath, PPADS concentration-dependently depressed transmission through that chamber of descending inhibitory reflexes, measured as inhibitory junction potentials in the circular muscle of the anal chamber. Reflexes evoked by distension in the central chamber were unaffected. A similar depression of transmission was seen when the specific P2Y(1 receptor antagonist MRS 2179 (10 μM was in the central chamber. Blocking either nicotinic receptors (hexamethonium 200 μM or 5-HT(3 receptors (granisetron 1 μM together with P2 receptors had no greater effect than blocking P2 receptors alone. CONCLUSIONS/SIGNIFICANCE: Slow EPSPs mediated by P2Y(1 receptors, play a primary role in transmission between descending interneurons of the inhibitory reflexes in the guinea-pig ileum. This is the first demonstration for a primary role of excitatory metabotropic receptors in physiological transmission at a functionally identified synapse.

  8. Bayesian network classifiers for categorizing cortical GABAergic interneurons.

    Science.gov (United States)

    Mihaljević, Bojan; Benavides-Piccione, Ruth; Bielza, Concha; DeFelipe, Javier; Larrañaga, Pedro

    2015-04-01

    An accepted classification of GABAergic interneurons of the cerebral cortex is a major goal in neuroscience. A recently proposed taxonomy based on patterns of axonal arborization promises to be a pragmatic method for achieving this goal. It involves characterizing interneurons according to five axonal arborization features, called F1-F5, and classifying them into a set of predefined types, most of which are established in the literature. Unfortunately, there is little consensus among expert neuroscientists regarding the morphological definitions of some of the proposed types. While supervised classifiers were able to categorize the interneurons in accordance with experts' assignments, their accuracy was limited because they were trained with disputed labels. Thus, here we automatically classify interneuron subsets with different label reliability thresholds (i.e., such that every cell's label is backed by at least a certain (threshold) number of experts). We quantify the cells with parameters of axonal and dendritic morphologies and, in order to predict the type, also with axonal features F1-F4 provided by the experts. Using Bayesian network classifiers, we accurately characterize and classify the interneurons and identify useful predictor variables. In particular, we discriminate among reliable examples of common basket, horse-tail, large basket, and Martinotti cells with up to 89.52% accuracy, and single out the number of branches at 180 μm from the soma, the convex hull 2D area, and the axonal features F1-F4 as especially useful predictors for distinguishing among these types. These results open up new possibilities for an objective and pragmatic classification of interneurons.

  9. Differential vulnerability of interneurons in the epileptic hippocampus

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    Markus eMarx

    2013-10-01

    Full Text Available The loss of hippocampal interneurons has been considered one reason for the onset of temporal lobe epilepsy (TLE by shifting the excitation-inhibition balance. Yet, there are many different interneuron types which show differential vulnerability in the context of an epileptogenic insult. We used the intrahippocampal kainate (KA mouse model for TLE in which a focal, unilateral KA injection induces status epilepticus (SE followed by development of granule cell dispersion (GCD and hippocampal sclerosis surrounding the injection site but not in the intermediate and temporal hippocampus. In this study, we characterized the loss of interneurons with respect to septotemporal position and to differential vulnerability of interneuron populations. To this end, we performed intrahippocampal recordings of the initial SE, in situ hybridization for glutamic acid decarboxylase 67 (GAD67 mRNA and immunohistochemistry for parvalbumin (PV and neuropeptide Y (NPY in the early phase of epileptogenesis at 2 days and at 21 days after KA injection, when recurrent epileptic activity and GCD have fully developed. We show that SE extended along the entire septotemporal axis of both hippocampi, but was stronger at distant sites than at the injection site. There was an almost complete loss of interneurons surrounding the injection site and expanding to the intermediate hippocampus already at 2 days but increasing until 21 days. We observed differential vulnerability of PV- and NPY-expressing cells: while the latter were lost at the injection site but preserved at intermediate sites, PV-expressing cells were gone even at sites more temporal than GCD. In addition, we found upregulation of GAD67 mRNA expression in dispersed granule cells and of NPY staining in ipsilateral granule cells and ipsi- and contralateral mossy fibers. Our data thus indicate differential survival capacity of interneurons in the epileptic hippocampus and compensatory mechanisms depending on the

  10. Differential vulnerability of interneurons in the epileptic hippocampus.

    Science.gov (United States)

    Marx, Markus; Haas, Carola A; Häussler, Ute

    2013-01-01

    The loss of hippocampal interneurons has been considered as one reason for the onset of temporal lobe epilepsy (TLE) by shifting the excitation-inhibition balance. Yet, there are many different interneuron types which show differential vulnerability in the context of an epileptogenic insult. We used the intrahippocampal kainate (KA) mouse model for TLE in which a focal, unilateral KA injection induces status epilepticus (SE) followed by development of granule cell dispersion (GCD) and hippocampal sclerosis surrounding the injection site but not in the intermediate and temporal hippocampus. In this study, we characterized the loss of interneurons with respect to septotemporal position and to differential vulnerability of interneuron populations. To this end, we performed intrahippocampal recordings of the initial SE, in situ hybridization for glutamic acid decarboxylase 67 (GAD67) mRNA and immunohistochemistry for parvalbumin (PV) and neuropeptide Y (NPY) in the early phase of epileptogenesis at 2 days and at 21 days after KA injection, when recurrent epileptic activity and GCD have fully developed. We show that SE extended along the entire septotemporal axis of both hippocampi, but was stronger at distant sites than at the injection site. There was an almost complete loss of interneurons surrounding the injection site and expanding to the intermediate hippocampus already at 2 days but increasing until 21 days after KA. Furthermore, we observed differential vulnerability of PV- and NPY-expressing cells: while the latter were lost at the injection site but preserved at intermediate sites, PV-expressing cells were gone even at sites more temporal than GCD. In addition, we found upregulation of GAD67 mRNA expression in dispersed granule cells and of NPY staining in ipsilateral granule cells and ipsi- and contralateral mossy fibers. Our data thus indicate differential survival capacity of interneurons in the epileptic hippocampus and compensatory plasticity mechanisms

  11. Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus.

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    Hájos, N; Papp, E C; Acsády, L; Levey, A I; Freund, T F

    1998-01-01

    hippocampal formation. Only calretinin and somatostatin showed an appreciable degree of co-localization with m2 (20% and 15%, respectively). Using retrograde tracing, some of the m2-positive cells in stratum oriens were shown to project to the medial septum, accouting for 38% of all projection neurons. The present results demonstrate that there is a differential distribution of m2 receptor immunoreactivity on the axonal vs the somadendritic membranes of distinct interneuron types and suggest that acetylcholine via m2 receptors may reduce GABA release presynaptically from the terminals of perisomatic inhibitory cells, while it may act to increase the activity of another class of interneuron, which innervates the dendritic region of pyramidal cells.

  12. Interneurons in the human olfactory system in Alzheimer's disease.

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    Saiz-Sanchez, Daniel; Flores-Cuadrado, Alicia; Ubeda-Bañon, Isabel; de la Rosa-Prieto, Carlos; Martinez-Marcos, Alino

    2016-02-01

    The principal olfactory structures display Alzheimer's disease (AD) related pathology at early stages of the disease. Consequently, olfactory deficits are among the earliest symptoms. Reliable olfactory tests for accurate clinical diagnosis are rarely made. In addition, neuropathological analysis postmortem of olfactory structures is often not made. Therefore, the relationship between the clinical features and the underlying pathology is poorly defined. Traditionally, research into Alzheimer's disease has focused on the degeneration of cortical temporal projection neurons and cholinergic neurons. Recent evidence has demonstrated the neurodegeneration of interneuron populations in AD. This review provides an updated overview of the pathological involvement of interneuron populations in the human olfactory system in Alzheimer's disease.

  13. Developmental abnormalities of cortical interneurons precede symptoms onset in a mouse model of Rett syndrome.

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    Tomassy, Giulio Srubek; Morello, Noemi; Calcagno, Eleonora; Giustetto, Maurizio

    2014-10-01

    Rett syndrome (RTT, MIM312750), a neurodevelopmental disorder predominantly occurring in females, is caused in the majority of cases by sporadic mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). In mice, impaired MeCP2 function results in severe motor, cognitive, and emotional defects. The lack of Mecp2 in γ-aminobutyric acid-(GABA) releasing forebrain interneurons (INs) recapitulate many RTT features, however, the role of this gene in the development of the cortical inhibitory system is still unknown. Here, we found that MeCP2 expression varies among the three major classes of cortical INs and its nuclear localization differs between neuronal types. The density of calretinin(+) and parvalbumin(+) INs increases in Mecp2 knockout mice (Mecp2(-/y) ) already at early post-natal developmental stages. In contrast, the density of somatostatin(+) INs is not affected. We also found that the development of multipolar-calretinin(+) INs is selectively affected by the absence of Mecp2. Additionally, we show that in Mecp2 heterozygous female mice, a model closely mimicking human RTT condition, IN abnormalities are similar to those observed in Mecp2(-/y) mice. Together, our study indicates that loss of function of Mecp2 strongly interferes with the correct establishment of the neocortical inhibitory system producing effects that are specific to different IN subtypes.

  14. Dopamine D4 receptor activation increases hippocampal gamma oscillations by enhancing synchronization of fast-spiking interneurons.

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    Richard Andersson

    Full Text Available BACKGROUND: Gamma oscillations are electric activity patterns of the mammalian brain hypothesized to serve attention, sensory perception, working memory and memory encoding. They are disrupted or altered in schizophrenic patients with associated cognitive deficits, which persist in spite of treatment with antipsychotics. Because cognitive symptoms are a core feature of schizophrenia it is relevant to explore signaling pathways that potentially regulate gamma oscillations. Dopamine has been reported to decrease gamma oscillation power via D1-like receptors. Based on the expression pattern of D4 receptors (D4R in hippocampus, and pharmacological effects of D4R ligands in animals, we hypothesize that they are in a position to regulate gamma oscillations as well. METHODOLOGY/PRINCIPAL FINDINGS: To address this hypothesis we use rat hippocampal slices and kainate-induced gamma oscillations. Local field potential recordings as well as intracellular recordings of pyramidal cells, fast-spiking and non-fast-spiking interneurons were carried out. We show that D4R activation with the selective ligand PD168077 increases gamma oscillation power, which can be blocked by the D4R-specific antagonist L745,870 as well as by the antipsychotic drug Clozapine. Pyramidal cells did not exhibit changes in excitatory or inhibitory synaptic current amplitudes, but inhibitory currents became more coherent with the oscillations after application of PD168077. Fast-spiking, but not non-fast spiking, interneurons, increase their action potential phase-coupling and coherence with regard to ongoing gamma oscillations in response to D4R activation. Among several possible mechanisms we found that the NMDA receptor antagonist AP5 also blocks the D4R mediated increase in gamma oscillation power. CONCLUSIONS/SIGNIFICANCE: We conclude that D4R activation affects fast-spiking interneuron synchronization and thereby increases gamma power by an NMDA receptor-dependent mechanism. This

  15. [Subpopulation of calbindin-immunoreactive interneurons in the dorsal horn of the mice spinal cord].

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    Porseva, V V; Shilkin, V V; Strelkov, A A; Masliukov, P M

    2014-01-01

    In the dorsal horn of the spinal cord in the plates I-IV on the thoracic and lumbar levels different subpopulations of interneurons immunoreactive for calbindin 28 kDa (CAB IR), which are specific to each plate. In the area of the medial edge of the dorsal horn, we have found a special subpopulation of CAB IR interneurons whose morphometric characteristics differ from CAB IR interneurons subpopulations of said plates. The number of CAB IR interneurons was maximal in the plate II at all levels of the spinal cord. Leveled differences are more CAB IR interneurons and larger area of the cross sections at the lumbar level.

  16. Subtype-specific reduction of olfactory bulb interneurons in Pax6 heterozygous mutant mice.

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    Haba, Hasumi; Nomura, Tadashi; Suto, Fumikazu; Osumi, Noriko

    2009-09-01

    Interneurons in the olfactory bulb (OB) play essential roles in the processing of olfactory information. They are classified into several subpopulations by the expression of different neurochemical markers. Here we focused on a transcription factor Pax6, and examined its expression and function in distinct subtypes of OB interneurons. We identified Pax6 expression in specific subtypes of interneurons in the external plexiform layer (EPL). The number of these interneuron subtypes was dramatically decreased in Pax6 heterozygous mutant mice. These results indicate that Pax6 is required for differentiation and/or maintenance of EPL interneurons in the adult mouse OB.

  17. Differential GABAB-receptor-mediated effects in perisomatic- and dendrite-targeting parvalbumin interneurons.

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    Booker, Sam A; Gross, Anna; Althof, Daniel; Shigemoto, Ryuichi; Bettler, Bernhard; Frotscher, Michael; Hearing, Matthew; Wickman, Kevin; Watanabe, Masahiko; Kulik, Ákos; Vida, Imre

    2013-05-01

    Inhibitory parvalbumin-containing interneurons (PVIs) control neuronal discharge and support the generation of theta- and gamma-frequency oscillations in cortical networks. Fast GABAergic input onto PVIs is crucial for their synchronization and oscillatory entrainment, but the role of metabotropic GABA(B) receptors (GABA(B)Rs) in mediating slow presynaptic and postsynaptic inhibition remains unknown. In this study, we have combined high-resolution immunoelectron microscopy, whole-cell patch-clamp recording, and computational modeling to investigate the subcellular distribution and effects of GABA(B)Rs and their postsynaptic effector Kir3 channels in rat hippocampal PVIs. Pre-embedding immunogold labeling revealed that the receptors and channels localize at high levels to the extrasynaptic membrane of parvalbumin-immunoreactive dendrites. Immunoreactivity for GABA(B)Rs was also present at lower levels on PVI axon terminals. Whole-cell recordings further showed that synaptically released GABA in response to extracellular stimulation evokes large GABA(B)R-mediated slow IPSCs in perisomatic-targeting (PT) PVIs, but only small or no currents in dendrite-targeting (DT) PVIs. In contrast, paired recordings demonstrated that GABA(B)R activation results in presynaptic inhibition at the output synapses of both PT and DT PVIs, but more strongly in the latter. Finally, computational analysis indicated that GABA(B) IPSCs can phasically modulate the discharge of PT interneurons at theta frequencies. In summary, our results show that GABA(B)Rs differentially mediate slow presynaptic and postsynaptic inhibition in PVIs and can contribute to the dynamic modulation of their activity during oscillations. Furthermore, these data provide evidence for a compartment-specific molecular divergence of hippocampal PVI subtypes, suggesting that activation of GABA(B)Rs may shift the balance between perisomatic and dendritic inhibition.

  18. Brain-derived neurotrophic factor controls functional differentiation and microcircuit formation of selectively isolated fast-spiking GABAergic interneurons.

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    Berghuis, Paul; Dobszay, Marton B; Sousa, Kyle M; Schulte, Gunnar; Mager, Peter P; Härtig, Wolfgang; Görcs, Tamás J; Zilberter, Yuri; Ernfors, Patrik; Harkany, Tibor

    2004-09-01

    GABAergic interneurons with high-frequency firing, fast-spiking (FS) cells, form synapses on perisomatic regions of principal cells in the neocortex and hippocampus to control the excitability of cortical networks. Brain-derived neurotrophic factor (BDNF) is essential for the differentiation of multiple interneuron subtypes and the formation of their synaptic contacts. Here, we examined whether BDNF, alone or in conjunction with sustained KCl-induced depolarization, drives functional FS cell differentiation and the formation of inhibitory microcircuits. Homogeneous FS cell cultures were established by target-specific isolation using the voltage-gated potassium channel 3.1b subunit as the selection marker. Isolated FS cells expressed parvalbumin, were surrounded by perineuronal nets, formed immature inhibitory connections and generated slow action potentials at 12 days in vitro. Brain-derived neurotrophic factor (BDNF) promoted FS cell differentiation by increasing the somatic diameter, dendritic branching and the frequency of action potential firing. In addition, BDNF treatment led to a significant up-regulation of synaptophysin and vesicular GABA transporter expression, components of the synaptic machinery critical for GABA release, which was paralleled by an increase in synaptic strength. Long-term membrane depolarization alone was detrimental to dendritic branching. However, we observed that BDNF and KCl exerted additive effects, as reflected by the significantly accelerated maturation of synaptic contacts and high discharge frequencies, and was required for the formation of reciprocal connections between FS cells. Our results show that BDNF, along with membrane depolarization, is critical for FS cells to establish inhibitory circuitries during corticogenesis.

  19. Contribution of Innate Cortical Mechanisms to the Maturation of Orientation Selectivity in Parvalbumin Interneurons.

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    Figueroa Velez, Dario X; Ellefsen, Kyle L; Hathaway, Ethan R; Carathedathu, Mathew C; Gandhi, Sunil P

    2017-01-25

    The maturation of cortical parvalbumin-positive (PV) interneurons depends on the interaction of innate and experience-dependent factors. Dark-rearing experiments suggest that visual experience determines when broad orientation selectivity emerges in visual cortical PV interneurons. Here, using neural transplantation and in vivo calcium imaging of mouse visual cortex, we investigated whether innate mechanisms contribute to the maturation of orientation selectivity in PV interneurons. First, we confirmed earlier findings showing that broad orientation selectivity emerges in PV interneurons by 2 weeks after vision onset, ∼35 d after these cells are born. Next, we assessed the functional development of transplanted PV (tPV) interneurons. Surprisingly, 25 d after transplantation (DAT) and >2 weeks after vision onset, we found that tPV interneurons have not developed broad orientation selectivity. By 35 DAT, however, broad orientation selectivity emerges in tPV interneurons. Transplantation does not alter orientation selectivity in host interneurons, suggesting that the maturation of tPV interneurons occurs independently from their endogenous counterparts. Together, these results challenge the notion that the onset of vision solely determines when PV interneurons become broadly tuned. Our results reveal that an innate cortical mechanism contributes to the emergence of broad orientation selectivity in PV interneurons.

  20. The early fetal development of human neocortical GABAergic interneurons.

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    Al-Jaberi, Nahidh; Lindsay, Susan; Sarma, Subrot; Bayatti, Nadhim; Clowry, Gavin J

    2015-03-01

    GABAergic interneurons are crucial to controlling the excitability and responsiveness of cortical circuitry. Their developmental origin may differ between rodents and human. We have demonstrated the expression of 12 GABAergic interneuron-associated genes in samples from human neocortex by quantitative rtPCR from 8 to 12 postconceptional weeks (PCW) and shown a significant anterior to posterior expression gradient, confirmed by in situ hybridization or immunohistochemistry for GAD1 and 2, DLX1, 2, and 5, ASCL1, OLIG2, and CALB2. Following cortical plate (CP) formation from 8 to 9 PCW, a proportion of cells were strongly stained for all these markers in the CP and presubplate. ASCL1 and DLX2 maintained high expression in the proliferative zones and showed extensive immunofluorescent double-labeling with the cell division marker Ki-67. CALB2-positive cells increased steadily in the SVZ/VZ from 10 PCW but were not double-labeled with Ki-67. Expression of GABAergic genes was generally higher in the dorsal pallium than in the ganglionic eminences, with lower expression in the intervening ventral pallium. It is widely accepted that the cortical proliferative zones may generate CALB2-positive interneurons from mid-gestation; we now show that the anterior neocortical proliferative layers especially may be a rich source of interneurons in the early neocortex.

  1. A subset of interneurons required for Drosophila larval locomotion.

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    Yoshikawa, Shingo; Long, Hong; Thomas, John B

    2016-01-01

    Efforts to define the neural circuits generating locomotor behavior have produced an initial understanding of some of the components within the spinal cord, as well as a basic understanding of several invertebrate motor pattern generators. However, how these circuits are assembled during development is poorly understood. We are defining the neural circuit that generates larval locomotion in the genetically tractable fruit fly Drosophila melanogaster to study locomotor circuit development. Forward larval locomotion involves a stereotyped posterior-to-anterior segmental translocation of body wall muscle contraction and is generated by a relatively small number of identified muscles, motor and sensory neurons, plus an unknown number of the ~270 bilaterally-paired interneurons per segment of the 1st instar larva. To begin identifying the relevant interneurons, we have conditionally inactivated synaptic transmission of interneuron subsets and assayed for the effects on locomotion. From this screen we have identified a subset of 25 interneurons per hemisegment, called the lateral locomotor neurons (LLNs), that are required for locomotion. Both inactivation and constitutive activation of the LLNs disrupt locomotion, indicating that patterned output of the LLNs is required. By expressing a calcium indicator in the LLNs, we found that they display a posterior-to-anterior wave of activity within the CNS corresponding to the segmental translocation of the muscle contraction wave. Identification of the LLNs represents the first step toward elucidating the circuit generating larval locomotion.

  2. Interneurons targeting similar layers receive synaptic inputs with similar kinetics.

    Science.gov (United States)

    Cossart, Rosa; Petanjek, Zdravko; Dumitriu, Dani; Hirsch, June C; Ben-Ari, Yehezkel; Esclapez, Monique; Bernard, Christophe

    2006-01-01

    GABAergic interneurons play diverse and important roles in controlling neuronal network dynamics. They are characterized by an extreme heterogeneity morphologically, neurochemically, and physiologically, but a functionally relevant classification is still lacking. Present taxonomy is essentially based on their postsynaptic targets, but a physiological counterpart to this classification has not yet been determined. Using a quantitative analysis based on multidimensional clustering of morphological and physiological variables, we now demonstrate a strong correlation between the kinetics of glutamate and GABA miniature synaptic currents received by CA1 hippocampal interneurons and the laminar distribution of their axons: neurons that project to the same layer(s) receive synaptic inputs with similar kinetics distributions. In contrast, the kinetics distributions of GABAergic and glutamatergic synaptic events received by a given interneuron do not depend upon its somatic location or dendritic arborization. Although the mechanisms responsible for this unexpected observation are still unclear, our results suggest that interneurons may be programmed to receive synaptic currents with specific temporal dynamics depending on their targets and the local networks in which they operate.

  3. Serotonin receptor 3A controls interneuron migration into the neocortex

    NARCIS (Netherlands)

    Murthy, S.; Niquille, M.; Hurni, N.; Limoni, G.; Frazer, S.; Chameau, P.; van Hooft, J.A.; Vitalis, T.; Dayer, A.

    2014-01-01

    Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Here we show that the ionotropic

  4. Increased GAD67 mRNA expression in cerebellar interneurons in autism: implications for Purkinje cell dysfunction.

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    Yip, Jane; Soghomonian, Jean-Jacques; Blatt, Gene J

    2008-02-15

    It has been widely reported that in autism, the number of Purkinje cells (PCs) is decreased, and recently, decreased expression of glutamic acid decarboxylase 67 (GAD67) mRNA in Purkinje cells also has been observed. However, the autism literature has not addressed key GABAergic inputs into Purkinje cells. Inhibitory basket and stellate cell interneurons in the molecular layer of the cerebellar cortex provide direct key GABAergic input into Purkinje cells and could potently influence the output of Purkinje cells to deep cerebellar nuclei. We investigated the capacity for interneuronal synthesis of gamma-amino butyric acid (GABA) in both types of interneurons that innervate the remaining PCs in the posterolateral cerebellar hemisphere in autism. The level of GAD67 mRNA, one of the isoforms of the key synthesizing enzymes for GABA, was quantified at the single-cell level using in situ hybridization in brains of autistic and aged-matched controls. The National Institutes of Health imaging system showed that expression of GAD67 mRNA in basket cells was significantly up-regulated, by 28%, in eight autistic brains compared with that in eight control brains (mean +/- SEM pixels per cell, 1.03 +/- 0.05 versus 0.69 +/- 0.05, respectively; P levels, but this did not reach significance. The results suggest that basket cells likely provide increased GABAergic feed-forward inhibition to PCs in autism, directly affecting PC output to target neurons in the dentate nucleus and potentially disrupting its modulatory role in key motor and/or cognitive behaviors in autistic individuals.

