WorldWideScience

Sample records for abnormal synaptic plasticity

  1. Synaptic Plasticity and Nociception

    Institute of Scientific and Technical Information of China (English)

    ChenJianguo

    2004-01-01

    Synaptic plasticity is one of the fields that progresses rapidly and has a lot of success in neuroscience. The two major types of synaptie plasticity: long-term potentiation ( LTP and long-term depression (LTD are thought to be the cellular mochanisms of learning and memory. Recently, accumulating evidence suggests that, besides serving as a cellular model for learning and memory, the synaptic plasticity involves in other physiological or pathophysiological processes, such as the perception of pain and the regulation of cardiovascular system. This minireview will focus on the relationship between synaptic plasticity and nociception.

  2. Mitochondria, synaptic plasticity, and schizophrenia.

    Science.gov (United States)

    Ben-Shachar, Dorit; Laifenfeld, Daphna

    2004-01-01

    The conceptualization of schizophrenia as a disorder of connectivity, i.e., of neuronal?synaptic plasticity, suggests abnormal synaptic modeling and neuronal signaling, possibly as a consequence of flawed interactions with the environment, as at least a secondary mechanism underlying the pathophysiology of this disorder. Indeed, deficits in episodic memory and malfunction of hippocampal circuitry, as well as anomalies of axonal sprouting and synapse formation, are all suggestive of diminished neuronal plasticity in schizophrenia. Evidence supports a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, and a dysfunction of the oxidative phosphorylation system, as well as altered mitochondrial-related gene expression. Mitochondrial dysfunction leads to alterations in ATP production and cytoplasmatic calcium concentrations, as well as reactive oxygen species and nitric oxide production. All of the latter processes have been well established as leading to altered synaptic strength or plasticity. Moreover, mitochondria have been shown to play a role in plasticity of neuronal polarity, and studies in the visual cortex show an association between mitochondria and synaptogenesis. Finally, mitochondrial gene upregulation has been observed following synaptic and neuronal activity. This review proposes that mitochondrial dysfunction in schizophrenia could cause, or arise from, anomalies in processes of plasticity in this disorder.

  3. Optogenetics and synaptic plasticity.

    Science.gov (United States)

    Xie, Yu-feng; Jackson, Michael F; Macdonald, John F

    2013-11-01

    The intricate and complex interaction between different populations of neurons in the brain has imposed limits on our ability to gain detailed understanding of synaptic transmission and its integration when employing classical electrophysiological approaches. Indeed, electrical field stimulation delivered via traditional microelectrodes does not permit the targeted, precise and selective control of neuronal activity amongst a varied population of neurons and their inputs (eg, cholinergic, dopaminergic or glutamatergic neurons). Recently established optogenetic techniques overcome these limitations allowing precise control of the target neuron populations, which is essential for the elucidation of the neural substrates underlying complex animal behaviors. Indeed, by introducing light-activated channels (ie, microbial opsin genes) into specific neuronal populations, optogenetics enables non-invasive optical control of specific neurons with milliseconds precision. These approaches can readily be applied to freely behaving live animals. Recently there is increased interests in utilizing optogenetics tools to understand synaptic plasticity and learning/memory. Here, we summarize recent progress in applying optogenetics in in the study of synaptic plasticity.

  4. Multiscale modeling and synaptic plasticity.

    Science.gov (United States)

    Bhalla, Upinder S

    2014-01-01

    Synaptic plasticity is a major convergence point for theory and computation, and the process of plasticity engages physiology, cell, and molecular biology. In its many manifestations, plasticity is at the hub of basic neuroscience questions about memory and development, as well as more medically themed questions of neural damage and recovery. As an important cellular locus of memory, synaptic plasticity has received a huge amount of experimental and theoretical attention. If computational models have tended to pick specific aspects of plasticity, such as STDP, and reduce them to an equation, some experimental studies are equally guilty of oversimplification each time they identify a new molecule and declare it to be the last word in plasticity and learning. Multiscale modeling begins with the acknowledgment that synaptic function spans many levels of signaling, and these are so tightly coupled that we risk losing essential features of plasticity if we focus exclusively on any one level. Despite the technical challenges and gaps in data for model specification, an increasing number of multiscale modeling studies have taken on key questions in plasticity. These have provided new insights, but importantly, they have opened new avenues for questioning. This review discusses a wide range of multiscale models in plasticity, including their technical landscape and their implications.

  5. Synaptic vesicle proteins and active zone plasticity

    Directory of Open Access Journals (Sweden)

    Robert J Kittel

    2016-04-01

    Full Text Available Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone. The complex molecular architecture of active zones mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of active zones vary significantly, even for a given connection. Thus, there appear to be distinct active zone states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the active zone.The protein-rich cytomatrix at the active zone (CAZ provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1 and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and active zone states, which has heretofore received little attention.

  6. Synaptic Vesicle Proteins and Active Zone Plasticity.

    Science.gov (United States)

    Kittel, Robert J; Heckmann, Manfred

    2016-01-01

    Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the AZ. The protein-rich cytomatrix at the active zone (CAZ) provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and AZ states, which has heretofore received little attention.

  7. Synaptic plasticity and the warburg effect

    KAUST Repository

    Magistretti, Pierre J.

    2014-01-01

    Functional brain imaging studies show that in certain brain regions glucose utilization exceeds oxygen consumption, indicating the predominance of aerobic glycolysis. In this issue, Goyal et al. (2014) report that this metabolic profile is associated with an enrichment in the expression of genes involved in synaptic plasticity and remodeling processes. © 2014 Elsevier Inc.