  5. The Neural Cell Adhesion Molecule (NCAM) Promotes Clustering and Activation of EphA3 Receptors in GABAergic Interneurons to Induce Ras Homolog Gene Family, Member A (RhoA)/Rho-associated protein kinase (ROCK)-mediated Growth Cone Collapse.

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    Sullivan, Chelsea S; Kümper, Maike; Temple, Brenda S; Maness, Patricia F

    2016-12-16

    Establishment of a proper balance of excitatory and inhibitory connectivity is achieved during development of cortical networks and adjusted through synaptic plasticity. The neural cell adhesion molecule (NCAM) and the receptor tyrosine kinase EphA3 regulate the perisomatic synapse density of inhibitory GABAergic interneurons in the mouse frontal cortex through ephrin-A5-induced growth cone collapse. In this study, it was demonstrated that binding of NCAM and EphA3 occurred between the NCAM Ig2 domain and EphA3 cysteine-rich domain (CRD). The binding interface was further refined through molecular modeling and mutagenesis and shown to be comprised of complementary charged residues in the NCAM Ig2 domain (Arg-156 and Lys-162) and the EphA3 CRD (Glu-248 and Glu-264). Ephrin-A5 induced co-clustering of surface-bound NCAM and EphA3 in GABAergic cortical interneurons in culture. Receptor clustering was impaired by a charge reversal mutation that disrupted NCAM/EphA3 association, emphasizing the importance of the NCAM/EphA3 binding interface for cluster formation. NCAM enhanced ephrin-A5-induced EphA3 autophosphorylation and activation of RhoA GTPase, indicating a role for NCAM in activating EphA3 signaling through clustering. NCAM-mediated clustering of EphA3 was essential for ephrin-A5-induced growth cone collapse in cortical GABAergic interneurons, and RhoA and a principal effector, Rho-associated protein kinase, mediated the collapse response. This study delineates a mechanism in which NCAM promotes ephrin-A5-dependent clustering of EphA3 through interaction of the NCAM Ig2 domain and the EphA3 CRD, stimulating EphA3 autophosphorylation and RhoA signaling necessary for growth cone repulsion in GABAergic interneurons in vitro, which may extend to remodeling of axonal terminals of interneurons in vivo.

  6. Impaired hippocampal-dependent memory and reduced parvalbumin-positive interneurons in a ketamine mouse model of schizophrenia.

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    Koh, Ming Teng; Shao, Yi; Sherwood, Andrew; Smith, Dani R

    2016-03-01

    The hippocampus of patients with schizophrenia displays aberrant excess neuronal activity which affects cognitive function. Animal models of the illness have recapitulated the overactivity in the hippocampus, with a corresponding regionally localized reduction of inhibitory interneurons, consistent with that observed in patients. To better understand whether cognitive function is similarly affected in these models of hippocampal overactivity, we tested a ketamine mouse model of schizophrenia for cognitive performance in hippocampal- and medial prefrontal cortex (mPFC)-dependent tasks. We found that adult mice exposed to ketamine during adolescence were impaired on a trace fear conditioning protocol that relies on the integrity of the hippocampus. Conversely, the performance of the mice was normal on a delayed response task that is sensitive to mPFC damage. We confirmed that ketamine-exposed mice had reduced parvalbumin-positive interneurons in the hippocampus, specifically in the CA1, but not in the mPFC in keeping with the behavioral findings. These results strengthened the utility of the ketamine model for preclinical investigations of hippocampal overactivity in schizophrenia.

  7. Neurogranin is expressed by principal cells but not interneurons in the rodent and monkey neocortex and hippocampus.

    Science.gov (United States)

    Singec, Ilyas; Knoth, Rolf; Ditter, Margarethe; Volk, Benedikt; Frotscher, Michael

    2004-11-01

    As a substrate of protein kinase C (PKC), neurogranin (NG) is involved in the regulation of calcium signaling and activity-dependent plasticity. Recently, we have shown that, in the rodent cerebellum, NG is exclusively expressed by gamma-aminobutyric acidergic Golgi cells, whereas, in the monkey cerebellum, brush cells were the only neuronal population expressing NG (Singec et al. [2003] J. Comp. Neurol. 459:278-289). In the present study, we analyzed the neocortical and hippocampal expression patterns of NG in adult mouse (C57Bl/6), rat (Wistar), and monkey (Cercopithecus aetiops). By using immunocytochemistry and nonradioactive in situ hybridization, we demonstrate strong NG expression by principal cells in different neocortical layers and in the hippocampus by granule cells of the dentate gyrus and pyramidal neurons of CA1-CA3. In contrast, double-labeling experiments in rodents revealed that neocortical and hippocampal interneurons expressing glutamate decarboxylase 67 (GAD67) were consistently devoid of NG. In addition, by using antibodies against parvalbumin, calbindin, and calretinin, we could demonstrate the absence of NG in interneurons of monkey frontal cortex and hippocampus. Together these findings corroborate the idea of different calcium signaling pathways in excitatory and inhibitory cells that may contribute to different modes of synaptic plasticity in these neurons.

  8. Target-specific effects of somatostatin-expressing interneurons on neocortical visual processing.

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    Cottam, James C H; Smith, Spencer L; Häusser, Michael

    2013-12-11

    A diverse array of interneuron types regulates activity in the mammalian neocortex. Two of the most abundant are the fast-spiking, parvalbumin-positive (PV(+)) interneurons, which target the axosomatic region of pyramidal cells, and the somatostatin-positive (SOM(+)) interneurons, which target the dendrites. Recent work has focused on the influence of PV(+) and SOM(+) interneurons on pyramidal cells. However, the connections among PV(+) and SOM(+) interneurons are poorly understood and could play an important role in cortical circuitry, since their interactions may alter the net influence on pyramidal cell output. We used an optogenetic approach to investigate the effect of SOM(+) interneurons on pyramidal cells and PV(+) interneurons during visual stimulation in mouse primary visual cortex. We find that SOM(+) interneuron activation suppresses PV(+) cell spiking at least twice as potently as pyramidal cell spiking during visual stimulation. This differential effect of SOM(+) cell stimulation is detectable even when only two to three SOM(+) cells are activated. Importantly, the remaining responses to oriented gratings in PV(+) cells are more orientation tuned and temporally modulated, suggesting that SOM(+) activity unmasks this tuning by suppressing untuned input. Our results highlight the importance of SOM(+) inhibition of PV(+) interneurons during sensory processing. This prominent competitive inhibition between interneuron types leads to a reconfiguration of inhibition along the somatodendritic axis of pyramidal cells, and enhances the orientation selectivity of PV(+) cells.

  9. Radial glial dependent and independent dynamics of interneuronal migration in the developing cerebral cortex.

    Directory of Open Access Journals (Sweden)

    Yukako Yokota

    Full Text Available Interneurons originating from the ganglionic eminence migrate tangentially into the developing cerebral wall as they navigate to their distinct positions in the cerebral cortex. Compromised connectivity and differentiation of interneurons are thought to be an underlying cause in the emergence of neurodevelopmental disorders such as schizophrenia. Previously, it was suggested that tangential migration of interneurons occurs in a radial glia independent manner. Here, using simultaneous imaging of genetically defined populations of interneurons and radial glia, we demonstrate that dynamic interactions with radial glia can potentially influence the trajectory of interneuronal migration and thus the positioning of interneurons in cerebral cortex. Furthermore, there is extensive local interneuronal migration in tangential direction opposite to that of pallial orientation (i.e., in a medial to lateral direction from cortex to ganglionic eminence all across the cerebral wall. This counter migration of interneurons may be essential to locally position interneurons once they invade the developing cerebral wall from the ganglionic eminence. Together, these observations suggest that interactions with radial glial scaffold and localized migration within the expanding cerebral wall may play essential roles in the guidance and placement of interneurons in the developing cerebral cortex.

  10. Nicotinic excitatory postsynaptic potentials in hippocampal CA1 interneurons are predominantly mediated by nicotinic receptors that contain α4 and β2 subunits.

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    Bell, Karen A; Shim, Hoon; Chen, Ching-Kang; McQuiston, A Rory

    2011-12-01

    In the hippocampus, activation of nicotinic receptors that include α4 and β2 subunits (α4β2*) facilitates memory formation. α4β2* receptors may also play a role in nicotine withdrawal, and their loss may contribute to cognitive decline in aging and Alzheimer's disease (AD). However, little is known about their cellular function in the hippocampus. Therefore, using optogenetics, whole cell patch clamping and voltage-sensitive dye (VSD) imaging, we measured nicotinic excitatory postsynaptic potentials (EPSPs) in hippocampal CA1. In a subpopulation of inhibitory interneurons, release of ACh resulted in slow depolarizations (rise time constant 33.2 ± 6.5 ms, decay time constant 138.6 ± 27.2 ms) mediated by the activation of α4β2* nicotinic receptors. These interneurons had somata and dendrites located in the stratum oriens (SO) and stratum lacunosum-moleculare (SLM). Furthermore, α4β2* nicotinic EPSPs were largest in the SLM. Thus, our data suggest that nicotinic EPSPs in hippocampal CA1 interneurons are predominantly mediated by α4β2* nicotinic receptors and their activation may preferentially affect extrahippocampal inputs in SLM of hippocampal CA1.

  11. Enkephalin levels and the number of neuropeptide Y-containing interneurons in the hippocampus are decreased in female cannabinoid-receptor 1 knock-out mice.

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    Rogers, Sophie A; Kempen, Tracey A Van; Pickel, Virginia M; Milner, Teresa A

    2016-05-04

    Drug addiction requires learning and memory processes that are facilitated by activation of cannabinoid-1 (CB1) and opioid receptors in the hippocampus. This involves activity-dependent synaptic plasticity that is partially regulated by endogenous opioid (enkephalin and dynorphin) and non-opioid peptides, specifically cholecystokinin, parvalbumin and neuropeptide Y, the neuropeptides present in inhibitory interneurons that co-express CB1 or selective opioid receptors. We tested the hypothesis that CB1 receptor expression is a determinant of the availability of one or more of these peptide modulators in the hippocampus. This was achieved by quantitatively analyzing the immunoperoxidase labeling for each of these neuropeptide in the dorsal hippocampus of female wild-type (CB1+/+) and cannabinoid receptor 1 knockout (CB1-/-) C57/BL6 mice. The levels of Leu(5)-enkephalin-immunoreactivity were significantly reduced in the hilus of the dentate gyrus and in stratum lucidum of CA3 in CB1-/- mice. Moreover, the numbers of neuropeptide Y-immunoreactive interneurons in the dentate hilus were significantly lower in the CB1-/- compared to wild-type mice. However, CB1+/+ and CB1-/- mice did not significantly differ in expression levels of either dynorphin or cholecystokinin, and showed no differences in numbers of parvalbumin-containing interneurons. These findings suggest that the cannabinoid and opioid systems have a nuanced, regulatory relationship that could affect the balance of excitation and inhibition in the hippocampus and thus processes such as learning that rely on this balance.

  12. Respiratory interneurones in the thoracic spinal cord of the cat.

    Science.gov (United States)

    Kirkwood, P A; Munson, J B; Sears, T A; Westgaard, R H

    1988-01-01

    1. The discharges of spontaneously firing neurones, whose activity was modulated in phase with the central respiratory cycle, were recorded in the thoracic ventral horn (T3-T9) of anaesthetized, paralysed cats. 2. Out of 310 neurones, forty-six were positively identified as motoneurones by antidromic activation or spike-triggered averaging, fifty-four were positively identified as interneurones by antidromic activation from other spinal cord segments and ninety were indirectly identified as interneurones by virtue of their positions or firing rates as compared to the motoneurones. 3. Units were classified as inspiratory (64%), expiratory (25%) or post-inspiratory (7%) according to the times of their maximum firing rates. The remaining 4% consisted of units whose discharges were either strongly locked to the respiratory pump cycle or did not fit into the other categories. All but one of the motoneurones were classified as inspiratory or expiratory. 4. Inspiratory and expiratory units were further classified as early, late or tonic according to the starting times of their discharges in the respiratory cycle. The interneurones (both positively and indirectly identified) included more of the early and tonic categories and more fast-firing units than did the motoneurones in both the inspiratory and expiratory groups. 5. The locations of the motoneurones corresponded to the known positions of the intercostal and interchondral motor nuclei, including clear segregation of inspiratory and expiratory populations. The locations of neither the interneurones nor the unidentified units were segregated according to their firing patterns. These neurones were concentrated in the medial half of the ventral horn and were found generally more dorsally than the positions of the motoneurones, though their positions overlapped considerably with this group. 6. The axons of the positively identified interneurones were identified from one to five segments caudally and mostly contralaterally

  13. Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC

    OpenAIRE

    Kang, SukJae Joshua; Kwak, Chuljung; Lee, Jaejyun; Sim, Su-Eon; Shim, Jaehoon; Choi, Taehyuk; Graham L. Collingridge; Zhou, Min; Kaang, B-K

    2015-01-01

    Neurons in the anterior cingulate cortex (ACC) are assumed to play important roles in the perception of nociceptive signals and the associated emotional responses. However, the neuronal types within the ACC that mediate these functions are poorly understood. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC and to assess their ability to modulate peripheral mechanical hypersensitivity in freely movi...

  14. Developmental expression and functional characterization of the potassium-channel subunit Kv3.1b in parvalbumin-containing interneurons of the rat hippocampus.

    Science.gov (United States)

    Du, J; Zhang, L; Weiser, M; Rudy, B; McBain, C J

    1996-01-15

    The expression of the voltage-gated K(+)-channel subunit Kv3.1b in the developing hippocampus was determined by immunoblot and immunohistochemical techniques. Kv3.1b protein was detected first at postnatal day (P) 8. The Kv3.1b-immunopositive cell number per tissue section reached a maximum at P14 and was maintained through P40. In contrast, the Kv3.1b protein content of isolated membrane vesicles in immunoblots progressively increased through P40, suggesting an increase in Kv3.1b content per cell throughout this time period. Kv3.1b protein was expressed selectively in the somata, proximal dendrites, and axons of cells lying within or near the pyramidal cell layer, consistent with their being GABAergic inhibitory interneurons. Kv3.1b was present in approximately 80% of parvalbumin-positive interneurons. The developmental onset of Kv3.1b and parvalbumin immunoreactivity was identical. In contrast, Kv3.1b was mostly absent from the subset of somatostatin-positive inhibitory interneurons. Electrophysiological recordings were made from stratum pyramidale interneurons in which morphology and Kv3.1b-positive immunoreactivity were confirmed post hoc. Outward currents had voltage-dependent and biophysical properties resembling those of channels formed by Kv3.1b. The current blocked by low concentrations of 4-aminopyridine (4-AP) showed marked inactivation, suggesting that Kv3.1b may coassemble with other members of the Kv3 subfamily. In current-clamp recordings, concentrations of 4-AP that blocked the current through Kv3.1b channels allowed us tentatively to assign a role to Kv3.1b-containing channels in action-potential repolarization. These data demonstrate that Kv3.1b is regulated developmentally in a specific subpopulation of hippocampal interneurons and that channels containing this subunit may be a major determinant in imparting "fast-spiking" characteristics to these and other cells throughout the central nervous system containing the Kv3.1b subunit.

  15. Cholinergic interneurons control local circuit activity and cocaine conditioning.

    Science.gov (United States)

    Witten, Ilana B; Lin, Shih-Chun; Brodsky, Matthew; Prakash, Rohit; Diester, Ilka; Anikeeva, Polina; Gradinaru, Viviana; Ramakrishnan, Charu; Deisseroth, Karl

    2010-12-17

    Cholinergic neurons are widespread, and pharmacological modulation of acetylcholine receptors affects numerous brain processes, but such modulation entails side effects due to limitations in specificity for receptor type and target cell. As a result, causal roles of cholinergic neurons in circuits have been unclear. We integrated optogenetics, freely moving mammalian behavior, in vivo electrophysiology, and slice physiology to probe the cholinergic interneurons of the nucleus accumbens by direct excitation or inhibition. Despite representing less than 1% of local neurons, these cholinergic cells have dominant control roles, exerting powerful modulation of circuit activity. Furthermore, these neurons could be activated by cocaine, and silencing this drug-induced activity during cocaine exposure (despite the fact that the manipulation of the cholinergic interneurons was not aversive by itself) blocked cocaine conditioning in freely moving mammals.

  16. Clonally Related Forebrain Interneurons Disperse Broadly across Both Functional Areas and Structural Boundaries.

    Science.gov (United States)

    Mayer, Christian; Jaglin, Xavier H; Cobbs, Lucy V; Bandler, Rachel C; Streicher, Carmen; Cepko, Constance L; Hippenmeyer, Simon; Fishell, Gord

    2015-09-02

    The medial ganglionic eminence (MGE) gives rise to the majority of mouse forebrain interneurons. Here, we examine the lineage relationship among MGE-derived interneurons using a replication-defective retroviral library containing a highly diverse set of DNA barcodes. Recovering the barcodes from the mature progeny of infected progenitor cells enabled us to unambiguously determine their respective lineal relationship. We found that clonal dispersion occurs across large areas of the brain and is not restricted by anatomical divisions. As such, sibling interneurons can populate the cortex, hippocampus striatum, and globus pallidus. The majority of interneurons appeared to be generated from asymmetric divisions of MGE progenitor cells, followed by symmetric divisions within the subventricular zone. Altogether, our findings uncover that lineage relationships do not appear to determine interneuron allocation to particular regions. As such, it is likely that clonally related interneurons have considerable flexibility as to the particular forebrain circuits to which they can contribute.

  17. Stem cell derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model

    Science.gov (United States)

    Donegan, Jennifer J.; Tyson, Jennifer A.; Branch, Sarah Y.; Beckstead, Michael J.; Anderson, Stewart A.; Lodge, Daniel J.

    2016-01-01

    An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol (MAM) rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity, and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia. PMID:27480492

  18. Diversity of Voltage Activated Calcium Currents in Identified Olfactory Interneurons

    OpenAIRE

    Husch, Andreas

    2007-01-01

    In the insect antennal lobe (AL) each olfactory receptor cell projects to one glomerulus and many receptor axons converge in each glomerulus, where they provide synaptic input to local interneurons (LNs) and projection (output) neurons (PNs). The arborizations of LNs are confined to the AL. In contrast, the PNs extend axons to higher order neuropiles of the protocerebrum, including the mushroom bodies and the lateral lobus of the protocerebrum. In particular PNs have been in the focus of inte...

  19. Muscarinic and dopaminergic receptor subtypes on striatal cholinergic interneurons

    Energy Technology Data Exchange (ETDEWEB)

    Dawson, V.L.; Dawson, T.M.; Wamsley, J.K. (Neuropsychiatric Research Institute, Fargo, ND (USA))

    1990-12-01

    Unilateral stereotaxic injection of small amounts of the cholinotoxin, AF64A, caused minimal nonselective tissue damage and resulted in a significant loss of the presynaptic cholinergic markers (3H)hemicholinium-3 (45% reduction) and choline acetyltransferase (27% reduction). No significant change from control was observed in tyrosine hydroxylase or tryptophan hydroxylase activity; presynaptic neuronal markers for dopamine- and serotonin-containing neurons, respectively. The AF64A lesion resulted in a significant reduction of dopamine D2 receptors as evidenced by a decrease in (3H)sulpiride binding (42% reduction) and decrease of muscarinic non-M1 receptors as shown by a reduction in (3H)QNB binding in the presence of 100 nM pirenzepine (36% reduction). Saturation studies revealed that the change in (3H)sulpiride and (3H)QNB binding was due to a change in Bmax not Kd. Intrastriatal injection of AF64A failed to alter dopamine D1 or muscarinic M1 receptors labeled with (3H)SCH23390 and (3H)pirenzepine, respectively. In addition, no change in (3H)forskolin-labeled adenylate cyclase was observed. These results demonstrate that a subpopulation of muscarinic receptors (non-M1) are presynaptic on cholinergic interneurons (hence, autoreceptors), and a subpopulation of dopamine D2 receptors are postsynaptic on cholinergic interneurons. Furthermore, dopamine D1, muscarinic M1 and (3H)forskolin-labeled adenylate cyclase are not localized to striatal cholinergic interneurons.

  20. The Number of Parvalbumin-Expressing Interneurons Is Decreased in the Medial Prefrontal Cortex in Autism.

    OpenAIRE

    E. Hashemi; Ariza, J.; Rogers, H.; Noctor, SC; Martínez-Cerdeño, V

    2016-01-01

    The cognitive phenotype of autism has been correlated with an altered balance of excitation to inhibition in the cerebral cortex, which could result from a change in the number, function, or morphology of GABA-expressing interneurons. The number of GABAergic interneuron subtypes has not been quantified in the autistic cerebral cortex. We classified interneurons into 3 subpopulations based on expression of the calcium-binding proteins parvalbumin, calbindin, or calretinin. We quantified the nu...

  1. Tonic GABAA conductance bidirectionally controls interneuron firing pattern and synchronization in the CA3 hippocampal network.

    OpenAIRE

    Pavlov, I.; Savtchenko, L P; Song, I.; Koo, J; A. PIMASHKIN; Rusakov, D A; A. SEMYANOV

    2013-01-01

    The spiking output of interneurons is key for rhythm generation in the brain. However, what controls interneuronal firing remains incompletely understood. Here we combine dynamic clamp experiments with neural network simulations to understand how tonic GABAA conductance regulates the firing pattern of CA3 interneurons. In baseline conditions, tonic GABAA depolarizes these cells, thus exerting an excitatory action while also reducing the excitatory postsynaptic potential (EPSP) amplitude throu...

  2. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus.

    Science.gov (United States)

    Song, Juan; Sun, Jiaqi; Moss, Jonathan; Wen, Zhexing; Sun, Gerald J; Hsu, Derek; Zhong, Chun; Davoudi, Heydar; Christian, Kimberly M; Toni, Nicolas; Ming, Guo-Li; Song, Hongjun

    2013-12-01

    Using immunohistology, electron microscopy, electrophysiology and optogenetics, we found that proliferating adult mouse hippocampal neural precursors received immature GABAergic synaptic inputs from parvalbumin-expressing interneurons. Recently shown to suppress adult quiescent neural stem cell activation, parvalbumin interneuron activation promoted newborn neuronal progeny survival and development. Our results suggest a niche mechanism involving parvalbumin interneurons that couples local circuit activity to the diametric regulation of two critical early phases of adult hippocampal neurogenesis.

  3. Elfn1 regulates target-specific release probability at CA1-interneuron synapses

    OpenAIRE

    Sylwestrak, Emily L.; Ghosh, Anirvan

    2012-01-01

    Although synaptic transmission may be unidirectional, the establishment of synaptic connections with specific properties can involve bidirectional signaling. Pyramidal neurons in the hippocampus form functionally distinct synapses onto two types of interneurons. Excitatory synapses onto oriens-lacunosum moleculare (O-LM) interneurons are facilitating and have a low release probability, whereas synapses onto parvalbumin interneurons are depressing and have a high release probability. Here, we ...

  4. Diversity and overlap of parvalbumin and somatostatin expressing interneurons in mouse presubiculum

    OpenAIRE

    Mérie eNassar; Jean eSimonnet; Roxanne eLofredi; Ivan eCohen; Etienne eSavary; Yuchio eYanagawa; Richard eMiles; Desdemona eFricker

    2015-01-01

    International audience; The presubiculum, located between hippocampus and entorhinal cortex, plays a fundamental role in representing spatial information, notably head direction. Little is known about GABAergic interneurons of this region. Here, we used three transgenic mouse lines, Pvalb-Cre, Sst-Cre, and X98, to examine distinct interneurons labeled with tdTomato or green fluorescent protein. The distribution of interneurons in presubicular lamina for each animal line was compared to that i...

  5. DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction

    OpenAIRE

    Zou, D.(Boston University, Boston, USA); Chen, L; Deng, D; Jiang, D.; Dong, F.; McSweeney, C.; Zhou, Y.; Liu, L.; Chen, G.; Wu, Y.; Mao, Y.

    2016-01-01

    Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in ...

  6. Deletion of Dlx1 results in reduced glutamatergic input to hippocampal interneurons.

    Science.gov (United States)

    Jones, Daniel L; Howard, MacKenzie A; Stanco, Amelia; Rubenstein, John L R; Baraban, Scott C

    2011-05-01

    Dlx transcription factors are important in the differentiation of GABAergic interneurons. In mice lacking Dlx1, early steps in interneuron development appear normal. Beginning at ∼ 1 mo of age, primarily dendrite-innervating interneuron subtypes begin to undergo apoptosis in Dlx1(-/-) mice; this is accompanied by a reduction in GABAergic transmission and late-onset epilepsy. The reported reduction of synaptic inhibition is greater than might be expected given that interneuron loss is relatively modest in Dlx1(-/-) mice. Here we report that voltage-clamp recordings of CA1 interneurons in hippocampal slices prepared from Dlx1(-/-) animals older than postnatal day 30 (>P30) revealed a significant reduction in excitatory postsynaptic current (EPSC) amplitude. No changes in EPSCs onto interneurons were observed in cells recorded from younger animals (P9-12). Current-clamp recordings from interneurons at these early postnatal ages showed that interneurons in Dlx1(-/-) mutants were immature and more excitable, although membrane properties normalized by P30. Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling, caspase-3, and NeuN staining did not reveal frank cell damage or loss in area CA3 of hippocampal sections from adult Dlx1(-/-) mice. Delayed interneuron maturation may lead to interneuron hyperexcitability, followed by a compensatory reduction in the strength of excitatory transmission onto interneurons. This reduced excitation onto surviving interneurons, coupled with the loss of a significant fraction of GABAergic inputs to excitatory neurons starting at P30, may underlie cortical dysrhythmia and seizures previously observed in adult Dlx1(-/-) mice.

  7. Rac-GTPases Regulate Microtubule Stability and Axon Growth of Cortical GABAergic Interneurons.

    Science.gov (United States)

    Tivodar, Simona; Kalemaki, Katerina; Kounoupa, Zouzana; Vidaki, Marina; Theodorakis, Kostas; Denaxa, Myrto; Kessaris, Nicoletta; de Curtis, Ivan; Pachnis, Vassilis; Karagogeos, Domna

    2015-09-01

    Cortical interneurons are characterized by extraordinary functional and morphological diversity. Although tremendous progress has been made in uncovering molecular and cellular mechanisms implicated in interneuron generation and function, several questions still remain open. Rho-GTPases have been implicated as intracellular mediators of numerous developmental processes such as cytoskeleton organization, vesicle trafficking, transcription, cell cycle progression, and apoptosis. Specifically in cortical interneurons, we have recently shown a cell-autonomous and stage-specific requirement for Rac1 activity within proliferating interneuron precursors. Conditional ablation of Rac1 in the medial ganglionic eminence leads to a 50% reduction of GABAergic interneurons in the postnatal cortex. Here we examine the additional role of Rac3 by analyzing Rac1/Rac3 double-mutant mice. We show that in the absence of both Rac proteins, the embryonic migration of medial ganglionic eminence-derived interneurons is further impaired. Postnatally, double-mutant mice display a dramatic loss of cortical interneurons. In addition, Rac1/Rac3-deficient interneurons show gross cytoskeletal defects in vitro, with the length of their leading processes significantly reduced and a clear multipolar morphology. We propose that in the absence of Rac1/Rac3, cortical interneurons fail to migrate tangentially towards the pallium due to defects in actin and microtubule cytoskeletal dynamics.

  8. Beta-adrenergic receptors are differentially expressed in distinct interneuron subtypes in the rat hippocampus.

    Science.gov (United States)

    Cox, David J; Racca, Claudia; LeBeau, Fiona E N

    2008-08-20

    Noradrenaline (NA) acting via beta-adrenergic receptors (betaARs) plays an important role in the modulation of memory in the hippocampus. betaARs have been shown to be expressed in principal cells, but their distribution across different interneuron classes is unknown. We have used specific interneuron markers including calcium binding proteins (parvalbumin, calbindin, and calretinin) and neuropeptides (somatostatin, neuropeptide Y, and cholecystokinin) together with either beta1AR or beta2AR to determine the distribution of these receptors in all major subfields of the hippocampus. We found that beta1AR-expressing interneurons were more prevalent in the CA3 and CA1 regions of the hippocampus than in the dentate gyrus, where they were relatively sparse. beta2AR-expressing interneurons were more uniformly distributed between all three regions of the hippocampus. A high proportion of neuropeptide Y-containing interneurons in the dentate gyrus co-expressed beta2AR. beta1AR labeling was common in interneurons expressing somatostatin and parvalbumin in the CA3 and CA1 regions, particularly in the stratum oriens of these regions. beta2AR labeling was more likely to be found than beta1AR labeling in cholecystokinin-expressing interneurons. In contrast, calretinin-containing interneurons were virtually devoid of beta1AR or beta2AR labeling. These regional and interneuron type-specific differences suggest functionally distinct roles for NA in modulating hippocampal activity via activation of betaARs.

  9. Parvalbumin tunes spike-timing and efferent short-term plasticity in striatal fast spiking interneurons.

    Science.gov (United States)

    Orduz, David; Bischop, Don Patrick; Schwaller, Beat; Schiffmann, Serge N; Gall, David

    2013-07-01

      Striatal fast spiking interneurons (FSIs) modulate output of the striatum by synchronizing medium-sized spiny neurons (MSNs). Recent studies have broadened our understanding of FSIs, showing that they are implicated in severe motor disorders such as parkinsonism, dystonia and Tourette syndrome. FSIs are the only striatal neurons to express the calcium-binding protein parvalbumin (PV). This selective expression of PV raises questions about the functional role of this Ca(2+) buffer in controlling FSI Ca(2+) dynamics and, consequently, FSI spiking mode and neurotransmission. To study the functional involvement of FSIs in striatal microcircuit activity and the role of PV in FSI function, we performed perforated patch recordings on enhanced green fluorescent protein-expressing FSIs in brain slices from control and PV-/- mice. Our results revealed that PV-/- FSIs fired more regularly and were more excitable than control FSIs by a mechanism in which Ca(2+) buffering is linked to spiking activity as a result of the activation of small conductance Ca(2+)-dependent K(+) channels. A modelling approach of striatal FSIs supports our experimental results. Furthermore, PV deletion modified frequency-specific short-term plasticity at inhibitory FSI to MSN synapses. Our results therefore reinforce the hypothesis that in FSIs, PV is crucial for fine-tuning of the temporal responses of the FSI network and for the orchestration of MSN populations. This, in turn, may play a direct role in the generation and pathology-related worsening of motor rhythms.

  10. A spiking network model of cerebellar Purkinje cells and molecular layer interneurons exhibiting irregular firing

    Directory of Open Access Journals (Sweden)

    William eLennon

    2014-12-01

    Full Text Available While the anatomy of the cerebellar microcircuit is well studied, how it implements cerebellar function is not understood. A number of models have been proposed to describe this mechanism but few emphasize the role of the vast network Purkinje cells (PKJs form with the molecular layer interneurons (MLIs – the stellate and basket cells. We propose a model of the MLI-PKJ network composed of simple spiking neurons incorporating the major anatomical and physiological features. In computer simulations, the model reproduces the irregular firing patterns observed in PKJs and MLIs in vitro and a shift toward faster, more regular firing patterns when inhibitory synaptic currents are blocked. In the model, the time between PKJ spikes is shown to be proportional to the amount of feedforward inhibition from an MLI on average. The two key elements of the model are: (1 spontaneously active PKJs and MLIs due to an endogenous depolarizing current, and (2 adherence to known anatomical connectivity along a parasagittal strip of cerebellar cortex. We propose this model to extend previous spiking network models of the cerebellum and for further computational investigation into the role of irregular firing and MLIs in cerebellar learning and function.

  11. Patterns of connectivity of spinal interneurons with single muscle afferents.

    Science.gov (United States)

    Quevedo, J; Eguibar, J R; Lomeli, J; Rudomin, P

    1997-07-01

    A technique was developed to measure, in the anesthetized and paralyzed cat under artificial ventilation, changes of excitability to intraspinal stimulation simultaneously in two different afferent fibers or in two collaterals of the same afferent fiber. Intraspinal stimulation reduced the threshold of single muscle afferent fibers ending in the intermediate nucleus. This effect was seen with strengths below those required to activate the afferent fiber tested (1.5-12 microA), occurred at a short latency (1.5-2.0 ms), reached a maximum between 15 and 30 ms, and lasted up to 100 ms. The effects produced by graded stimulation applied at the shortest conditioning-testing stimulus time intervals increased by fixed steps, suggesting recruitment of discrete elements, most likely of last-order interneurons mediating primary afferent depolarization (PAD). The short-latency increases in excitability produced by the weakest effective intraspinal stimuli were usually detected only in the collateral closest to the stimulating micropipette, indicating that the stimulated interneurons mediating PAD have spatially restricted actions. The short-latency PAD produced by intraspinal stimuli, as well as the PAD produced by stimulation of the posterior biceps and semitendinosus (PBSt) nerve or by stimulation of the bulbar reticular formation (RF), was depressed 19-30 min after the i.v. injection of 0.5 mg/kg of picrotoxin, suggesting that all these effects were mediated by GABAergic mechanisms. The PAD elicited by stimulation of muscle and/or cutaneous nerves was depressed following the i.v. injection of (-)-baclofen, whereas the PAD elicited in the same collateral by stimulation of the RF was baclofen-resistant. The short-latency PAD produced by intraspinal stimulation was not always depressed by i.v. injections of (-)-baclofen. Baclofen-sensitive and baclofen-resistant monosynaptic PADs could be produced in different collaterals of the same afferent fiber. The results suggest that

  12. Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning.

    Science.gov (United States)

    Brown, Matthew T C; Tan, Kelly R; O'Connor, Eoin C; Nikonenko, Irina; Muller, Dominique; Lüscher, Christian

    2012-12-20

    The ventral tegmental area (VTA) and nucleus accumbens (NAc) are essential for learning about environmental stimuli associated with motivationally relevant outcomes. The task of signalling such events, both rewarding and aversive, from the VTA to the NAc has largely been ascribed to dopamine neurons. The VTA also contains GABA (γ-aminobutyric acid)-releasing neurons, which provide local inhibition and also project to the NAc. However, the cellular targets and functional importance of this long-range inhibitory projection have not been ascertained. Here we show that GABA-releasing neurons of the VTA that project to the NAc (VTA GABA projection neurons) inhibit accumbal cholinergic interneurons (CINs) to enhance stimulus-outcome learning. Combining optogenetics with structural imaging and electrophysiology, we found that VTA GABA projection neurons selectively target NAc CINs, forming multiple symmetrical synaptic contacts that generated inhibitory postsynaptic currents. This is remarkable considering that CINs represent a very small population of all accumbal neurons, and provide the primary source of cholinergic tone in the NAc. Brief activation of this projection was sufficient to halt the spontaneous activity of NAc CINs, resembling the pause recorded in animals learning stimulus-outcome associations. Indeed, we found that forcing CINs to pause in behaving mice enhanced discrimination of a motivationally important stimulus that had been associated with an aversive outcome. Our results demonstrate that VTA GABA projection neurons, through their selective targeting of accumbal CINs, provide a novel route through which the VTA communicates saliency to the NAc. VTA GABA projection neurons thus emerge as orchestrators of dopaminergic and cholinergic modulation in the NAc.

  13. Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses

    Science.gov (United States)

    Trouche, Stéphanie; Sasaki, Jennifer M.; Tu, Tiffany; Reijmers, Leon G.

    2013-01-01

    SUMMARY A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. PMID:24183705

  14. Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses.

    Science.gov (United States)

    Trouche, Stéphanie; Sasaki, Jennifer M; Tu, Tiffany; Reijmers, Leon G

    2013-11-20

    A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos-based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Early sequential formation of functional GABA(A) and glutamatergic synapses on CA1 interneurons of the rat foetal hippocampus.

    Science.gov (United States)

    Hennou, Sonia; Khalilov, Ilgam; Diabira, Diabé; Ben-Ari, Yehezkel; Gozlan, Henri

    2002-07-01

    During postnatal development of CA1 pyramidal neurons, GABAergic synapses are excitatory and established prior to glutamatergic synapses. As interneurons are generated before pyramidal cells, we have tested the hypothesis that the GABAergic interneuronal network is operative before glutamate pyramidal neurons and provides the initial patterns of activity. We patch-clamp recorded interneurons in foetal (69 neurons) and neonatal P0 (162 neurons) hippocampal slices and performed a morphofunctional analysis of biocytin-filled neurons. At P0, three types of interneurons were found: (i) non-innervated "silent" interneurons (5%) with no spontaneous or evoked synaptic currents; (ii) G interneurons (17%) with GABA(A) synapses only; and (iii) GG interneurons with GABA and glutamatergic synapses (78%). Relying on the neuronal capacitance, cell body size and arborization of dendrites and axons, the three types of interneurons correspond to three stages of development with non-innervated neurons and interneurons with GABA(A) and glutamatergic synapses being, respectively, the least and the most developed. Recordings from both pyramidal neurons and interneurons in foetuses (E18-20) revealed that the majority of interneurons (65%) had functional synapses whereas nearly 90% of pyramidal neurons were quiescent. Therefore, interneurons follow the same GABA-glutamate sequence of synapse formation but earlier than the principal cells. Interneurons are the source and the target of the first synapses formed in the hippocampus and are thus in a position to modulate the development of the hippocampus in the foetal stage.

  16. Computational modeling of distinct neocortical oscillations driven by cell-type selective optogenetic drive: Separable resonant circuits controlled by low-threshold spiking and fast-spiking interneurons

    Directory of Open Access Journals (Sweden)

    Dorea Vierling-Claassen

    2010-11-01

    Full Text Available Selective optogenetic drive of fast spiking interneurons (FS leads to enhanced local field potential (LFP power across the traditional gamma frequency band (20-80Hz; Cardin et al., 2009. In contrast, drive to regular-spiking pyramidal cells (RS enhances power at lower frequencies, with a peak at 8 Hz. The first result is consistent with previous computational studies emphasizing the role of FS and the time constant of GABAA synaptic inhibition in gamma rhythmicity. However, the same theoretical models do not typically predict low-frequency LFP enhancement with RS drive. To develop hypotheses as to how the same network can support these contrasting behaviors, we constructed a biophysically principled network model of primary somatosensory neocortex containing FS, RS and low-threshold-spiking (LTS interneurons. Cells were modeled with detailed cell anatomy and physiology, multiple dendritic compartments, and included active somatic and dendritic ionic currents. Consistent with prior studies, the model demonstrated gamma resonance during FS drive, dependent on the time-constant of GABAA inhibition induced by synchronous FS activity. Lower frequency enhancement during RS drive was replicated only on inclusion of an inhibitory LTS population, whose activation was critically dependent on RS synchrony and evoked longer-lasting inhibition. Our results predict that differential recruitment of FS and LTS inhibitory populations is essential to the observed cortical dynamics and may provide a means for amplifying the natural expression of distinct oscillations in normal cortical processing.

  17. Synaptotagmin-2 is a reliable marker for parvalbumin positive inhibitory boutons in the mouse visual cortex.

    Directory of Open Access Journals (Sweden)

    Jean-Pierre Sommeijer

    Full Text Available BACKGROUND: Inhibitory innervation by parvalbumin (PV expressing interneurons has been implicated in the onset of the sensitive period of visual plasticity. Immunohistochemical analysis of the development and plasticity of these inhibitory inputs is difficult because PV expression is low in young animals and strongly influenced by neuronal activity. Moreover, the synaptic boutons that PV neurons form onto each other cannot be distinguished from the innervated cell bodies by immunostaining for this protein because it is present throughout the cells. These problems call for the availability of a synaptic, activity-independent marker for PV+ inhibitory boutons that is expressed before sensitive period onset. We investigated whether synaptotagmin-2 (Syt2 fulfills these properties in the visual cortex. Syt2 is a synaptic vesicle protein involved in fast Ca(2+ dependent neurotransmitter release. Its mRNA expression follows a pattern similar to that of PV throughout the brain and is present in 30-40% of hippocampal PV expressing basket cells. Up to now, no quantitative analyses of Syt2 expression in the visual cortex have been carried out. METHODOLOGY/PRINCIPAL FINDINGS: We used immunohistochemistry to analyze colocalization of Syt2 with multiple interneuron markers including vesicular GABA transporter VGAT, calbindin, calretinin, somatostatin and PV in the primary visual cortex of mice during development and after dark-rearing. CONCLUSIONS/SIGNIFICANCE: We show that in the adult visual cortex Syt2 is only found in inhibitory, VGAT positive boutons. Practically all Syt2 positive boutons also contain PV and vice versa. During development, Syt2 expression can be detected in synaptic boutons prior to PV and in contrast to PV expression, Syt2 is not down-regulated by dark-rearing. These properties of Syt2 make it an excellent marker for analyzing the development and plasticity of perisomatic inhibitory innervations onto both excitatory and inhibitory

  18. Postnatal development of GABAergic interneurons in the neocortical subplate of mice.

    Science.gov (United States)

    Qu, G-J; Ma, J; Yu, Y-C; Fu, Y

    2016-05-13

    The subplate (SP) plays important roles in developmental and functional events in the neocortex, such as thalamocortical and corticofugal projection, cortical oscillation generation and corticocortical connectivity. Although accumulated evidence indicates that SP interneurons are crucial for SP function, the molecular composition of SP interneurons as well as their developmental profile and distribution remain largely unclear. In this study, we systematically investigated dynamic development of SP thickness and chemical marker expression in SP interneurons in distinct cortical regions during the first postnatal month. We found that, although the relative area of the SP in the cerebral cortex significantly declined with postnatal development, the absolute thickness did not change markedly. We also found that somatostatin (SOM), the ionotropic serotonin receptor 3A (5HT3AR), and parvalbumin (PV) reliably identify three distinct non-overlapping subpopulations of SP interneurons. The SOM group, which represents ~30% of total SP interneurons, expresses neuronal nitric oxide synthase (nNOS) and calbindin (CB) and colocalizes entirely with neuropeptide Y (NPY). The 5HT3AR group, which accounts for ~60% of the total interneuronal population, expresses calretinin (CR) and GABA-A receptor subunit delta (GABAARδ). The PV group accounts for ~10% of total SP interneurons and coexpressed GABAARδ. Moreover, distinct interneuron subtypes show characteristic temporal and spatial distribution in the SP. nNOS(+) interneurons in the SP increase from the anterior motor cortex to posterior visual cortex, while CR(+) and CB(+) interneurons the opposite. Interestedly, the majority of GABAARδ(+) neurons in SP are non-GABAergic neurons in contrast to other cortical layers. These findings clarify and extend our understanding of SP interneurons in the developing cerebral cortex and will underpin further study of SP function.

  19. The loss of interneuron functional diversity in the piriform cortex after induction of experimental epilepsy.

    Science.gov (United States)

    Gavrilovici, Cezar; Pollock, Emily; Everest, Michelle; Poulter, Michael O

    2012-12-01

    Interneuronal functional diversity is thought to be an important factor in the control of neural network oscillations in many brain regions. Specifically, interneuron action potential firing patterns are thought to modulate brain rhythms. In neurological disorders such as epilepsy where brain rhythms are significantly disturbed interneuron function is largely unexplored. Thus the purpose of this study was to examine the functional diversity of piriform cortex interneurons (PC; an area of the brain that easily supports seizures) before and after kindling-induced epilepsy. Using cluster analysis, we found five control firing behaviors. These groups were termed: non-adapting very high frequency (NAvHF), adapting high frequency (AHF), adapting low frequency (ALF), strongly adapting low frequency (sALF), and weakly adapting low frequency (wALF). A morphological analysis showed these spiking patterns were not associated with any specific interneuronal morphology although we found that most of the cells displaying NAvHF firing pattern were multipolar. After kindling about 40% of interneuronal firing pattern changed, and neither the NAvHF nor the wALF phenotypes were found. We also found that in multipolar interneurons a long-lasting potassium current was increased. A qPCR analysis indicated Kv1.6 subtype was up-regulated after kindling. An immunocytochemical analysis showed that Kv1.6 protein expression on parvalbumin (multipolar) interneurons increased by greater than 400%. We also examined whether these changes could be due to the selective death of a subset of interneurons but found that there was no change in cell number. These data show an important loss of the functional diversity of interneurons in the PC. Our data suggest that under pathophysiological condition interneurons are plastic resulting in the attenuation of high frequency network oscillations in favor of low frequency network activity. This may be an important new mechanism by which network synchrony is

  20. Multi-dimensional classification of GABAergic interneurons with Bayesian network-modeled label uncertainty

    Science.gov (United States)

    Mihaljević, Bojan; Bielza, Concha; Benavides-Piccione, Ruth; DeFelipe, Javier; Larrañaga, Pedro

    2014-01-01

    Interneuron classification is an important and long-debated topic in neuroscience. A recent study provided a data set of digitally reconstructed interneurons classified by 42 leading neuroscientists according to a pragmatic classification scheme composed of five categorical variables, namely, of the interneuron type and four features of axonal morphology. From this data set we now learned a model which can classify interneurons, on the basis of their axonal morphometric parameters, into these five descriptive variables simultaneously. Because of differences in opinion among the neuroscientists, especially regarding neuronal type, for many interneurons we lacked a unique, agreed-upon classification, which we could use to guide model learning. Instead, we guided model learning with a probability distribution over the neuronal type and the axonal features, obtained, for each interneuron, from the neuroscientists' classification choices. We conveniently encoded such probability distributions with Bayesian networks, calling them label Bayesian networks (LBNs), and developed a method to predict them. This method predicts an LBN by forming a probabilistic consensus among the LBNs of the interneurons most similar to the one being classified. We used 18 axonal morphometric parameters as predictor variables, 13 of which we introduce in this paper as quantitative counterparts to the categorical axonal features. We were able to accurately predict interneuronal LBNs. Furthermore, when extracting crisp (i.e., non-probabilistic) predictions from the predicted LBNs, our method outperformed related work on interneuron classification. Our results indicate that our method is adequate for multi-dimensional classification of interneurons with probabilistic labels. Moreover, the introduced morphometric parameters are good predictors of interneuron type and the four features of axonal morphology and thus may serve as objective counterparts to the subjective, categorical axonal features

  1. Differential expression of group I metabotropic glutamate receptors in functionally distinct hippocampal interneurons.

    Science.gov (United States)

    van Hooft, J A; Giuffrida, R; Blatow, M; Monyer, H

    2000-05-15

    Metabotropic glutamate receptors (mGluRs) have been proposed to be involved in oscillatory rhythmic activity in the hippocampus. However, the subtypes of mGluRs involved and their precise distribution in different populations of interneurons is unclear. In this study, we combined functional analysis of mGluR-mediated inward currents in CA1 oriens-alveus interneurons with anatomical and immunocytochemical identification of these interneurons and expression analysis of group I mGluR using single-cell reverse transcription-PCR (RT-PCR). Four major interneuron subtypes could be distinguished based on the mGluR-mediated inward current induced by the application of 100 microm trans-(1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid (ACPD) under voltage-clamp conditions and the action potential firing pattern under current-clamp conditions. Type I interneurons responded with a large inward current of approximately 224 pA, were positive for somatostatin, and the majority expressed both mGluR1 and mGluR5. Type II interneurons responded with an inward current of approximately 80 pA, contained calbindin, and expressed mainly mGluR1. Type III interneurons responded with an inward current of approximately 60 pA. These interneurons were fast-spiking, contained parvalbumin, and expressed mainly mGluR5. Type IV interneurons did not respond with an inward current upon application of ACPD, yet they expressed group I mGluRs. Activation of group I mGluRs under current-clamp conditions increased spike frequency and resulted in rhythmic firing activity in type I and II, but not in type III and IV, interneurons. RT-PCR results suggest that activation of mGluR1 in the subsets of GABAergic interneurons, classified here as type I and II, may play an important role in mediating synchronous activity.

  2. Pharmacologic analysis of inhibition produced by last-order intermediate nucleus interneurons mediating nonreciprocal inhibition of motoneurons in cat spinal cord.

    Science.gov (United States)

    Rudomin, P; Jiménez, I; Quevedo, J; Solodkin, M

    1990-01-01

    1. The aim of this study was to investigate the effects of drugs blocking glycinergic and GABAergic transmission on the postsynaptic inhibition of hindlimb motoneurons produced by activation of last-order laminae V-VI interneurons, which are coexcited by muscle and cutaneous afferents and have axonal branches projecting to the Clarke's column. 2. In anesthetized cats with right spinal cord hemisected and both dorsal columns cut between L4 and L5 segments, stimulation of the Clarke's column (CC) at L3-L4 level produced a short-latency, presumably monosynaptic, inhibitory potential that could be recorded either from L7 or S1 ventral rootlets by means of the sucrose-gap technique (iVRP) or intracellularly from hindlimb motoneurons (IPSP). These potentials have been attributed to antidromic activation of a population of last-order interneurons mediating nonreciprocal inhibition of motoneurons. 3. The early iVRP and IPSP produced by CC stimulation was practically abolished 10-20 s after the intravenous injection of strychnine (0.1 mg/kg) and replaced by an excitatory synaptic potential followed by delayed, slow, strychnine-resistant inhibitory potential. 4. Monosynaptic reflexes (MSR) elicited by stimulation of group I gastrocnemius (GS) afferents were inhibited during the occurrence of the CC-iVRP. This inhibition was significantly reduced after intravenous strychnine. On the other hand, the inhibition of the GS-MSR, produced by conditioning stimulation of the posterior biceps and semitendinosus (PBSt) nerve with trains of pulses applied 25-35 ms before the test stimulus, was practically unchanged after the intravenous injection of strychnine. 5. The CC-iVRP and the associated inhibition of GS-MSRs were not significantly affected after the intravenous injection of 0.1 mg/kg of picrotoxin, which clearly reduced the dorsal root potentials (DRP), the late component of the iVRP, and the inhibition of MSRs produced by PBSt volleys. 6. The effect of strychnine and picrotoxin

  3. Optogenetic identification of an intrinsic cholinergically driven inhibitory oscillator sensitive to cannabinoids and opioids in hippocampal CA1.

    Science.gov (United States)

    Nagode, Daniel A; Tang, Ai-Hui; Yang, Kun; Alger, Bradley E

    2014-01-01

    Neuronal electrical oscillations in the theta (4-14 Hz) and gamma (30-80 Hz) ranges are necessary for the performance of certain animal behaviours and cognitive processes. Perisomatic GABAergic inhibition is prominently involved in cortical oscillations driven by ACh release from septal cholinergic afferents. In neocortex and hippocampal CA3 regions, parvalbumin (PV)-expressing basket cells, activated by ACh and glutamatergic agonists, largely mediate oscillations. However, in CA1 hippocampus in vitro, cholinergic agonists or the optogenetic release of endogenous ACh from septal afferents induces rhythmic, theta-frequency inhibitory postsynaptic currents (IPSCs) in pyramidal cells, even with glutamatergic transmission blocked. The IPSCs are regulated by exogenous and endogenous cannabinoids, suggesting that they arise from type 1 cannabinoid receptor-expressing (CB1R+) interneurons - mainly cholecystokinin (CCK)-expressing cells. Nevertheless, an occult contribution of PV-expressing interneurons to these rhythms remained conceivable. Here, we directly test this hypothesis by selectively silencing CA1 PV-expressing cells optogenetically with halorhodopsin or archaerhodopsin. However, this had no effect on theta-frequency IPSC rhythms induced by carbachol (CCh). In contrast, the silencing of glutamic acid decarboxylase 2-positive interneurons, which include the CCK-expressing basket cells, strongly suppressed inhibitory oscillations; PV-expressing interneurons appear to play no role. The low-frequency IPSC oscillations induced by CCh or optogenetically stimulated ACh release were also inhibited by a μ-opioid receptor (MOR) agonist, which was unexpected because MORs in CA1 are not usually associated with CCK-expressing cells. Our results reveal novel properties of an inhibitory oscillator circuit within CA1 that is activated by muscarinic agonists. The oscillations could contribute to behaviourally relevant, atropine-sensitive, theta rhythms and link cannabinoid and

  4. Calretinin periglomerular interneurons in mice olfactory bulb: cells of few words

    Directory of Open Access Journals (Sweden)

    Alex Fogli Iseppe

    2016-10-01

    Full Text Available Within the olfactory bulb (OB, periglomerular (PG cells consist of various types of interneurons, generally classified by their chemical properties such as neurotransmitter and calcium binding proteins.Calretinin (CR characterizes morphologically and functionally the more numerous and one of the less known subpopulation of PG cells in the OB. Using of transgenic mice expressing eGFP under the CR promoter, we have tried to obtain the first functional characterization of these cells. Electrophysiological recordings were made in these cells using the patch-clamp technique in thin slices. Using ion substitution methods and specific blockers, we dissected the main voltage-dependent conductances present, obtaining a complete kinetic description for each of them.The more peculiar property of these cells from the electrophysiological point of view is the presence only of a single K-current, the IA - there is no trace of delayed rectifier or of Ca-dependent K-current. Other currents identified, isolated and fully characterised are two inward currents, a fast sodium current and a small L-type calcium current, and an inward rectifier, h-type cationic current. As a consequence of the peculiar complement of voltage-dependent conductances present in these cells, and in particular the absence of delayed-rectifier potassium currents, under the functional point of view these cells present two interesting properties.First, in response to prolonged depolarisations, after the inactivation of the A-current, these cells behave as a purely ohmic elements, showing no outward rectification. Second, the CR cells studied can respond only with a single action potential to excitatory inputs; since they send inhibitory synapses to projection neurones, they seem to be designed to inhibit responses of the main neurones to isolated, random excitatory signals, losing their vetoing effect for more structured, repetitive excitatory signals, as result from odour detection

  5. Calretinin-Periglomerular Interneurons in Mice Olfactory Bulb: Cells of Few Words.

    Science.gov (United States)

    Fogli Iseppe, Alex; Pignatelli, Angela; Belluzzi, Ottorino

    2016-01-01

    Within the olfactory bulb (OB), periglomerular (PG) cells consist of various types of interneurons, generally classified by their chemical properties such as neurotransmitter and calcium binding proteins. Calretinin (CR) characterizes morphologically and functionally the more numerous and one of the less known subpopulation of PG cells in the OB. Using of transgenic mice expressing eGFP under the CR promoter, we have tried to obtain the first functional characterization of these cells. Electrophysiological recordings were made in these cells using the patch-clamp technique in thin slices. Using ion substitution methods and specific blockers, we dissected the main voltage-dependent conductances present, obtaining a complete kinetic description for each of them. The more peculiar property of these cells from the electrophysiological point of view is the presence only of a single K-current, A-type - there is no trace of delayed rectifier or of Ca-dependent K-current. Other currents identified, isolated and fully characterized are a fast sodium current, a small L-type calcium current, and an inward rectifier, h-type cationic current. As a consequence of the peculiar complement of voltage-dependent conductances present in these cells, and in particular the absence of delayed-rectifier potassium currents, under the functional point of view these cells present two interesting properties. First, in response to prolonged depolarisations, after the inactivation of the A-current these cells behave as a purely ohmic elements, showing no outward rectification. Second, the CR cells studied can respond only with a single action potential to excitatory inputs; since they send inhibitory synapses to projection neurones, they seem to be designed to inhibit responses of the main neurones to isolated, random excitatory signals, rapidly losing their vetoing effect in response to more structured, repetitive excitatory signals. We propose that a possible role for these rather untalkative

  6. Energy deprivation transiently enhances rhythmic inhibitory events in the CA3 hippocampal network in vitro.

    Science.gov (United States)

    Gee, C E; Benquet, P; Demont-Guignard, S; Wendling, F; Gerber, U

    2010-07-14

    Oxygen glucose deprivation (OGD) leads to rapid suppression of synaptic transmission. Here we describe an emergence of rhythmic activity at 8 to 20 Hz in the CA3 subfield of hippocampal slice cultures occurring for a few minutes prior to the OGD-induced cessation of evoked responses. These oscillations, dominated by inhibitory events, represent network activity, as they were abolished by tetrodotoxin. They were also completely blocked by the GABAergic antagonist picrotoxin, and strongly reduced by the glutamatergic antagonist NBQX. Applying CPP to block NMDA receptors had no effect and neither did UBP302, an antagonist of GluK1-containing kainate receptors. The gap junction blocker mefloquine disrupted rhythmicity. Simultaneous whole-cell voltage-clamp recordings from neighboring or distant CA3 pyramidal cells revealed strong cross-correlation of the incoming rhythmic activity. Interneurons in the CA3 area received similar correlated activity. Interestingly, oscillations were much less frequently observed in the CA1 area. These data, together with the observation that the recorded activity consists primarily of inhibitory events, suggest that CA3 interneurons are important for generating these oscillations. This transient increase in inhibitory network activity during OGD may represent a mechanism contributing to the lower vulnerability to ischemic insults of the CA3 area as compared to the CA1 area.

  7. Development and physiology of GABAergic feedback excitation in parvalbumin expressing interneurons of the mouse basolateral amygdala.

    Science.gov (United States)

    Spampanato, Jay; Sullivan, Robert K P; Perumal, Madhusoothanan B; Sah, Pankaj

    2016-01-01

    We have previously shown that in the basolateral amygdala (BLA), action potentials in one type of parvalbumin (PV)-expressing GABAergic interneuron can evoke a disynaptic feedback excitatory postsynaptic potential (fbEPSP) onto the same presynaptic interneuron. Here, using whole-cell recordings from PV-expressing interneurons in acute brain slices we expand on this finding to show that this response is first detectable at 2-week postnatal, and is most prevalent in animals beyond 3 weeks of age (>P21). This circuit has a very high fidelity, and single action potential evoked fbEPSPs display few failures. Reconstruction of filled neurons, and electron microscopy show that interneurons that receive feedback excitation make symmetrical synapses on both the axon initial segments (AIS), as well as the soma and proximal dendrites of local pyramidal neurons, suggesting fbEPSP interneurons are morphologically distinct from the highly specialized chandelier neurons that selectively target the axon initial segment of pyramidal neurons. Single PV interneurons could trigger very large (~ 1 nA) feedback excitatory postsynaptic currents (fbEPSCs) suggesting that these neurons are heavily reciprocally connected to local glutamatergic principal cells. We conclude that in the BLA, a subpopulation of PV interneurons forms a distinct neural circuit in which a single action potential can recruit multiple pyramidal neurons to discharge near simultaneously and feed back onto the presynaptic interneuron.

  8. Membrane properties and synaptic connectivity of fast-spiking interneurons in rat ventral striatum

    NARCIS (Netherlands)

    Taverna, S.; Canciani, B.; Pennartz, C.M.A.

    2007-01-01

    In vitro patch-clamp recordings were made to study the membrane properties and synaptic connectivity of fast-spiking interneurons in rat ventral striatum. Using a whole-cell configuration in acutely prepared slices, fast-spiking interneurons were recognized based on their firing properties and their

  9. GABAergic interneurons form transient layer-specific circuits in early postnatal neocortex.

    Science.gov (United States)

    Anastasiades, Paul G; Marques-Smith, Andre; Lyngholm, Daniel; Lickiss, Tom; Raffiq, Sayda; Kätzel, Dennis; Miesenböck, Gero; Butt, Simon J B

    2016-02-04

    GABAergic interneurons play key roles in cortical circuits, yet little is known about their early connectivity. Here we use glutamate uncaging and a novel optogenetic strategy to track changes in the afferent and efferent synaptic connections of developing neocortical interneuron subtypes. We find that Nkx2-1-derived interneurons possess functional synaptic connections before emerging pyramidal cell networks. Subsequent interneuron circuit maturation is both subtype and layer dependent. Glutamatergic input onto fast spiking (FS), but not somatostatin-positive, non-FS interneurons increases over development. Interneurons of both subtype located in layers (L) 4 and 5b engage in transient circuits that disappear after the somatosensory critical period. These include a pathway mediated by L5b somatostatin-positive interneurons that specifically targets L4 during the first postnatal week. The innervation patterns of immature cortical interneuron circuits are thus neither static nor progressively strengthened but follow a layer-specific choreography of transient connections that differ from those of the adult brain.

  10. Electrophysiological and morphological characterization of propriospinal interneurons in the thoracic spinal cord

    DEFF Research Database (Denmark)

    Saywell, S A; Ford, T W; Meehan, Claire Francesca;

    2011-01-01

    Propriospinal interneurons in the thoracic spinal cord have vital roles not only in controlling respiratory and trunk muscles, but also in providing possible substrates for recovery from spinal cord injury. Intracellular recordings were made from such interneurons in anesthetized cats under neuro...

  11. Intracerebroventricular kainic acid administration to neonatal rats alters interneuron development in the hippocampus.

    Science.gov (United States)

    Dong, Hongxin; Csernansky, Cynthia A; Chu, Yunxiang; Csernansky, John G

    2003-10-10

    The effects of neonatal exposure to excitotoxins on the development of interneurons have not been well characterized, but may be relevant to the pathogenesis of neuropsychiatric disorders. In this study, the excitotoxin, kainic acid (KA) was administered to rats at postnatal day 7 (P7) by intracerebroventricular (i.c.v.) infusion. At P14, P25, P40 and P60, Nissl staining and immunohistochemical studies with the interneuron markers, glutamic acid decarboxylase (GAD-67), calbindin-D28k (CB) and parvalbumin (PV) were performed in the hippocampus. In control animals, the total number of interneurons, as well as the number of interneurons stained with GAD-67, CB and PV, was nearly constant from P14 through P60. In KA-treated rats, Nissl staining, GAD-67 staining, and CB staining revealed a progressive decline in the overall number of interneurons in the CA1 and CA3 subfields from P14 to P60. In contrast, PV staining in KA-treated rats showed initial decreases in the number of interneurons in the CA1 and CA3 subfields at P14 followed by increases that approached control levels by P60. These results suggest that, in general, early exposure to the excitotoxin KA decreases the number of hippocampal interneurons, but has a more variable effect on the specific population of interneurons labeled by PV. The functional impact of these changes may be relevant to the pathogenesis of neuropsychiatric disorders, such as schizophrenia.

  12. Altered dendritic distribution of dopamine D2 receptors and reduction in mitochondrial number in parvalbumin-containing interneurons in the medial prefrontal cortex of cannabinoid-1 (CB1) receptor knockout mice.

    Science.gov (United States)

    Fitzgerald, Megan L; Chan, June; Mackie, Kenneth; Lupica, Carl R; Pickel, Virginia M

    2012-12-01

    The prelimbic prefrontal cortex (PL) is a brain region integral to complex behaviors that are highly influenced by cannabinoids and by dopamine D2 receptor (D2R)-mediated regulation of fast-firing parvalbumin-containing interneurons. We have recently shown that constitutive deletion of the cannabinoid-1 receptor (CB1R) greatly reduces parvalbumin levels in these neurons. The effects of CB1R deletion on PL parvalbumin interneurons may be ascribed to loss of CB1R-mediated retrograde signaling on mesocortical dopamine transmission, and, in turn, altered expression and/or subcellular distribution of D2R in the PL. Furthermore, diminished parvalbumin expression could indicate metabolic changes in fast-firing interneurons that may be reflected in changes in mitochondrial density in this population. We therefore comparatively examined electron microscopic dual labeling of D2R and parvalbumin in CB1 (-/-) and CB1 (+/+) mice to test the hypothesis that absence of CB1R produces changes in D2R localization and mitochondrial distribution in parvalbumin-containing interneurons of the PL. CB1 (-/-) mice had a significantly lower density of cytoplasmic D2R-immunogold particles in medium parvalbumin-labeled dendrites and a concomitant increase in the density of these particles in small dendrites. These dendrites received both excitatory and inhibitory-type synapses from unlabeled terminals and contained many mitochondria, whose numbers were significantly reduced in CB1 (-/-) mice. Non-parvalbumin dendrites showed no between-group differences in either D2R distribution or mitochondrial number. These results suggest that cannabinoid signaling provides an important determinant of dendritic D2 receptor distribution and mitochondrial availability in fast-spiking interneurons.

  13. Dense, unspecific connectivity of neocortical parvalbumin-positive interneurons: a canonical microcircuit for inhibition?

    Science.gov (United States)

    Packer, Adam M; Yuste, Rafael

    2011-09-14

    GABAergic interneurons play a major role in the function of the mammalian neocortex, but their circuit connectivity is still poorly understood. We used two-photon RuBi-Glutamate uncaging to optically map how the largest population of cortical interneurons, the parvalbumin-positive cells (PV+), are connected to pyramidal cells (PCs) in mouse neocortex. We found locally dense connectivity from PV+ interneurons onto PCs across cortical areas and layers. In many experiments, all nearby PV+ cells were connected to every local PC sampled. In agreement with this, we found no evidence for connection specificity, as PV+ interneurons contacted PC pairs similarly regardless of whether they were synaptically connected or not. We conclude that the microcircuit architecture for PV+ interneurons, and probably neocortical inhibition in general, is an unspecific, densely homogenous matrix covering all nearby pyramidal cells.

  14. An Overview of the Mechanisms of Abnormal GABAergic Interneuronal Cortical Migration Associated with Prenatal Ethanol Exposure.

    Science.gov (United States)

    Shenoda, Botros B

    2017-02-03

    GABAergic Interneuronal migration constitutes an essential process during corticogenesis. Derived from progenitor cells located in the proliferative zones of the ventral telencephalon, newly generated GABAergic Interneuron migrate to their cortical destinations. Cortical dysfunction associated with defects in neuronal migration results in severe developmental consequences. There is growing evidence linking prenatal ethanol exposure to abnormal GABAergic interneuronal migration and subsequent cortical dysfunction. Investigating the pathophysiological mechanisms behind disrupted GABAergic interneuronal migration encountered with prenatal alcohol exposure is crucial for understanding and managing fetal alcohol spectrum disorders. This review explores the molecular pathways regulating GABAergic interneuronal cortical migration that might be altered by prenatal ethanol exposure thus opening new avenues for further research in this topic.

  15. Subpopulations of PKCγ interneurons within the medullary dorsal horn revealed by electrophysiologic and morphologic approach.

    Science.gov (United States)

    Alba-Delgado, Cristina; El Khoueiry, Corinne; Peirs, Cédric; Dallel, Radhouane; Artola, Alain; Antri, Myriam

    2015-09-01

    Mechanical allodynia, a cardinal symptom of persistent pain, is associated with the unmasking of usually blocked local circuits within the superficial spinal or medullary dorsal horn (MDH) through which low-threshold mechanical inputs can gain access to the lamina I nociceptive output neurons. Specific interneurons located within inner lamina II (IIi) and expressing the gamma isoform of protein kinase C (PKCγ⁺) have been shown to be key elements for such circuits. However, their morphologic and electrophysiologic features are still unknown. Using whole-cell patch-clamp recordings and immunohistochemical techniques in slices of adult rat MDH, we characterized such lamina IIi PKCγ⁺ interneurons and compared them with neighboring PKCγ⁻ interneurons. Our results reveal that PKCγ⁺ interneurons display very specific activity and response properties. Compared with PKCγ⁻ interneurons, they exhibit a smaller membrane input resistance and rheobase, leading to a lower threshold for action potentials. Consistently, more than half of PKCγ⁺ interneurons respond with tonic firing to step current. They also receive a weaker excitatory synaptic drive. Most PKCγ⁺ interneurons express Ih currents. The neurites of PKCγ⁺ interneurons arborize extensively within lamina IIi, can spread dorsally into lamina IIo, but never reach lamina I. In addition, at least 2 morphologically and functionally different subpopulations of PKCγ⁺ interneurons can be identified: central and radial PKCγ⁺ interneurons. The former exhibit a lower membrane input resistance, rheobase and, thus, action potential threshold, and less PKCγ⁺ immunoreactivity than the latter. These 2 subpopulations might thus differently contribute to the gating of dorsally directed circuits within the MDH underlying mechanical allodynia.

  16. Diversity and overlap of Parvalbumin and Somatostatin expressing interneurons in mouse presubiculum

    Directory of Open Access Journals (Sweden)

    Mérie eNassar

    2015-05-01

    Full Text Available The presubiculum, located between hippocampus and entorhinal cortex, plays a fundamental role in representing spatial information, notably head direction. Little is known about GABAergic interneurons of this region. Here, we used three transgenic mouse lines, Pvalb-Cre, Sst-Cre and X98, to examine distinct interneurons labeled with tdTomato or green fluorescent protein. The distribution of interneurons in presubicular lamina for each animal line was compared to that in the GAD67-GFP knock-in animal line. Labelling was specific in the Pvalb-Cre line with 87% of labeled interneurons immunopositive for (PV. Immunostaining for somatostatin (SOM revealed good specificity in the X98 line with 89% of fluorescent cells, but a lesser specificity in Sst-Cre animals where only 71% of labeled cells were immunopositive. A minority of ~ 6% of interneurons co-expressed PV and SOM in the presubiculum of Sst-Cre animals. The electrophysiological and morphological properties of fluorescent interneurons from Pvalb-Cre, Sst-Cre and X98 mice differed. Distinct physiological groups of presubicular interneurons were resolved by unsupervised cluster analysis of parameters describing passive properties, firing patterns and AP shapes. One group consisted of SOM-positive, Martinotti type neurons with a low firing threshold (cluster 1. Fast spiking basket cells, mainly from the Pvalb-Cre line, formed a distinct group (cluster 3. Another group (cluster 2 contained interneurons of intermediate electrical properties and basket-cell like morphologies. These labeled neurons were recorded from both Sst-Cre and Pvalb-Cre animals. Thus, our results reveal a wide variation in anatomical and physiological properties for these interneurons, a real overlap of interneurons immuno-positive for both PV and SOM as well as an off-target recombination in the Sst-Cre line, possibly linked to maternal cre inheritance.

  17. Diversity and overlap of parvalbumin and somatostatin expressing interneurons in mouse presubiculum.

    Science.gov (United States)

    Nassar, Mérie; Simonnet, Jean; Lofredi, Roxanne; Cohen, Ivan; Savary, Etienne; Yanagawa, Yuchio; Miles, Richard; Fricker, Desdemona

    2015-01-01

    The presubiculum, located between hippocampus and entorhinal cortex, plays a fundamental role in representing spatial information, notably head direction. Little is known about GABAergic interneurons of this region. Here, we used three transgenic mouse lines, Pvalb-Cre, Sst-Cre, and X98, to examine distinct interneurons labeled with tdTomato or green fluorescent protein. The distribution of interneurons in presubicular lamina for each animal line was compared to that in the GAD67-GFP knock-in animal line. Labeling was specific in the Pvalb-Cre line with 87% of labeled interneurons immunopositive for parvalbumin (PV). Immunostaining for somatostatin (SOM) revealed good specificity in the X98 line with 89% of fluorescent cells, but a lesser specificity in Sst-Cre animals where only 71% of labeled cells were immunopositive. A minority of ∼6% of interneurons co-expressed PV and SOM in the presubiculum of Sst-Cre animals. The electrophysiological and morphological properties of fluorescent interneurons from Pvalb-Cre, Sst-Cre, and X98 mice differed. Distinct physiological groups of presubicular interneurons were resolved by unsupervised cluster analysis of parameters describing passive properties, firing patterns and AP shapes. One group consisted of SOM-positive, Martinotti type neurons with a low firing threshold (cluster 1). Fast spiking basket cells, mainly from the Pvalb-Cre line, formed a distinct group (cluster 3). Another group (cluster 2) contained interneurons of intermediate electrical properties and basket-cell like morphologies. These labeled neurons were recorded from both Sst-Cre and Pvalb-Cre animals. Thus, our results reveal a wide variation in anatomical and physiological properties for these interneurons, a real overlap of interneurons immuno-positive for both PV and SOM as well as an off-target recombination in the Sst-Cre line, possibly linked to maternal cre inheritance.

  18. Persistent discharges in dentate gyrus perisoma-inhibiting interneurons require hyperpolarization-activated cyclic nucleotide-gated channel activation.

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    Elgueta, Claudio; Köhler, Johannes; Bartos, Marlene

    2015-03-11

    Parvalbumin (PV)-expressing perisoma-inhibiting interneurons (PIIs) of the dentate gyrus integrate rapidly correlated synaptic inputs and generate short-duration action potentials that propagate along the axon to their output synapses, supporting fast inhibitory signaling onto their target cells. Here we show that PV-PIIs in rat and mouse dentate gyrus (DG) integrate their intrinsic activity over time and can turn into a persistent firing mode characterized by the ability to generate long-lasting trains of action potentials at ∼50 Hz in the absence of additional inputs. Persistent firing emerges in the axons remote from the axon initial segment and markedly depends on hyperpolarization-activated cyclic nucleotide-gated channel (HCNC) activation. Persistent firing properties are modulated by intracellular Ca(2+) levels and somatic membrane potential. Detailed computational single-cell PIIs models reveal that HCNC-mediated conductances can contribute to persistent firing during conditions of a shift in their voltage activation curve to more depolarized potentials. Paired recordings from PIIs and their target granule cells show that persistent firing supports strong inhibitory output signaling. Thus, persistent firing may emerge during conditions of intense activation of the network, thereby providing silencing to the circuitry and the maintenance of sparse activity in the dentate gyrus. Copyright © 2015 the authors 0270-6474/15/354131-09$15.00/0.

  19. Selective pharmacological modulation of pyramidal neurons and interneurons in the CA1 region of the rat hippocampus

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    Marzia eMartina

    2013-03-01

    Full Text Available The hippocampus is a complex network tightly regulated by interactions between excitatory and inhibitory neurons. In neurodegenerative disorders where cognitive functions such as learning and memory are impaired this excitation-inhibition balance may be altered. Interestingly, the uncompetitive NMDAR antagonist memantine, currently in clinical use for the treatment of Alzheimer’s disease (AD, may alter the excitation-inhibition balance in the hippocampus. However, the specific mechanism by which memantine exerts this action is not clear. To better elucidate the effect of memantine on hippocampal circuitry, we studied its pharmacology on NMDAR currents in both pyramidal cells (PCs and interneurons (Ints in the CA1 region of the hippocampus. Applying whole-cell patch-clamp methodology to acute rat hippocampal slices, we report that memantine antagonism is more robust in PCs than in Ints. Using specific NMDAR subunit antagonists, we determined that this selective antagonism of memantine is attributable to specific differences in the molecular make up of the NMDARs in excitatory and inhibitory neurons. These findings offer new insight into the mechanism of action and therapeutic potential of NMDA receptor pharmacology in modulating hippocampal excitability.

  20. Cholinergic modulation of local pyramid-interneuron synapses exhibiting divergent short-term dynamics in rat sensory cortex.

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    Levy, Robert B; Reyes, Alex D; Aoki, Chiye

    2008-06-18

    Acetylcholine (ACh) influences attention, short-term memory, and sleep/waking transitions, through its modulatory influence on cortical neurons. It has been proposed that behavioral state changes mediated by ACh result from its selective effects on the intrinsic membrane properties of diverse cortical inhibitory interneuron classes. ACh has been widely shown to reduce the strength of excitatory (glutamatergic) synapses. But past studies using extracellular stimulation have not been able to examine the effects of ACh on local cortical connections important for shaping sensory processing. Here, using dual intracellular recording in slices of rat somatosensory cortex, we show that reduction of local excitatory input to inhibitory neurons by ACh is coupled to differences in the underlying short-term synaptic plasticity (STP). In synapses with short-term depression, where successive evoked excitatory postsynaptic potentials (EPSPs; >5 Hz) usually diminish in strength (short-term depression), cholinergic agonist (5-10 microM carbachol (CCh)) reduced the amplitude of the first EPSP in an evoked train, but CCh's net effect on subsequent EPSPs rapidly diminished. In synapses where successive EPSPs increased in strength (facilitation), the effect of CCh on later EPSPs in an evoked train became progressively greater. The effect of CCh on both depressing and facilitating synapses was blocked by the muscarinic antagonist, 1-5 microM atropine. It is suggested that selective influence on STP contributes fundamentally to cholinergic "switching" between cortical rhythms that underlie different behavioral states.

  1. Short promoters in viral vectors drive selective expression in mammalian inhibitory neurons, but do not restrict activity to specific inhibitory cell-types

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    Jason L Nathanson

    2009-11-01

    Full Text Available Short cell-type specific promoter sequences are important for targeted gene therapy and studies of brain circuitry. We report on the ability of short promoter sequences to drive fluorescent protein expression in specific types of mammalian cortical inhibitory neurons using adeno-associated virus (AAV and lentivirus (LV vectors. We tested many gene regulatory sequences derived from fugu (Takifugu rubripes, mouse, human, and synthetic composite regulatory elements. All fugu compact promoters expressed in mouse cortex, with only the somatostatin (SST and the neuropeptide Y (NPY promoters largely restricting expression to GABAergic neurons. However these promoters did not control expression in inhibitory cells in a subtype specific manner. We also tested mammalian promoter sequences derived from genes putatively coexpressed or coregulated within three major inhibitory interneuron classes (PV, SST, VIP. In contrast to the fugu promoters, many of the mammalian sequences failed to express, and only the promoter from gene A930038C07Rik conferred restricted expression, although as in the case of the fugu sequences, this too was not inhibitory neuron subtype specific. Lastly and more promisingly, a synthetic sequence consisting of a composite regulatory element assembled with PAX6 E1.1 binding sites, NRSE and a minimal CMV promoter showed markedly restricted expression to a small subset of mostly inhibitory neurons, but whose commonalities are unknown.

  2. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression.

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    Courtin, Julien; Chaudun, Fabrice; Rozeske, Robert R; Karalis, Nikolaos; Gonzalez-Campo, Cecilia; Wurtz, Hélène; Abdi, Azzedine; Baufreton, Jerome; Bienvenu, Thomas C M; Herry, Cyril

    2014-01-02

    Synchronization of spiking activity in neuronal networks is a fundamental process that enables the precise transmission of information to drive behavioural responses. In cortical areas, synchronization of principal-neuron spiking activity is an effective mechanism for information coding that is regulated by GABA (γ-aminobutyric acid)-ergic interneurons through the generation of neuronal oscillations. Although neuronal synchrony has been demonstrated to be crucial for sensory, motor and cognitive processing, it has not been investigated at the level of defined circuits involved in the control of emotional behaviour. Converging evidence indicates that fear behaviour is regulated by the dorsomedial prefrontal cortex (dmPFC). This control over fear behaviour relies on the activation of specific prefrontal projections to the basolateral complex of the amygdala (BLA), a structure that encodes associative fear memories. However, it remains to be established how the precise temporal control of fear behaviour is achieved at the level of prefrontal circuits. Here we use single-unit recordings and optogenetic manipulations in behaving mice to show that fear expression is causally related to the phasic inhibition of prefrontal parvalbumin interneurons (PVINs). Inhibition of PVIN activity disinhibits prefrontal projection neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. Our results identify two complementary neuronal mechanisms mediated by PVINs that precisely coordinate and enhance the neuronal activity of prefrontal projection neurons to drive fear expression.

  3. Alterations of interneurons of the gerbil hippocampus after transient cerebral ischemia: effect of pitavastatin.

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    Himeda, Toshiki; Hayakawa, Natsumi; Tounai, Hiroko; Sakuma, Mio; Kato, Hiroyuki; Araki, Tsutomu

    2005-11-01

    We investigated the immunohistochemical alterations of parvalbumin (PV)-expressing interneurons in the hippocampus after transient cerebral ischemia in gerbils in comparison with neuronal nitric oxide synthase (nNOS)-expressing interneurons. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the damage of neurons and interneurons in the hippocampus after cerebral ischemia. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons 5 and 14 days after ischemia. The PV immunoreactivity was unchanged up to 2 days after ischemia. At 5 and 14 days after ischemia, in contrast, a conspicuous reduction of PV immunoreactivity was observed in interneurons of the hippocampal CA1 sector. Furthermore, a significant decrease of PV immunoreactivity was found in interneurons of the hippocampal CA3 sector. No damage of nNOS-immunopositive interneurons was detected in the gerbil hippocampus up to 1 day after ischemia. Thereafter, a decrease of nNOS immunoreactive interneurons was found in the hippocampal CA1 sector up to 14 days after ischemia. Pitavastatin significantly prevented the neuronal cell loss in the hippocampal CA1 sector 5 days after ischemia. Our immunohistochemical study also showed that pitavastatin prevented significant decrease of PV- and nNOS-positive interneurons in the hippocampus after ischemia. Double-labeled immunostainings showed that PV immunoreactivity was not found in nNOS-immunopositive interneurons of the brain. The present study demonstrates that cerebral ischemia can cause a loss of both PV- and nNOS-immunoreactive interneurons in the hippocampal CA1 sector. Our findings also show that the damage to nNOS-immunopositive interneurons may precede the neuronal cell loss in the hippocampal CA1 sector after ischemia and nNOS-positive interneurons may play some role in the pathogenesis of cerebral ischemic diseases. Furthermore, our present study indicates that pitavastatin can

  4. ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation.

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    Chen, Yong-Jun; Zhang, Meng; Yin, Dong-Min; Wen, Lei; Ting, Annie; Wang, Pu; Lu, Yi-Sheng; Zhu, Xin-Hong; Li, Shu-Ji; Wu, Cui-Ying; Wang, Xue-Ming; Lai, Cary; Xiong, Wen-Cheng; Mei, Lin; Gao, Tian-Ming

    2010-12-14

    Neuregulin 1 (NRG1) is a trophic factor that acts by stimulating ErbB receptor tyrosine kinases and has been implicated in neural development and synaptic plasticity. In this study, we investigated mechanisms of its suppression of long-term potentiation (LTP) in the hippocampus. We found that NRG1 did not alter glutamatergic transmission at SC-CA1 synapses but increased the GABA(A) receptor-mediated synaptic currents in CA1 pyramidal cells via a presynaptic mechanism. Inhibition of GABA(A) receptors blocked the suppressing effect of NRG1 on LTP and prevented ecto-ErbB4 from enhancing LTP, implicating a role of GABAergic transmission. To test this hypothesis further, we generated parvalbumin (PV)-Cre;ErbB4(-/-) mice in which ErbB4, an NRG1 receptor in the brain, is ablated specifically in PV-positive interneurons. NRG1 was no longer able to increase inhibitory postsynaptic currents and to suppress LTP in PV-Cre;ErbB4(-/-) hippocampus. Accordingly, contextual fear conditioning, a hippocampus-dependent test, was impaired in PV-Cre;ErbB4(-/-) mice. In contrast, ablation of ErbB4 in pyramidal neurons had no effect on NRG1 regulation of hippocampal LTP or contextual fear conditioning. These results demonstrate a critical role of ErbB4 in PV-positive interneurons but not in pyramidal neurons in synaptic plasticity and support a working model that NRG1 suppresses LTP by enhancing GABA release. Considering that NRG1 and ErbB4 are susceptibility genes of schizophrenia, these observations contribute to a better understanding of how abnormal NRG1/ErbB4 signaling may be involved in the pathogenesis of schizophrenia.

  5. Activity-dependent induction of multitransmitter signaling onto pyramidal cells and interneurons of hippocampal area CA3.

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    Romo-Parra, Héctor; Vivar, Carmen; Maqueda, Jasmín; Morales, Miguel A; Gutiérrez, Rafael

    2003-06-01

    The granule cells of the dentate gyrus (DG) are considered to be glutamatergic, but they contain glutamic acid decarboxylase, gamma-amino butyric acid (GABA), and the vesicular GABA transporter mRNA. Their expression is regulated in an activity-dependent manner and coincides with the appearance of GABAergic transmission from the mossy fibers (MF) to pyramidal cells in area CA3. These data support the hypothesis that MF are able to release glutamate and GABA. Following the principle that a given neuron releases the same neurotransmitter(s) onto all its targets, we here demonstrate the emergence, after a generalized convulsive seizure, of MF GABAergic signaling sensitive to activation mGluR-III onto pyramidal cells and interneurons of CA3. Despite this, excitation overrides inhibition in interneurons, preventing disinhibition. Furthermore, on blockade of GABA and glutamate ionotropic receptors, an M1-cholinergic depolarizing signal is also revealed in both targets, which postsynaptically modulates the glutamatergic and GABAergic fast neurotransmission. The emergence of these nonglutamatergic signals depends on protein synthesis. In contrast to cholinergic responses evoked by associational/commissural fibers activation, cholinergic transmission evoked by DG stimulation is only observed after seizures and is strongly depressed by the activation of mGluR-II, whereas both are depressed by M2-AChR activation. With immunohistological experiments, we show that this cholinergic pathway runs parallel to the MF. Thus seizures compromise a delicate balance of excitation and inhibition, on which a complex interaction of different neurotransmitters emerges to counteract excitation at pre- and postsynaptic sites. Particularly, MF GABAergic inhibition emerges to exert an overall inhibitory action on CA3.

  6. Cerebellar cortex granular layer interneurons in the macaque monkey are functionally driven by mossy fiber pathways through net excitation or inhibition.

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    Jean Laurens

    Full Text Available The granular layer is the input layer of the cerebellar cortex. It receives information through mossy fibers, which contact local granular layer interneurons (GLIs and granular layer output neurons (granule cells. GLIs provide one of the first signal processing stages in the cerebellar cortex by exciting or inhibiting granule cells. Despite the importance of this early processing stage for later cerebellar computations, the responses of GLIs and the functional connections of mossy fibers with GLIs in awake animals are poorly understood. Here, we recorded GLIs and mossy fibers in the macaque ventral-paraflocculus (VPFL during oculomotor tasks, providing the first full inventory of GLI responses in the VPFL of awake primates. We found that while mossy fiber responses are characterized by a linear monotonic relationship between firing rate and eye position, GLIs show complex response profiles characterized by "eye position fields" and single or double directional tunings. For the majority of GLIs, prominent features of their responses can be explained by assuming that a single GLI receives inputs from mossy fibers with similar or opposite directional preferences, and that these mossy fiber inputs influence GLI discharge through net excitatory or inhibitory pathways. Importantly, GLIs receiving mossy fiber inputs through these putative excitatory and inhibitory pathways show different firing properties, suggesting that they indeed correspond to two distinct classes of interneurons. We propose a new interpretation of the information flow through the cerebellar cortex granular layer, in which mossy fiber input patterns drive the responses of GLIs not only through excitatory but also through net inhibitory pathways, and that excited and inhibited GLIs can be identified based on their responses and their intrinsic properties.

  7. Cortical plasticity induced by transplantation of embryonic somatostatin or parvalbumin interneurons.

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    Tang, Yunshuo; Stryker, Michael P; Alvarez-Buylla, Arturo; Espinosa, Juan Sebastian

    2014-12-23

    GABAergic inhibition has been shown to play an important role in the opening of critical periods of brain plasticity. We recently have shown that transplantation of GABAergic precursors from the embryonic medial ganglionic eminence (MGE), the source of neocortical parvalbumin- (PV(+)) and somatostatin-expressing (SST(+)) interneurons, can induce a new period of ocular dominance plasticity (ODP) after the endogenous period has closed. Among the diverse subtypes of GABAergic interneurons PV(+) cells have been thought to play the crucial role in ODP. Here we have used MGE transplantation carrying a conditional allele of diphtheria toxin alpha subunit and cell-specific expression of Cre recombinase to deplete PV(+) or SST(+) interneurons selectively and to investigate the contributions of each of these types of interneurons to ODP. As expected, robust plasticity was observed in transplants containing PV(+) cells but in which the majority of SST(+) interneurons were depleted. Surprisingly, transplants in which the majority of PV(+) cells were depleted induced plasticity as effectively as those containing PV(+) cells. In contrast, depleting both cell types blocked induction of plasticity. These findings reveal that PV(+) cells do not play an exclusive role in ODP; SST(+) interneurons also can drive cortical plasticity and contribute to the reshaping of neural networks. The ability of both PV(+) and SST(+) interneurons to induce de novo cortical plasticity could help develop new therapeutic approaches for brain repair.

  8. Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome.

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    Xu, Meiyu; Kobets, Andrew; Du, Jung-Chieh; Lennington, Jessica; Li, Lina; Banasr, Mounira; Duman, Ronald S; Vaccarino, Flora M; DiLeone, Ralph J; Pittenger, Christopher

    2015-01-20

    Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect ∼ 5% of the population. Available treatments are frequently inadequate, and the pathophysiology is poorly understood. Postmortem studies have revealed a reduction in specific striatal interneurons, including the large cholinergic interneurons, in severe disease. We tested the hypothesis that this deficit is sufficient to produce aspects of the phenomenology of TS, using a strategy for targeted, specific cell ablation in mice. We achieved ∼ 50% ablation of the cholinergic interneurons of the striatum, recapitulating the deficit observed in patients postmortem, without any effect on GABAergic markers or on parvalbumin-expressing fast-spiking interneurons. Interneuron ablation in the dorsolateral striatum (DLS), corresponding roughly to the human putamen, led to tic-like stereotypies after either acute stress or d-amphetamine challenge; ablation in the dorsomedial striatum, in contrast, did not. DLS interneuron ablation also led to a deficit in coordination on the rotorod, but not to any abnormalities in prepulse inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to produce some, but not all, of the characteristic symptoms of TS.

  9. GluN2B-containing NMDA receptors promote glutamate synapse development in hippocampal interneurons.

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    Kelsch, Wolfgang; Li, Zhijun; Wieland, Sebastian; Senkov, Oleg; Herb, Anne; Göngrich, Christina; Monyer, Hannah

    2014-11-26

    In postnatal development, GluN2B-containing NMDARs are critical for the functional maturation of glutamatergic synapses. GluN2B-containing NMDARs prevail until the second postnatal week when GluN2A subunits are progressively added, conferring mature properties to NMDARs. In cortical principal neurons, deletion of GluN2B results in an increase in functional AMPAR synapses, suggesting that GluN2B-containing NMDARs set a brake on glutamate synapse maturation. The function of GluN2B in the maturation of glutamatergic inputs to cortical interneurons is not known. To examine the function of GluN2B in interneurons, we generated mutant mice with conditional deletion of GluN2B in interneurons (GluN2B(ΔGAD67)). In GluN2B(ΔGAD67) mice interneurons distributed normally in cortical brain regions. After the second postnatal week, GluN2B(ΔGAD67) mice developed hippocampal seizures and died shortly thereafter. Before the onset of seizures, GluN2B-deficient hippocampal interneurons received fewer glutamatergic synaptic inputs than littermate controls, indicating that GluN2B-containing NMDARs positively regulate the maturation of glutamatergic input synapses in interneurons. These findings suggest that GluN2B-containing NMDARs keep the circuit activity under control by promoting the maturation of excitatory synapses in interneurons.

  10. Parvalbumin interneurons provide grid cell-driven recurrent inhibition in the medial entorhinal cortex.

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    Buetfering, Christina; Allen, Kevin; Monyer, Hannah

    2014-05-01

    Grid cells in the medial entorhinal cortex (MEC) generate metric spatial representations. Recent attractor-network models suggest an essential role for GABAergic interneurons in the emergence of the grid-cell firing pattern through recurrent inhibition dependent on grid-cell phase. To test this hypothesis, we studied identified parvalbumin-expressing (PV(+)) interneurons that are the most likely candidate for providing this recurrent inhibition onto grid cells. Using optogenetics and tetrode recordings in mice, we found that PV(+) interneurons exhibited high firing rates, low spatial sparsity and no spatial periodicity. PV(+) interneurons inhibited all functionally defined cell types in the MEC and were in turn recruited preferentially by grid cells. To our surprise, we found that individual PV(+) interneurons received input from grid cells with various phases, which most likely accounts for the broadly tuned spatial firing activity of PV(+) interneurons. Our data argue against the notion that PV(+) interneurons provide phase-dependent recurrent inhibition and challenge recent attractor-network models of grid cells.

  11. Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons

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    Avital eAdler

    2013-09-01

    Full Text Available The striatum is populated by a single projection neuron group, the medium spiny neurons (MSNs, and several groups of interneurons. Two of the electrophysiologically well-characterized striatal interneuron groups are the tonically active neurons (TANs, which are presumably cholinergic interneurons, and the fast spiking interneurons (FSIs, presumably parvalbumin (PV expressing GABAergic interneurons. To better understand striatal processing it is thus crucial to define the functional relationship between MSNs and these interneurons in the awake and behaving animal. We used multiple electrodes and standard physiological methods to simultaneously record MSN spiking activity and the activity of TANs or FSIs from monkeys engaged in a classical conditioning paradigm. All three cell populations were highly responsive to the behavioral task. However, they displayed different average response profiles and a different degree of response synchronization (signal correlation. TANs displayed the most transient and synchronized response, MSNs the most diverse and sustained response and FSIs were in between on both parameters. We did not find evidence for direct monosynaptic connectivity between the MSNs and either the TANs or the FSIs. However, while the cross correlation histograms of TAN to MSN pairs were flat, those of FSI to MSN displayed positive asymmetrical broad peaks. The FSI-MSN correlogram profile implies that the spikes of MSNs follow those of FSIs and both are driven by a common, most likely cortical, input. Thus, the two populations of striatal interneurons are probably driven by different afferents and play complementary functional roles in the physiology of the striatal microcircuit.

  12. Dlx5 and Dlx6 regulate the development of parvalbumin-expressing cortical interneurons.

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    Wang, Yanling; Dye, Catherine A; Sohal, Vikaas; Long, Jason E; Estrada, Rosanne C; Roztocil, Tomas; Lufkin, Thomas; Deisseroth, Karl; Baraban, Scott C; Rubenstein, John L R

    2010-04-14

    Dlx5 and Dlx6 homeobox genes are expressed in developing and mature cortical interneurons. Simultaneous deletion of Dlx5 and 6 results in exencephaly of the anterior brain; despite this defect, prenatal basal ganglia differentiation appeared largely intact, while tangential migration of Lhx6(+) and Mafb(+) interneurons to the cortex was reduced and disordered. The migration deficits were associated with reduced CXCR4 expression. Transplantation of mutant immature interneurons into a wild-type brain demonstrated that loss of either Dlx5 or Dlx5&6 preferentially reduced the number of mature parvalbumin(+) interneurons; those parvalbumin(+) interneurons that were present had increased dendritic branching. Dlx5/6(+/-) mice, which appear normal histologically, show spontaneous electrographic seizures and reduced power of gamma oscillations. Thus, Dlx5&6 appeared to be required for development and function of somal innervating (parvalbumin(+)) neocortical interneurons. This contrasts with Dlx1, whose function is required for dendrite innervating (calretinin(+), somatostatin(+), and neuropeptide Y(+)) interneurons (Cobos et al., 2005).

  13. Cell type-specific tuning of hippocampal interneuron firing during gamma oscillations in vivo.

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    Tukker, John J; Fuentealba, Pablo; Hartwich, Katja; Somogyi, Peter; Klausberger, Thomas

    2007-08-01

    Cortical gamma oscillations contribute to cognitive processing and are thought to be supported by perisomatic-innervating GABAergic interneurons. We performed extracellular recordings of identified interneurons in the hippocampal CA1 area of anesthetized rats, revealing that the firing patterns of five distinct interneuron types are differentially correlated to spontaneous gamma oscillations. The firing of bistratified cells, which target dendrites of pyramidal cells coaligned with the glutamatergic input from hippocampal area CA3, is strongly phase locked to field gamma oscillations. Parvalbumin-expressing basket, axo-axonic, and cholecystokinin-expressing interneurons exhibit moderate gamma modulation, whereas the spike timing of distal dendrite-innervating oriens-lacunosum moleculare interneurons is not correlated to field gamma oscillations. Cholecystokinin-expressing interneurons fire earliest in the gamma cycle, a finding that is consistent with their suggested function of thresholding individual pyramidal cells. Furthermore, we show that field gamma amplitude correlates with interneuronal spike-timing precision and firing rate. Overall, our recordings suggest that gamma synchronization in vivo is assisted by temporal- and domain-specific GABAergic inputs to pyramidal cells and is initiated in pyramidal cell dendrites in addition to somata and axon initial segments.

  14. The morphology and fine structure of the giant interneurons of the wood cricket Nemobius sylvestris.

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    Insausti, T C; Lazzari, C R; Casas, J

    2011-02-01

    The structural and ultrastructural characteristics of giant interneurons in the terminal abdominal ganglion of the cricket Nemobius sylvestris were investigated by means of cobalt and fluorescent dye backfilling and transmission electron microscopy. The projections of the 8 eight pairs of the biggest ascending interneurons (giant interneurons) are described in detail. The somata of all interneurons analyzed are located contralateral to their axons, which project to the posterior region of the terminal ganglion and arborise in the cercal glomerulus. Neuron 7-1a is an exception, because its arborisation is restricted to the anterior region of the ganglion. The fine structure of giant interneurons shows typical features of highly active cells. We observed striking indentations in the perineural layer, enabling the somata of the giant interneurons to be very close to the haemolymph. The cercal glomerulus exhibits a high diversity of synaptic contacts (i.e. axo-dendritic, axo-axonic, dendro-axonic, and dendro-dendritic), as well as areas of tight junctions. Electrical synapses seem to be present, as well as mixed synapses. The anatomical organization of the giant interneurons is finally discussed in terms of functional implications and on a comparative basis.

  15. DREADD in parvalbumin interneurons of the dentate gyrus modulates anxiety, social interaction and memory extinction.

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    Zou, D; Chen, L; Deng, D; Jiang, D; Dong, F; McSweeney, C; Zhou, Y; Liu, L; Chen, G; Wu, Y; Mao, Y

    2016-01-01

    Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PVpositive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3DGq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

  16. DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction

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    Zou, D.; Chen, L.; Deng, D.; Jiang, D.; Dong, F.; McSweeney, C.; Zhou, Y.; Liu, L.; Chen, G.; Wu, Y.; Mao, Y.

    2016-01-01

    Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PV-positive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3D-Gq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus. PMID:26733123

  17. Electrophysiological heterogeneity of fast-spiking interneurons: chandelier versus basket cells.

    Directory of Open Access Journals (Sweden)

    Nadezhda V Povysheva

    Full Text Available In the prefrontal cortex, parvalbumin-positive inhibitory neurons play a prominent role in the neural circuitry that subserves working memory, and alterations in these neurons contribute to the pathophysiology of schizophrenia. Two morphologically distinct classes of parvalbumin neurons that target the perisomatic region of pyramidal neurons, chandelier cells (ChCs and basket cells (BCs, are generally thought to have the same "fast-spiking" phenotype, which is characterized by a short action potential and high frequency firing without adaptation. However, findings from studies in different species suggest that certain electrophysiological membrane properties might differ between these two cell classes. In this study, we assessed the physiological heterogeneity of fast-spiking interneurons as a function of two factors: species (macaque monkey vs. rat and morphology (chandelier vs. basket. We showed previously that electrophysiological membrane properties of BCs differ between these two species. Here, for the first time, we report differences in ChCs membrane properties between monkey and rat. We also found that a number of membrane properties differentiate ChCs from BCs. Some of these differences were species-independent (e.g., fast and medium afterhyperpolarization, firing frequency, and depolarizing sag, whereas the differences in the first spike latency between ChCs and BCs were species-specific. Our findings indicate that different combinations of electrophysiological membrane properties distinguish ChCs from BCs in rodents and primates. Such electrophysiological differences between ChCs and BCs likely contribute to their distinctive roles in cortical circuitry in each species.

  18. Cholinergic Interneurons Underlie Spontaneous Dopamine Release in Nucleus Accumbens.

    Science.gov (United States)

    Yorgason, Jordan T; Zeppenfeld, Douglas M; Williams, John T

    2017-02-22

    The release of dopamine from terminals in the NAc is regulated by a number of factors, including voltage-gated ion channels, D2-autoreceptors, and nAChRs. Cholinergic interneurons (CINs) drive dopamine release through activation of nAChRs on dopamine terminals. Using cyclic voltammetry in mouse brain slices, nAChR-dependent spontaneous dopamine transients and the mechanisms underlying the origin were examined in the NAc. Spontaneous events were infrequent (0.3 per minute), but the rate and amplitude were increased after blocking Kv channels with 4-aminopyridine. Although the firing frequency of CINs was increased by blocking glutamate reuptake with TBOA and the Sk blocker apamin, only 4-aminopyridine increased the frequency of dopamine transients. In contrast, inhibition of CIN firing with the μ/δ selective opioid [Met(5)]enkephalin (1 μm) decreased spontaneous dopamine transients. Cocaine increased the rate and amplitude of dopamine transients, suggesting that the activity of the dopamine transporter limits the detection of these events. In the presence of cocaine, the rate of spontaneous dopamine transients was further increased after blocking D2-autoreceptors. Blockade of muscarinic receptors had no effect on evoked dopamine release, suggesting that feedback inhibition of acetylcholine release was not involved. Thus, although spontaneous dopamine transients are reliant on nAChRs, the frequency was not strictly governed by the activity of CINs. The increase in frequency of spontaneous dopamine transients induced by cocaine was not due to an increase in cholinergic tone and is likely a product of an increase in detection resulting from decreased dopamine reuptake.SIGNIFICANCE STATEMENT The actions of dopamine in the NAc are thought to be responsible for endogenous reward and the reinforcing properties of drugs of abuse, such as psychostimulants. The present work examines the mechanisms underlying nAChR-induced spontaneous dopamine release. This study

  19. Persistent sodium current contributes to induced voltage oscillations in locomotor-related hb9 interneurons in the mouse spinal cord.

    Science.gov (United States)

    Ziskind-Conhaim, Lea; Wu, Linying; Wiesner, Eric P

    2008-10-01

    Neurochemically induced membrane voltage oscillations and firing episodes in spinal excitatory interneurons expressing the HB9 protein (Hb9 INs) are synchronous with locomotor-like rhythmic motor outputs, suggesting that they contribute to the excitatory drive of motoneurons during locomotion. Similar to central pattern generator neurons in other systems, Hb9 INs are interconnected via electrical coupling, and their rhythmic activity does not depend on fast glutamatergic synaptic transmission. The primary objective of this study was to determine the contribution of fast excitatory and inhibitory synaptic transmission and subthreshold voltage-dependent currents to the induced membrane oscillations in Hb9 INs in the postnatal mouse spinal cord. The non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced the amplitude of voltage oscillations but did not alter their frequency. CNQX suppressed rhythmic motor activity. Blocking glycine and GABAA receptor-mediated inhibitory synapses as well as cholinergic transmission did not change the properties of CNQX-resistant membrane oscillations. However, disinhibition triggered new episodes of slow motor bursting that were not correlated with induced locomotor-like rhythms in Hb9 INs. Our observations indicated that fast excitatory and inhibitory synaptic inputs did not control the frequency of induced rhythmic activity in Hb9 INs. We next examined the contribution of persistent sodium current (INaP) to subthreshold membrane oscillations in the absence of primary glutamatergic, GABAergic and glycinergic synaptic drive to Hb9 INs. Low concentrations of riluzole that blocked the slow-inactivating component of sodium current gradually suppressed the amplitude and reduced the frequency of voltage oscillations. Our finding that INaP regulates locomotor-related rhythmic activity in Hb9 INs independently of primary synaptic transmission supports the concept that these neurons constitute an

  20. Differential expression of parvalbumin interneurons in neonatal phencyclidine treated rats and socially isolated rats

    DEFF Research Database (Denmark)

    Kaalund, Sanne Simone; Riise, Jesper; Broberg, Brian

    2013-01-01

    of parvalbumin-positive interneurons (PV(+) interneurons). In this study we examined PV(+) expression in two rat models of cognitive dysfunction in schizophrenia, the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. Using a stereological method, the optical...... cells (p = 0.024) in the mPFC of neonatal phencyclidine rats. We observed no alterations in the total number of neurons, hippocampal PV(+) interneurons, parvalbumin mRNA expression or volume of the mPFC or HPC in the two models. Thus, as the total number of neurons remains unchanged following...

  1. Interneurones in pathways from group II muscle afferents in sacral segments of the feline spinal cord.

    Science.gov (United States)

    Jankowska, E; Riddell, J S

    1994-03-15

    1. Properties of dorsal horn interneurones that process information from group II muscle afferents in the sacral segments of the spinal cord have been investigated in the cat using both intracellular and extracellular recording. 2. The interneurones were excited by group II muscle afferents and cutaneous afferents but not by group I muscle afferents. They were most effectively excited by group II afferents of the posterior biceps, semitendinosus, triceps surae and quadriceps muscle nerves and by cutaneous afferents running in the cutaneous femoris, pudendal and sural nerves. The earliest synaptic actions were evoked monosynaptically and were very tightly locked to the stimuli. 3. EPSPs evoked monosynaptically by group II muscle afferents and cutaneous afferents of the most effective nerves were often cut short by disynaptic IPSPs. As a consequence of this negative feedback the EPSPs gave rise to single or double spike potentials and only a minority of interneurones responded with repetitive discharges. However, the neurones that did respond repetitively did so at a very high frequency of discharges (0.8-1.2 ms intervals between the first 2-3 spikes). 4. Sacral dorsal horn group II interneurones do not appear to act directly upon motoneurones because: (i) these interneurones are located outside the area within which last order interneurones have previously been found and (ii) the latencies of PSPs evoked in motoneurones by stimulation of the posterior biceps and semitendinosus, cutaneous femoris and pudendal nerves (i.e. the main nerves providing input to sacral interneurones) are compatible with a tri- but not with a disynaptic coupling. Spatial facilitation of EPSPs and IPSPs following synchronous stimulation of group II and cutaneous afferents of these nerves shows, however, that sacral interneurones may induce excitation or inhibition of motoneurones via other interneurones. 5. Comparison of the properties of group II interneurones in the sacral segments with

  2. Development and physiology of GABAergic feedback excitation in parvalbumin expressing interneurons of the mouse basolateral amygdala

    OpenAIRE

    Spampanato, Jay; Sullivan, Robert K. P.; Perumal, Madhusoothanan B.; Sah, Pankaj

    2016-01-01

    Abstract We have previously shown that in the basolateral amygdala (BLA), action potentials in one type of parvalbumin (PV)‐expressing GABAergic interneuron can evoke a disynaptic feedback excitatory postsynaptic potential (fbEPSP) onto the same presynaptic interneuron. Here, using whole‐cell recordings from PV‐expressing interneurons in acute brain slices we expand on this finding to show that this response is first detectable at 2‐week postnatal, and is most prevalent in animals beyond 3 we...

  3. Long-term effects of brain-derived neurotrophic factor on the frequency of inhibitory synaptic events in the rat superficial dorsal horn.

    Science.gov (United States)

    Lu, V B; Colmers, W F; Smith, P A

    2009-07-21

    Chronic constriction injury (CCI) of rat sciatic nerve produces a specific pattern of electrophysiological changes in the superficial dorsal horn that lead to central sensitization that is associated with neuropathic pain. These changes can be recapitulated in spinal cord organotypic cultures by long term (5-6 days) exposure to brain-derived neurotrophic factor (BDNF) (200 ng/ml). Certain lines of evidence suggest that both CCI and BDNF increase excitatory synaptic drive to putative excitatory neurons while reducing that to putative inhibitory interneurons. Because BDNF slows the rate of discharge of synaptically-driven action potentials in inhibitory neurons, it should also decrease the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) throughout the superficial dorsal horn. To test this possibility, we characterized superficial dorsal horn neurons in organotypic cultures according to five electrophysiological phenotypes that included tonic, delay and irregular firing neurons. Five to 6 days of treatment with 200 ng/ml BDNF decreased sIPSC frequency in tonic and irregular neurons as might be expected if BDNF selectively decreases excitatory synaptic drive to inhibitory interneurons. The frequency of sIPSCs in delay neurons was however increased. Further analysis of the action of BDNF on tetrodotoxin-resistant miniature inhibitory postsynaptic currents (mIPSC) showed that the frequency was increased in delay neurons, unchanged in tonic neurons and decreased in irregular neurons. BDNF may thus reduce action potential frequency in those inhibitory interneurons that project to tonic and irregular neurons but not in those that project to delay neurons.

  4. Changes in excitatory and inhibitory circuits of the rat hippocampus 12-14 months after complete forebrain ischemia.

    Science.gov (United States)

    Arabadzisz, D; Freund, T F

    1999-01-01

    Changes in interneuron distribution and excitatory connectivity have been investigated in animals which had survived 12-14 months after complete forebrain ischemia, induced by four-vessel occlusion. Anterograde tracing with Phaseolus vulgaris leucoagglutinin revealed massive Schaffer collateral input even to those regions of the CA1 subfield where hardly any surviving pyramidal cells were found. Boutons of these Schaffer collaterals formed conventional synaptic contacts on dendritic spines and shafts, many of which likely belong to interneurons. Mossy fibres survived the ischemic challenge, however, large mossy terminals showed altered morphology, namely, the number of filopodiae on these terminals decreased significantly. The entorhinal input to the hippocampus did not show any morphological alterations. The distribution of interneurons was investigated by neurochemical markers known to label functionally distinct GABAergic cell populations. In the hilus, spiny interneurons showed a profound decrease in number. This phenomenon was not as obvious in CA3, but the spiny metabotropic glutamate receptor 1alpha-positive non-pyramidal cells, some of which contain calretinin or substance P receptor, disappeared from stratum lucidum of this area. In the CA1 region, somatostatin immunoreactivity disappeared from stratum oriens/lacunosum-moleculare-associated cells, while in metabotropic glutamate receptor 1alpha-stained sections these cells seemed unaffected in number. Other interneurons did not show an obvious decrease in number. In stratum radiatum of the CA1 subfield, some interneuron types had altered morphology: the substance P receptor-positive dendrites lost their characteristic radial orientation, and the metabotropic glutamate receptor 1alpha-expressing cells became extremely spiny. The loss of inhibitory interneurons at the first two stages of the trisynaptic loop coupled with a well-preserved excitatory connectivity among the subfields suggests that

  5. Selective gene expression by postnatal electroporation during olfactory interneuron neurogenesis.

    Directory of Open Access Journals (Sweden)

    Alexander T Chesler

    Full Text Available Neurogenesis persists in the olfactory system throughout life. The mechanisms of how new neurons are generated, how they integrate into circuits, and their role in coding remain mysteries. Here we report a technique that will greatly facilitate research into these questions. We found that electroporation can be used to robustly and selectively label progenitors in the Subventicular Zone. The approach was performed postnatally, without surgery, and with near 100% success rates. Labeling was found in all classes of interneurons in the olfactory bulb, persisted to adulthood and had no adverse effects. The broad utility of electroporation was demonstrated by encoding a calcium sensor and markers of intracellular organelles. The approach was found to be effective in wildtype and transgenic mice as well as rats. Given its versatility, robustness, and both time and cost effectiveness, this method offers a powerful new way to use genetic manipulation to understand adult neurogenesis.

  6. Carrier-dependent temporal processing in an auditory interneuron.

    Science.gov (United States)

    Sabourin, Patrick; Gottlieb, Heather; Pollack, Gerald S

    2008-05-01

    Signal processing in the auditory interneuron Omega Neuron 1 (ON1) of the cricket Teleogryllus oceanicus was compared at high- and low-carrier frequencies in three different experimental paradigms. First, integration time, which corresponds to the time it takes for a neuron to reach threshold when stimulated at the minimum effective intensity, was found to be significantly shorter at high-carrier frequency than at low-carrier frequency. Second, phase locking to sinusoidally amplitude modulated signals was more efficient at high frequency, especially at high modulation rates and low modulation depths. Finally, we examined the efficiency with which ON1 detects gaps in a constant tone. As reflected by the decrease in firing rate in the vicinity of the gap, ON1 is better at detecting gaps at low-carrier frequency. Following a gap, firing rate increases beyond the pre-gap level. This "rebound" phenomenon is similar for low- and high-carrier frequencies.

  7. Loss of embryonic MET signaling alters profiles of hippocampal interneurons.

    Science.gov (United States)

    Martins, Gabriela J; Plachez, Céline; Powell, Elizabeth M

    2007-01-01

    Hippocampal interneurons arise in the ventral forebrain and migrate dorsally in response to cues, including hepatocyte growth factor/scatter factor which signals via its receptor MET. Examination of the hippocampus in adult mice in which MET had been inactivated in the embryonic proliferative zones showed an increase in parvalbumin-expressing cells in the dentate gyrus, but a loss of these cells in the CA3 region. An overall loss of calretinin-expressing cells was seen throughout the hippocampus. A similar CA3 deficit of parvalbumin and calretinin cells was observed when MET was eliminated only in postmitotic cells. These data suggest that MET is required for the proper hippocampal development, and embryonic perturbations lead to long-term anatomical defects with possible learning and memory dysfunction.

  8. Singing modulates parvalbumin interneurons throughout songbird forebrain vocal control circuitry

    Science.gov (United States)

    Zengin-Toktas, Yildiz

    2017-01-01

    Across species, the performance of vocal signals can be modulated by the social environment. Zebra finches, for example, adjust their song performance when singing to females (‘female-directed’ or FD song) compared to when singing in isolation (‘undirected’ or UD song). These changes are salient, as females prefer the FD song over the UD song. Despite the importance of these performance changes, the neural mechanisms underlying this social modulation remain poorly understood. Previous work in finches has established that expression of the immediate early gene EGR1 is increased during singing and modulated by social context within the vocal control circuitry. Here, we examined whether particular neural subpopulations within those vocal control regions exhibit similar modulations of EGR1 expression. We compared EGR1 expression in neurons expressing parvalbumin (PV), a calcium buffer that modulates network plasticity and homeostasis, among males that performed FD song, males that produced UD song, or males that did not sing. We found that, overall, singing but not social context significantly affected EGR1 expression in PV neurons throughout the vocal control nuclei. We observed differences in EGR1 expression between two classes of PV interneurons in the basal ganglia nucleus Area X. Additionally, we found that singing altered the amount of PV expression in neurons in HVC and Area X and that distinct PV interneuron types in Area X exhibited different patterns of modulation by singing. These data indicate that throughout the vocal control circuitry the singing-related regulation of EGR1 expression in PV neurons may be less influenced by social context than in other neuron types and raise the possibility of cell-type specific differences in plasticity and calcium buffering. PMID:28235074

  9. Passive electrotonic properties of rat hippocampal CA3 interneurones.

    Science.gov (United States)

    Chitwood, R A; Hubbard, A; Jaffe, D B

    1999-03-15

    1. The linear membrane responses of CA3 interneurones were determined with the use of whole-cell patch recording methods. The mean input resistance (RN) for all cells in this study was 526 +/- 16 MOmega and the slowest membrane time constant (tau0) was 73 +/- 3 ms. 2. The three-dimensional morphology of 63 biocytin-labelled neurones was used to construct compartmental models. Specific membrane resistivity (Rm) and specific membrane capacitance (Cm) were estimated by fitting the linear membrane response. Acceptable fits were obtained for 24 CA3 interneurones. The mean Rm was 61.9 +/- 34.2 Omega cm2 and the mean Cm was 0.9 +/- 0.3 microF cm-2. Intracellular resistance (Ri) could not be resolved in this study. 3. Examination of voltage attenuation revealed a significantly low synaptic efficiency from most dendritic synaptic input locations to the soma. 4. Simulations of excitatory postsynaptic potentials (EPSPs) were analysed at both the site of synaptic input and at the soma. There was little variability in the depolarization at the soma from synaptic inputs placed at different locations along the dendritic tree. The EPSP amplitude at the site of synaptic input was progressively larger with distance from the soma, consistent with a progressive increase in input impedance. 5. The 'iso-efficiency' of spatially different synaptic inputs arose from two opposing factors: an increase in EPSP amplitude at the synapse with distance from the soma was opposed by a nearly equivalent increase in voltage attenuation. These simulations suggest that, in these particular neurones, the amplitude of EPSPs measured at the soma will not be significantly affected by the location of synaptic inputs.

  10. Early life stress disrupts social behavior and prefrontal cortex parvalbumin interneurons at an earlier time-point in females than in males.

    Science.gov (United States)

    Holland, Freedom H; Ganguly, Prabarna; Potter, David N; Chartoff, Elena H; Brenhouse, Heather C

    2014-04-30

    Early life stress exposure (ELS) yields risk for psychiatric disorders that might occur though a population-specific mechanism that impacts prefrontal cortical development. Sex differences in ELS effects are largely unknown and are also essential to understand social and cognitive development. ELS can cause dysfunction within parvalbumin (PVB)-containing inhibitory interneurons in the prefrontal cortex and in several prefrontal cortex-mediated behaviors including social interaction. Social behavior deficits are often the earliest observed changes in psychiatric disorders, therefore the time-course and causation of social interaction deficits after ELS are important to determine. PVB interneuron dysfunction can disrupt social behavior, and has been correlated in males with elevated markers of oxidative stress and inflammation, such as cyclooxygenase-2 after ELS. Here, we measured the effects of maternal separation ELS on social interaction behaviors in males and females. Prefrontal cortex PVB and cyclooxygenase-2 were also measured in juveniles and adolescents using Western blots. ELS led to social interaction alterations earlier in females than males. Sexually dimorphic behavioral changes were consistent with prefrontal cortex PVB loss after ELS. PVB levels were decreased in ELS-exposed juvenile females, while males exposed to ELS do not display parvalbumin decreases until adolescence. Early behavioral and PVB changes in females did not appear to be mediated through cyclooxygenase-2, since levels were not affected in ELS females. Therefore, these data suggest that ELS affects males and females differently and with distinct developmental profiles.

  11. Major amyloid-β-degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex.

    Science.gov (United States)

    Pacheco-Quinto, Javier; Eckman, Christopher B; Eckman, Elizabeth A

    2016-12-01

    Impaired clearance of amyloid-β peptide (Aβ) has been postulated to significantly contribute to the amyloid accumulation typical of Alzheimer's disease. Among the enzymes known to degrade Aβ in vivo are endothelin-converting enzyme (ECE)-1, ECE-2, and neprilysin (NEP), and evidence suggests that they regulate independent pools of Aβ that may be functionally significant. To better understand the differential regulation of Aβ concentration by its physiological degrading enzymes, we characterized the cell and region-specific expression pattern of ECE-1, ECE-2, and NEP by in situ hybridization and immunohistochemistry in brain areas relevant to Alzheimer's disease. In contrast to the broader distribution of ECE-1, ECE-2 and NEP were found enriched in GABAergic neurons. ECE-2 was majorly expressed by somatostatin-expressing interneurons and was active in isolated synaptosomes. NEP messenger RNA was found mainly in parvalbumin-expressing interneurons, with NEP protein localized to perisomatic parvalbuminergic synapses. The identification of somatostatinergic and parvalbuminergic synapses as hubs for Aβ degradation is consistent with the possibility that Aβ may have a physiological function related to the regulation of inhibitory signaling.

  12. Topochemistry of Internuclear and Intranuclear Interneurons of the Vasomotor Area in the Medulla Oblongata of Hypertensive Rats.

    Science.gov (United States)

    Chertok, V M; Kotsyuba, A E; Startseva, M S

    2016-01-01

    Immunohistochemical examination with the antiserum against neuronal NO synthase and cystathionine β-synthase was used to study the following two pools of interneurons in Wistar rats at various periods after the development of renovascular hypertension: intranuclear interneurons (lying in the projection of the solitary nucleus, reticular gigantocellular nucleus, and parvocellular nucleus) and 2 groups of internuclear interneurons (small interneurons, area 50-300 μ(2); and large interneurons, area above 350 μ(2)). Intranuclear and internuclear interneurons probably play a role in the central mechanisms of hemodynamics regulation. These interneurons differ by not only in topochemical parameters, but also functional properties (different resistances to BP changes). Intranuclear interneurons are characterized by high sensitivity of the gas transmitter systems to a continuous increase in BP, which results in remodeling and dysfunction of the bulbar part of the cardiovascular center. Large internuclear interneurons demonstrate a strong reaction to BP rise, which confirms their involvement into hemodynamics regulation. By contrast, small internuclear interneurons retain their characteristics in arterial hypertension and probably perform an integrative function.

  13. The transcription factor Sp8 is required for the production of parvalbumin-expressing interneurons in the olfactory bulb.

    Science.gov (United States)

    Li, Xiaosu; Sun, Chifei; Lin, Chao; Ma, Tong; Madhavan, Mayur C; Campbell, Kenneth; Yang, Zhengang

    2011-06-08

    Interneurons in the olfactory bulb (OB) represent a heterogeneous population, which are first produced at embryonic stages and persisting into adulthood. Using the BrdU birthdating method combined with immunostaining for several different neuronal markers, we provide the integrated temporal patterns of distinct mouse OB interneuron production from embryonic day 14 to postnatal day 365. We show that although the majority of OB interneuron subtypes continue to be generated throughout life, most subtypes show a similar "bell-like" temporal production pattern with a peak around birth. Tyrosine hydroxylase and calretinin-expressing interneurons are produced at a relatively low rate in the adult OB, while parvalbumin-expressing (PV+) interneuron production is confined to later embryonic and early postnatal stages. We also show that Dlx5/6-expressing progenitors contribute to PV+ interneurons in the OB. Interestingly, all PV+ interneurons in the external plexiform layer (EPL) express the transcription factor Sp8. Genetic ablation of Sp8 by cre/loxP-based recombination severely reduces the number of PV+ interneurons in the EPL of the OB. Our results suggest that Sp8 is required for the normal production of PV+ interneurons in the EPL of the OB. These data expand our understanding of the temporal and molecular regulation of OB interneuron neurogenesis.

  14. Interneurons are the source and the targets of the first synapses formed in the rat developing hippocampal circuit.

    Science.gov (United States)

    Gozlan, Henri; Ben-Ari, Yehezkel

    2003-06-01

    In hippocampal CA1 pyramidal neurons, GABAergic synapses are established before glutamatergic synapses. GABAergic interneurons should therefore develop and acquire synapses at an earlier stage to provide the source for GABAergic synapses. We now report that this is indeed the case. At birth and in utero, when nearly all pyramidal neurons are not yet functional, most interneurons have already either GABAergic only or GABAergic and glutamatergic postsynaptic currents. At birth, the morphological maturation of interneurons parallels their individual functional responses. In addition, the formation of functional interneurons types appears to be a sequential process. Interneurons that innervate other interneurons acquire GABA(A) synapses before peridendritic interneurons, but also before perisomatic interneurons that are not yet functional at birth. Therefore, interneurons are the source and the targets of the first synapses formed in the developing circuit. Since GABA was shown to be excitatory in utero, interneurons provide all the excitatory drive at a time when the principal cells are silent. They could therefore play a central role in the formation of the cortical circuit at early developmental stages.

  15. Myelination of parvalbumin interneurons: a parsimonious locus of pathophysiological convergence in schizophrenia

    NARCIS (Netherlands)

    Stedehouder, J.; S.A. Kushner (Steven)

    2017-01-01

    textabstractSchizophrenia is a debilitating psychiatric disorder characterized by positive, negative and cognitive symptoms. Despite more than a century of research, the neurobiological mechanism underlying schizophrenia remains elusive. White matter abnormalities and interneuron dysfunction are the

  16. Time Windows of Interneuron Development: Implications to Our Understanding of the Aetiology and Treatment of Schizophrenia

    Directory of Open Access Journals (Sweden)

    Zarina Greenberg

    2015-11-01

    Full Text Available Schizophrenia is a devastating neuropsychiatric disorder widely believed to arise from defects during brain development. Indeed, dysfunction in the formation and function of GABAergic cortical interneurons has been implicated as a central pathogenic mechanism in this, and other, neurodevelopmental disorders. Understanding the coordination and timing of interneuron development including the complex processes of specification, proliferation, migration and their incorporation into finely tuned cortical networks is therefore essential in determining their role in neurodevelopmental disease. Studies using mouse models have highlighted the functional relevance of transcription factor networks and common signalling pathways in interneuron development but have faced challenges in identifying clear time windows where these factors are essential. Here we discuss recent developments highlighting critical time frames in the specification and migration of cortical interneurons and the impact of aberrant development to aetiology and treatments of schizophrenia.

  17. Whole-brain mapping of inputs to projection neurons and cholinergic interneurons in the dorsal striatum.

    Science.gov (United States)

    Guo, Qingchun; Wang, Daqing; He, Xiaobin; Feng, Qiru; Lin, Rui; Xu, Fuqiang; Fu, Ling; Luo, Minmin

    2015-01-01

    The dorsal striatum integrates inputs from multiple brain areas to coordinate voluntary movements, associative plasticity, and reinforcement learning. Its projection neurons consist of the GABAergic medium spiny neurons (MSNs) that express dopamine receptor type 1 (D1) or dopamine receptor type 2 (D2). Cholinergic interneurons account for a small portion of striatal neuron populations, but they play important roles in striatal functions by synapsing onto the MSNs and other local interneurons. By combining the modified rabies virus with specific Cre- mouse lines, a recent study mapped the monosynaptic input patterns to MSNs. Because only a small number of extrastriatal neurons were labeled in the prior study, it is important to reexamine the input patterns of MSNs with higher labeling efficiency. Additionally, the whole-brain innervation pattern of cholinergic interneurons remains unknown. Using the rabies virus-based transsynaptic tracing method in this study, we comprehensively charted the brain areas that provide direct inputs to D1-MSNs, D2-MSNs, and cholinergic interneurons in the dorsal striatum. We found that both types of projection neurons and the cholinergic interneurons receive extensive inputs from discrete brain areas in the cortex, thalamus, amygdala, and other subcortical areas, several of which were not reported in the previous study. The MSNs and cholinergic interneurons share largely common inputs from areas outside the striatum. However, innervations within the dorsal striatum represent a significantly larger proportion of total inputs for cholinergic interneurons than for the MSNs. The comprehensive maps of direct inputs to striatal MSNs and cholinergic interneurons shall assist future functional dissection of the striatal circuits.

  18. INVOLVEMENT OF PRE- AND POSTSYNAPTIC NMDA RECEPTORS AT LOCAL CIRCUIT INTERNEURON CONNECTIONS IN RAT NEOCORTEX

    OpenAIRE

    De-May, C.L.; Ali, A.B.

    2013-01-01

    To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings – combined with biocytin labelling – were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II–V of rat (postnatal days 17–22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appe...

  19. Interneurons Differentially Contribute to Spontaneous Network Activity in the Developing Hippocampus Dependent on Their Embryonic Lineage

    OpenAIRE

    Wester, Jason C.; McBain, Chris J.

    2016-01-01

    Spontaneously generated network activity is a hallmark of developing neural circuits, and plays an important role in the formation of synaptic connections. In the rodent hippocampus, this activity is observed in vitro as giant depolarizing potentials (GDPs) during the first postnatal week. Interneurons importantly contribute to GDPs, due to the depolarizing actions of GABA early in development. While they are highly diverse, cortical interneurons can be segregated into two distinct groups bas...

  20. Involvement of pre- and postsynaptic NMDA receptors at local circuit interneuron connections in rat neocortex

    OpenAIRE

    De-May, C.L.; Ali, A. B.

    2013-01-01

    To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings – combined with biocytin labelling – were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II–V of rat (postnatal days 17–22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appe...

  1. Terminal Field and Firing Selectivity of Cholecystokinin-Expressing Interneurons in the Hippocampal CA3 Area

    OpenAIRE

    Lasztóczi, Bálint; Tukker, John J.; Somogyi, Peter; Klausberger, Thomas

    2011-01-01

    Hippocampal oscillations reflect coordinated neuronal activity on many timescales. Distinct types of GABAergic interneuron participate in the coordination of pyramidal cells over different oscillatory cycle phases. In the CA3 area, which generates sharp waves and gamma oscillations, the contribution of identified GABAergic neurons remains to be defined. We have examined the firing of a family of cholecystokinin-expressing interneurons during network oscillations in urethane-anesthetized rats ...

  2. Interneurons and oligodendrocyte progenitors form a structured synaptic network in the developing neocortex.

    Science.gov (United States)

    Orduz, David; Maldonado, Paloma P; Balia, Maddalena; Vélez-Fort, Mateo; de Sars, Vincent; Yanagawa, Yuchio; Emiliani, Valentina; Angulo, Maria Cecilia

    2015-04-22

    NG2 cells, oligodendrocyte progenitors, receive a major synaptic input from interneurons in the developing neocortex. It is presumed that these precursors integrate cortical networks where they act as sensors of neuronal activity. We show that NG2 cells of the developing somatosensory cortex form a transient and structured synaptic network with interneurons that follows its own rules of connectivity. Fast-spiking interneurons, highly connected to NG2 cells, target proximal subcellular domains containing GABAA receptors with γ2 subunits. Conversely, non-fast-spiking interneurons, poorly connected with these progenitors, target distal sites lacking this subunit. In the network, interneuron-NG2 cell connectivity maps exhibit a local spatial arrangement reflecting innervation only by the nearest interneurons. This microcircuit architecture shows a connectivity peak at PN10, coinciding with a switch to massive oligodendrocyte differentiation. Hence, GABAergic innervation of NG2 cells is temporally and spatially regulated from the subcellular to the network level in coordination with the onset of oligodendrogenesis.

  3. Cortical inputs innervate calbindin-immunoreactive interneurons of the rat basolateral amygdaloid complex.

    Science.gov (United States)

    Unal, Gunes; Paré, Jean-Francois; Smith, Yoland; Paré, Denis

    2014-06-01

    The present study was undertaken to shed light on the synaptic organization of the rat basolateral amygdala (BLA). The BLA contains multiple types of GABAergic interneurons that are differentially connected with extrinsic afferents and other BLA cells. Previously, it was reported that parvalbumin immunoreactive (PV(+) ) interneurons receive strong excitatory inputs from principal BLA cells but very few cortical inputs, implying a prevalent role in feedback inhibition. However, because prior physiological studies indicate that cortical afferents do trigger feedforward inhibition in principal cells, the present study aimed to determine whether a numerically important subtype of interneurons, expressing calbindin (CB(+) ), receives cortical inputs. Rats received injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHAL) in the perirhinal cortex or adjacent temporal neocortex. Light and electron microscopic observations of the relations between cortical inputs and BLA neurons were performed in the lateral (LA) and basolateral (BL) nuclei. Irrespective of the injection site (perirhinal or temporal neocortex) and target nucleus (LA or BL), ~90% of cortical axon terminals formed asymmetric synapses with dendritic spines of principal BLA neurons, while 10% contacted the dendritic shafts of presumed interneurons, half of which were CB(+) . Given the previously reported pattern of CB coexpression among GABAergic interneurons of the BLA, these results suggest that a subset of PV-immunonegative cells that express CB, most likely the somatostatin-positive interneurons, are important mediators of cortically evoked feedforward inhibition in the BLA.

  4. Loss of dopamine D2 receptors increases parvalbumin-positive interneurons in the anterior cingulate cortex.

    Science.gov (United States)

    Graham, Devon L; Durai, Heather H; Garden, Jamie D; Cohen, Evan L; Echevarria, Franklin D; Stanwood, Gregg D

    2015-02-18

    Disruption to dopamine homeostasis during brain development has been implicated in a variety of neuropsychiatric disorders, including depression and schizophrenia. Inappropriate expression or activity of GABAergic interneurons are common features of many of these disorders. We discovered a persistent upregulation of GAD67+ and parvalbumin+ neurons within the anterior cingulate cortex of dopamine D2 receptor knockout mice, while other GABAergic interneuron markers were unaffected. Interneuron distribution and number were not altered in the striatum or in the dopamine-poor somatosensory cortex. The changes were already present by postnatal day 14, indicating a developmental etiology. D2eGFP BAC transgenic mice demonstrated the presence of D2 receptor expression within a subset of parvalbumin-expressing cortical interneurons, suggesting the possibility of a direct cellular mechanism through which D2 receptor stimulation regulates interneuron differentiation or survival. D2 receptor knockout mice also exhibited decreased depressive-like behavior compared with wild-type controls in the tail suspension test. These data indicate that dopamine signaling modulates interneuron number and emotional behavior and that developmental D2 receptor loss or blockade could reveal a potential mechanism for the prodromal basis of neuropsychiatric disorders.

  5. Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor.

    Science.gov (United States)

    Berghuis, Paul; Dobszay, Marton B; Wang, Xinyu; Spano, Sabrina; Ledda, Fernanda; Sousa, Kyle M; Schulte, Gunnar; Ernfors, Patrik; Mackie, Ken; Paratcha, Gustavo; Hurd, Yasmin L; Harkany, Tibor

    2005-12-27

    In utero exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie Delta(9)-THC-induced cognitive impairments, the neuronal basis of Delta(9)-THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB(1) cannabinoid receptor (CB(1)R) on cholecystokinin-expressing interneurons induces chemotaxis that is additive with brain-derived neurotrophic factor (BDNF)-induced interneuron migration. We find that Src kinase-dependent TrkB receptor transactivation mediates endocannabinoid (eCB)-induced chemotaxis in the absence of BDNF. Simultaneously, eCBs suppress the BDNF-dependent morphogenesis of interneurons, and this suppression is abolished by Src kinase inhibition in vitro. Because sustained prenatal Delta(9)-THC stimulation of CB(1)Rs selectively increases the density of cholecystokinin-expressing interneurons in the hippocampus in vivo, we conclude that prenatal CB(1)R activity governs proper interneuron placement and integration during corticogenesis. Moreover, eCBs use TrkB receptor-dependent signaling pathways to regulate subtype-selective interneuron migration and specification.

  6. Ripple-associated high-firing interneurons in the hippocampal CA1 region

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    By simultaneously recording the activity of individual neurons and field potentials in freely behaving mice, we found two types of interneurons firing at high frequency in the hippocampal CA1 region, which had high correlations with characteristic sharp wave-associated ripple oscillations (100―250 Hz) during slow-wave sleep. The firing of these two types of interneurons highly synchronized with ripple oscillations during slow-wave sleep, with strongly increased firing rates corresponding to individual ripple episodes. Interneuron type I had at most one spike in each sub-ripple cycle of ripple episodes and the peak firing rate was 310±33.17 Hz. Interneuron type II had one or two spikes in each sub-ripple cycle and the peak firing rate was 410±47.61 Hz. During active exploration, their firing was phase locked to theta oscillations with the highest probability at the trough of theta wave. Both two types of interneurons increased transiently their firing rates responding to the startling shake stimuli. The results showed that these two types of high-frequency interneurons in the hippocampal CA1 region were involved in the modulation of the hippocampal neural network during different states.

  7. Ripple-associated high-firing interneurons in the hippocampal CA1 region

    Institute of Scientific and Technical Information of China (English)

    WANG Ying; ZHANG Lu; PAN JingWei; XIE Kun; LI ShiQi; WANG ZhiRu; LIN LongNian

    2008-01-01

    By simultaneously recording the activity of individual neurons and field potentials in freely behaving mice, we found two types of interneurons firing at high frequency in the hippocampal CA1 region,which had high correlations with characteristic sharp wave-associated ripple oscillations (100-250 Hz)during slow-wave sleep. The firing of these two types of interneurons highly synchronized with ripple oscillations during slow-wave sleep, with strongly increased firing rates corresponding to individual ripple episodes. Interneuron type Ⅰ had at most one spike in each sub-ripple cycle of ripple episodes and the peak firing rate was 310±33.17 Hz. Interneuron type Ⅱ had one or two spikes in each sub-ripple cycle and the peak firing rate was 410±47.61 Hz. During active exploration, their firing was phase locked to theta oscillations with the highest probability at the trough of theta wave. Both two types of interneurons increased transiently their firing rates responding to the startling shake stimuli. The results showed that these two types of high-frequency interneurone in the hippocsmpal CA1 region were involved in the modulation of the hippocampal neural network during different states.

  8. Tonic GABAA conductance bidirectionally controls interneuron firing pattern and synchronization in the CA3 hippocampal network.

    Science.gov (United States)

    Pavlov, Ivan; Savtchenko, Leonid P; Song, Inseon; Koo, Jaeyeon; Pimashkin, Alexey; Rusakov, Dmitri A; Semyanov, Alexey

    2014-01-07

    The spiking output of interneurons is key for rhythm generation in the brain. However, what controls interneuronal firing remains incompletely understood. Here we combine dynamic clamp experiments with neural network simulations to understand how tonic GABAA conductance regulates the firing pattern of CA3 interneurons. In baseline conditions, tonic GABAA depolarizes these cells, thus exerting an excitatory action while also reducing the excitatory postsynaptic potential (EPSP) amplitude through shunting. As a result, the emergence of weak tonic GABAA conductance transforms the interneuron firing pattern driven by individual EPSPs into a more regular spiking mode determined by the cell intrinsic properties. The increased regularity of spiking parallels stronger synchronization of the local network. With further increases in tonic GABAA conductance the shunting inhibition starts to dominate over excitatory actions and thus moderates interneuronal firing. The remaining spikes tend to follow the timing of suprathreshold EPSPs and thus become less regular again. The latter parallels a weakening in network synchronization. Thus, our observations suggest that tonic GABAA conductance can bidirectionally control brain rhythms through changes in the excitability of interneurons and in the temporal structure of their firing patterns.

  9. Maternal Immune Activation Leads to Selective Functional Deficits in Offspring Parvalbumin Interneurons

    Science.gov (United States)

    Canetta, Sarah; Bolkan, Scott; Padilla-Coreano, Nancy; Song, LouJin; Sahn, Ryan; Harrison, Neil; Gordon, Joshua A.; Brown, Alan; Kellendonk, Christoph

    2015-01-01

    Summary Abnormalities in prefrontal GABAergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to maternal immune activation, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders. PMID:26830140

  10. SDF1 reduces interneuron leading process branching through dual regulation of actin and microtubules.

    Science.gov (United States)

    Lysko, Daniel E; Putt, Mary; Golden, Jeffrey A

    2014-04-02

    Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process.

  11. Disproportionate loss of CA4 parvalbumin-immunoreactive interneurons in patients with Ammon's horn sclerosis.

    Science.gov (United States)

    Zhu, Z Q; Armstrong, D L; Hamilton, W J; Grossman, R G

    1997-09-01

    We studied differences in the number and morphology of parvalbumin-immunoreactive (PV-IR) interneurons in 43 hippocampal specimens from patients with classical Ammon's horn sclerosis (AHS) who underwent anterior temporal lobectomy, as compared with 14 autopsy and non-AHS surgical control specimens. PV-IR neuronal loss in the AHS specimens varied significantly from that expected based on overall AHS-associated pyramidal and granule neuron loss. Most striking was the loss of PV-IR interneurons in CA4 of the AHS specimens, which was 12 times greater than AHS-associated pyramidal neuron loss, and significantly exceeded the PV-IR interneuron loss observed in the other sectors of the hippocampus. In addition, the PV-IR interneurons in the AHS specimens had markedly smaller and less defined cell bodies and shortened and simplified dendritic arbors compared with the PV-IR interneurons in the control specimens. Other differences noted in the AHS specimens included prominent dendritic varicosities; the loss or interruption of a band formed by PV-IR terminals in the dentate gyrus; and the virtual absence of a small, intensely staining PV-IR interneuron with a short, exuberant dendritic arbor that was readily identified in the autopsy specimens. We discuss these findings in relationship to the development of classical AHS and complex partial seizures (CPS).

  12. SDF1 Reduces Interneuron Leading Process Branching through Dual Regulation of Actin and Microtubules

    Science.gov (United States)

    Lysko, Daniel E.; Putt, Mary

    2014-01-01

    Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process. PMID:24695713

  13. Parvalbumin and neuropeptide Y expressing hippocampal GABA-ergic inhibitory interneuron numbers decline in a model of Gulf War illness

    OpenAIRE

    Tarick eMegahed; Bharathi eHattiangady; Bing eShuai; Shetty, Ashok K.

    2015-01-01

    Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf War illness (GWI). Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR) chemicals and mild stress for 4 weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. I...

  14. Distinct synaptic properties of perisomatic inhibitory cell types and their different modulation by cholinergic receptor activation in the CA3 region of the mouse hippocampus.

    Science.gov (United States)

    Szabó, Gergely G; Holderith, Noémi; Gulyás, Attila I; Freund, Tamás F; Hájos, Norbert

    2010-06-01

    Perisomatic inhibition originates from three types of GABAergic interneurons in cortical structures, including parvalbumin-containing fast-spiking basket cells (FSBCs) and axo-axonic cells (AACs), as well as cholecystokinin-expressing regular-spiking basket cells (RSBCs). These interneurons may have significant impact in various cognitive processes, and are subjects of cholinergic modulation. However, it is largely unknown how cholinergic receptor activation modulates the function of perisomatic inhibitory cells. Therefore, we performed paired recordings from anatomically identified perisomatic interneurons and pyramidal cells in the CA3 region of the mouse hippocampus. We determined the basic properties of unitary inhibitory postsynaptic currents (uIPSCs) and found that they differed among cell types, e.g. GABA released from axon endings of AACs evoked uIPSCs with the largest amplitude and with the longest decay measured at room temperature. RSBCs could also release GABA asynchronously, the magnitude of the release increasing with the discharge frequency of the presynaptic interneuron. Cholinergic receptor activation by carbachol significantly decreased the uIPSC amplitude in all three types of cell pairs, but to different extents. M2-type muscarinic receptors were responsible for the reduction in uIPSC amplitudes in FSBC- and AAC-pyramidal cell pairs, while an antagonist of CB(1) cannabinoid receptors recovered the suppression in RSBC-pyramidal cell pairs. In addition, carbachol suppressed or even eliminated the short-term depression of uIPSCs in FSBC- and AAC-pyramidal cell pairs in a frequency-dependent manner. These findings suggest that not only are the basic synaptic properties of perisomatic inhibitory cells distinct, but acetylcholine can differentially control the impact of perisomatic inhibition from different sources.

  15. Even-Skipped(+) Interneurons Are Core Components of a Sensorimotor Circuit that Maintains Left-Right Symmetric Muscle Contraction Amplitude.

    Science.gov (United States)

    Heckscher, Ellie S; Zarin, Aref Arzan; Faumont, Serge; Clark, Matthew Q; Manning, Laurina; Fushiki, Akira; Schneider-Mizell, Casey M; Fetter, Richard D; Truman, James W; Zwart, Maarten F; Landgraf, Matthias; Cardona, Albert; Lockery, Shawn R; Doe, Chris Q

    2015-10-21

    Bilaterally symmetric motor patterns--those in which left-right pairs of muscles contract synchronously and with equal amplitude (such as breathing, smiling, whisking, and locomotion)--are widespread throughout the animal kingdom. Yet, surprisingly little is known about the underlying neural circuits. We performed a thermogenetic screen to identify neurons required for bilaterally symmetric locomotion in Drosophila larvae and identified the evolutionarily conserved Even-skipped(+) interneurons (Eve/Evx). Activation or ablation of Eve(+) interneurons disrupted bilaterally symmetric muscle contraction amplitude, without affecting the timing of motor output. Eve(+) interneurons are not rhythmically active and thus function independently of the locomotor CPG. GCaMP6 calcium imaging of Eve(+) interneurons in freely moving larvae showed left-right asymmetric activation that correlated with larval behavior. TEM reconstruction of Eve(+) interneuron inputs and outputs showed that the Eve(+) interneurons are at the core of a sensorimotor circuit capable of detecting and modifying body wall muscle contraction.

  16. Development of Adult-Generated Cell Connectivity with Excitatory and Inhibitory Cell Populations in the Hippocampus.

    Science.gov (United States)

    Restivo, Leonardo; Niibori, Yosuke; Mercaldo, Valentina; Josselyn, Sheena A; Frankland, Paul W

    2015-07-22

    New neurons are generated continuously in the subgranular zone of the hippocampus and integrate into existing hippocampal circuits throughout adulthood. Although the addition of these new neurons may facilitate the formation of new memories, as they integrate, they provide additional excitatory drive to CA3 pyramidal neurons. During development, to maintain homeostasis, new neurons form preferential contacts with local inhibitory circuits. Using retroviral and transgenic approaches to label adult-generated granule cells, we first asked whether a comparable process occurs in the adult hippocampus in mice. Similar to development, we found that, during adulthood, new neurons form connections with inhibitory cells in the dentate gyrus, hilus, and CA3 regions as they integrate into hippocampal circuits. In particular, en passant bouton and filopodia connections with CA3 interneurons peak when adult-generated dentate granule cells (DGCs) are ∼4 weeks of age, a time point when these cells are most excitable. Consistent with this, optical stimulation of 4-week-old (but not 6- or 8-week-old) adult-generated DGCs strongly activated CA3 interneurons. Finally, we found that CA3 interneurons were activated robustly during learning and that their activity was strongly coupled with activity of 4-week-old (but not older) adult-generated DGCs. These data indicate that, as adult-generated neurons integrate into hippocampal circuits, they transiently form strong anatomical, effective, and functional connections with local inhibitory circuits in CA3. Significance statement: New neurons are generated continuously in the subgranular zone of the hippocampus and integrate into existing hippocampal circuits throughout adulthood. Understanding how these cells integrate within well formed circuits will increase our knowledge about the basic principles governing circuit assembly in the adult hippocampus. This study uses a combined connectivity analysis (anatomical, functional, and effective

  17. Experimentally constrained CA1 fast-firing parvalbumin-positive interneuron network models exhibit sharp transitions into coherent high frequency rhythms

    Directory of Open Access Journals (Sweden)

    Katie A Ferguson

    2013-10-01

    Full Text Available The coupling of high frequency oscillations (HFOs; >100 Hz and theta oscillations (3-12 Hz in the CA1 region of rats increases during REM sleep, indicating that it may play a role in memory processing. However, it is unclear whether the CA1 region itself is capable of providing major contributions to the generation of HFOs, or if they are strictly driven through input projections. Parvalbumin-positive (PV+ interneurons may play an essential role in these oscillations due to their extensive connections with neighbouring pyramidal cells, and their characteristic fast-spiking. Thus, we created mathematical network models to investigate the conditions under which networks of CA1 fast-spiking PV+ interneurons are capable of producing high frequency population rhythms.We used whole-cell patch clamp recordings of fast-spiking, PV+ cells in the CA1 region of an intact hippocampal preparation in vitro to derive cellular properties, from which we constrained an Izhikevich-type model. Novel, biologically constrained network models were constructed with these individual cell models, and we investigated networks across a range of experimentally determined excitatory inputs and inhibitory synaptic strengths. For each network, we determined network frequency and coherence.Network simulations produce coherent firing at high frequencies (> 90 Hz for parameter ranges in which PV-PV inhibitory synaptic conductances are necessarily small and external excitatory inputs are relatively large. Interestingly, our networks produce sharp transitions between random and coherent firing, and this sharpness is lost when connectivity is increased beyond biological estimates. Our work suggests that CA1 networks may be designed with mechanisms for quickly gating in and out of high frequency coherent population rhythms, which may be essential in the generation of nested theta/high frequency rhythms.

  18. Differential synaptic integration of interneurons in the outer and inner molecular layers of the developing dentate gyrus.

    Science.gov (United States)

    Chittajallu, Ramesh; Kunze, Albrecht; Mangin, Jean-Marie; Gallo, Vittorio

    2007-08-01

    The dentate gyrus (DG) undergoes continued reorganization and lamination during early postnatal development. Interneurons with anatomically identified synaptic contacts migrate from the outer to the inner regions of the molecular layer (ML) of the DG. By using the 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP)-enhanced green fluorescent protein transgenic mouse, we were able to target and physiologically characterize Dlx2(+) developing ML interneurons. We investigated whether synapses on migrating ML interneurons were functional and defined properties of synaptic inputs onto interneurons that were located in the outer ML (OML) or inner ML (IML). Consistent with ongoing maturation, IML interneurons displayed lower input resistances and more hyperpolarized resting membrane potentials than OML interneurons. Both OML and IML interneurons received a direct excitatory monosynaptic input from the entorhinal cortex via the perforant paths, but this input was differentially sensitive to activation of presynaptic group II and III metabotropic glutamate receptors. Furthermore, only IML interneurons also received significant synaptic input from the CA3/hilar region, especially under conditions of experimentally induced disinhibition. These changes are attributed to a significant reorganization of dendritic fields. GABA(A) receptor-mediated innervation of OML and IML interneurons also displayed significant differences in miniature IPSC amplitude, frequency, and decay kinetics. Finally, cell-attached recordings indicated that GABA(A) receptor activation was depolarizing in OML interneurons but predominantly shunting in IML interneurons. Our data provide evidence that developing ML interneurons receive functional glutamatergic and GABAergic inputs and undergo significant changes in synaptic integration during migration from the OML to the IML.

  19. Dichotomous Distribution of Putative Cholinergic Interneurons in Mouse Accessory Olfactory Bulb

    Science.gov (United States)

    Marking, Sarah; Krosnowski, Kurt; Ogura, Tatsuya; Lin, Weihong

    2017-01-01

    Sensory information processing in the olfactory bulb (OB) relies on diverse populations of bulbar interneurons. In rodents, the accessory OB (AOB) is divided into two bulbar regions, the anterior (aAOB) and posterior (pAOB), which differ substantially in their circuitry connections and associated behaviors. We previously identified and characterized a large number of morphologically diverse cholinergic interneurons in the main OB (MOB) using transgenic mice to visualize the cell bodies of choline acetyltransferase (ChAT-expressing neurons and immunolabeling (Krosnowski et al., 2012)). However, whether there are cholinergic neurons in the AOB is controversial and there is no detailed characterization of such neurons. Using the same line of ChAT(bacterial artificial chromosome, BAC)-enhanced green fluorescent protein (eGFP) transgenic mice, we investigated cholinergic neurons in the AOB. We found significant differences in the number and location of GFP-expressing (GFP+), putative cholinergic interneurons between the aAOB and pAOB. The highest numbers of GFP+ interneurons were found in the aAOB glomerular layer (aGL) and pAOB mitral/tufted cell layer (pMCL). We also noted a high density of GFP+ interneurons encircling the border region of the pMCL. Interestingly, a small subset of glomeruli in the middle of the GL receives strong MCL GFP+ nerve processes. These local putative cholinergic-innervated glomeruli are situated just outside the aGL, setting the boundary between the pGL and aGL. Many but not all GFP+ neurons in the AOB were weakly labeled with antibodies against ChAT and vesicular acetylcholine transporter (VAChT). We further determined if these GFP+ interneurons differ from other previously characterized interneuron populations in the AOB and found that AOB GFP+ interneurons express neither GABAergic nor dopaminergic markers and most also do not express the glutamatergic marker. Similar to the cholinergic interneurons of the MOB, some AOB GFP+ interneurons

  20. Alterations of interneurons in the striatum and frontal cortex of mice during postnatal development.

    Science.gov (United States)

    Eto, Risa; Abe, Manami; Kimoto, Hiroki; Imaoka, Eri; Kato, Hiroyuki; Kasahara, Jiro; Araki, Tsutomu

    2010-08-01

    We investigated the postnatal alterations of neuronal nuclei (NeuN)-positive neurons, parvalbumin (PV)-positive interneurons, neuronal nitric oxide synthase (nNOS)-positive interneurons, and neurotrophic factors in the mouse striatum and frontal cortex using immunohistochemistry. NeuN, PV, nNOS, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) immunoreactivity were measured in 1-, 2-, 4- and 8-week-old mice. Total number of NeuN-positive neurons was unchanged in the mouse striatum and frontal cortex from 1 up to 8 weeks of age. In contrast, a significant decrease in the number of PV-positive interneurons was observed in the striatum and frontal cortex of 1-, 2- and 4-week-old mice. Furthermore, a significant increase of nNOS-positive interneurons was found in the striatum and frontal cortex of 1- and/or 2-week-old mice. NGF-positive neurons were unchanged in the mouse striatum from 1 up to 8 weeks of age. In the frontal cortex, a significant increase in the number of NGF-positive neurons was observed only in 1-week-old mice. In contrast, a significant increase in the number of NGF-positive glia 1 cells was found in the striatum and frontal cortex of 4-week-old mice. Our double-labeled immunostaining showed that nNOS immunoreactivity was not found in PV-immunopositive interneurons. Furthermore, BDNF immunoreactivity was observed in both nNOS-positive and PV-positive interneurons in the striatum of 1- or 2-week-old mice. These results show that the maturation of nNOS-immunopositive interneurons precedes the maturation of PV-immunopositive interneurons in the striatum and frontal cortex during postnatal development. Furthermore, our results demonstrate that the expression of BDNF may play some role in the maturation of interneurons in the striatum and frontal cortex during postnatal development. Moreover, our findings suggest that the expression of NGF in glia cells may play some role in the maturation of glial cells and PV-positive interneurons

  1. ProNGF Drives Localized and Cell Selective Parvalbumin Interneuron and Perineuronal Net Depletion in the Dentate Gyrus of Transgenic Mice

    Science.gov (United States)

    Fasulo, Luisa; Brandi, Rossella; Arisi, Ivan; La Regina, Federico; Berretta, Nicola; Capsoni, Simona; D'Onofrio, Mara; Cattaneo, Antonino

    2017-01-01

    ProNGF, the precursor of mature Nerve Growth Factor (NGF), is the most abundant NGF form in the brain and increases markedly in the cortex in Alzheimer's Disease (AD), relative to mature NGF. A large body of evidence shows that the actions of ProNGF and mature NGF are often conflicting, depending on the receptors expressed in target cells. TgproNGF#3 mice, expressing furin-cleavage resistant proNGF in CNS neurons, directly reveal consequences of increased proNGF levels on brain homeostasis. Their phenotype clearly indicates that proNGF can be a driver of neurodegeneration, including severe learning and memory behavioral deficits, cholinergic deficits, and diffuse immunoreactivity for A-beta and A-beta-oligomers. In aged TgproNGF#3 mice spontaneous epileptic-like events are detected in entorhinal cortex-hippocampal slices, suggesting occurrence of excitatory/inhibitory (E/I) imbalance. In this paper, we investigate the molecular events linking increased proNGF levels to the epileptiform activity detected in hippocampal slices. The occurrence of spontaneous epileptiform discharges in the hippocampal network in TgproNGF#3 mice suggests an impaired inhibitory interneuron homeostasis. In the present study, we detect the onset of hippocampal epileptiform events at 1-month of age. Later, we observe a regional- and cellular-selective Parvalbumin interneuron and perineuronal net (PNN) depletion in the dentate gyrus (DG), but not in other hippocampal regions of TgproNGF#3 mice. These results demonstrate that, in the hippocampus, the DG is selectively vulnerable to altered proNGF/NGF signaling. Parvalbumin interneuron depletion is also observed in the amygdala, a region strongly connected to the hippocampus and likewise receiving cholinergic afferences. Transcriptome analysis of TgproNGF#3 hippocampus reveals a proNGF signature with broad down-regulation of transcription. The most affected mRNAs modulated at early times belong to synaptic transmission and plasticity and

  2. ProNGF Drives Localized and Cell Selective Parvalbumin Interneuron and Perineuronal Net Depletion in the Dentate Gyrus of Transgenic Mice.

    Science.gov (United States)

    Fasulo, Luisa; Brandi, Rossella; Arisi, Ivan; La Regina, Federico; Berretta, Nicola; Capsoni, Simona; D'Onofrio, Mara; Cattaneo, Antonino

    2017-01-01

    ProNGF, the precursor of mature Nerve Growth Factor (NGF), is the most abundant NGF form in the brain and increases markedly in the cortex in Alzheimer's Disease (AD), relative to mature NGF. A large body of evidence shows that the actions of ProNGF and mature NGF are often conflicting, depending on the receptors expressed in target cells. TgproNGF#3 mice, expressing furin-cleavage resistant proNGF in CNS neurons, directly reveal consequences of increased proNGF levels on brain homeostasis. Their phenotype clearly indicates that proNGF can be a driver of neurodegeneration, including severe learning and memory behavioral deficits, cholinergic deficits, and diffuse immunoreactivity for A-beta and A-beta-oligomers. In aged TgproNGF#3 mice spontaneous epileptic-like events are detected in entorhinal cortex-hippocampal slices, suggesting occurrence of excitatory/inhibitory (E/I) imbalance. In this paper, we investigate the molecular events linking increased proNGF levels to the epileptiform activity detected in hippocampal slices. The occurrence of spontaneous epileptiform discharges in the hippocampal network in TgproNGF#3 mice suggests an impaired inhibitory interneuron homeostasis. In the present study, we detect the onset of hippocampal epileptiform events at 1-month of age. Later, we observe a regional- and cellular-selective Parvalbumin interneuron and perineuronal net (PNN) depletion in the dentate gyrus (DG), but not in other hippocampal regions of TgproNGF#3 mice. These results demonstrate that, in the hippocampus, the DG is selectively vulnerable to altered proNGF/NGF signaling. Parvalbumin interneuron depletion is also observed in the amygdala, a region strongly connected to the hippocampus and likewise receiving cholinergic afferences. Transcriptome analysis of TgproNGF#3 hippocampus reveals a proNGF signature with broad down-regulation of transcription. The most affected mRNAs modulated at early times belong to synaptic transmission and plasticity and

  3. Primary afferent terminals acting as excitatory interneurons contribute to spontaneous motor activities in the immature spinal cord.

    Science.gov (United States)

    Bos, Rémi; Brocard, Frédéric; Vinay, Laurent

    2011-07-13

    Patterned, spontaneous activity plays a critical role in the development of neuronal networks. A robust spontaneous activity is observed in vitro in spinal cord preparations isolated from immature rats. The rhythmic ventral root discharges rely mainly on the depolarizing/excitatory action of GABA and glycine early during development, whereas at later stages glutamate drive is primarily responsible for the rhythmic activity and GABA/glycine are thought to play an inhibitory role. However, rhythmic discharges mediated by the activation of GABA(A) receptors are recorded from dorsal roots (DRs). In the present study, we used the in vitro spinal cord preparation of neonatal rats to identify the relationship between discharges that are conducted antidromically along DRs and the spontaneous activity recorded from lumbar motoneurons. We show that discharges in DRs precede those in ventral roots and that primary afferent depolarizations (PADs) start earlier than EPSPs in motoneurons. EPSP-triggered averaging revealed that the action potentials propagate not only antidromically in the DR but also centrally and trigger EPSPs in motoneurons. Potentiating GABAergic antidromic discharges by diazepam increased the EPSPs recorded from motoneurons; conversely, blocking DR bursts markedly reduced these EPSPs. High intracellular concentrations of chloride are maintained in primary afferent terminals by the sodium-potassium-chloride cotransporter NKCC1. Blocking these cotransporters by bumetanide decreased both dorsal and ventral root discharges. We conclude that primary afferent fibers act as excitatory interneurons and that GABA, through PADs reaching firing threshold, is still playing a key role in promoting spontaneous activity in neonates.

  4. Topiramate reduces excitability in the basolateral amygdala by selectively inhibiting GluK1 (GluR5) kainate receptors on interneurons and positively modulating GABAA receptors on principal neurons.

    Science.gov (United States)

    Braga, Maria F M; Aroniadou-Anderjaska, Vassiliki; Li, He; Rogawski, Michael A

    2009-08-01

    Topiramate [2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] is a structurally novel antiepileptic drug that has broad efficacy in epilepsy, but the mechanisms underlying its therapeutic activity are not fully understood. We have found that topiramate selectively inhibits GluK1 (GluR5) kainate receptor-mediated excitatory postsynaptic responses in rat basolateral amygdala (BLA) principal neurons and protects against seizures induced by the GluK1 kainate receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA). Here, we demonstrate that topiramate also modulates inhibitory function in the BLA. Using whole-cell recordings in rat amygdala slices, we found that 0.3 to 10 microM topiramate 1) inhibited ATPA-evoked postsynaptic currents recorded from BLA interneurons; 2) suppressed ATPA-induced enhancement of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from BLA pyramidal cells; and 3) blocked ATPA-induced suppression of evoked IPSCs, which is mediated by presynaptic GluK1 kainate receptors present on BLA interneurons. Topiramate (10 microM) had no effect on the AMPA [(R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid]-induced enhancement of spontaneous activity of BLA neurons. Thus, although topiramate inhibits GluK1 kainate receptor-mediated enhancement of interneuron firing, it promotes evoked GABA release, leading to a net inhibition of circuit excitability. In addition, we found that topiramate (0.3-10 microM) increased the amplitude of evoked, spontaneous, and miniature IPSCs in BLA pyramidal neurons, indicating an enhancement of postsynaptic GABA(A) receptor responses. Taken together with our previous findings, we conclude that topiramate protects against hyperexcitability in the BLA by suppressing the GluK1 kainate receptor-mediated excitation of principal neurons by glutamatergic afferents, blocking the suppression of GAB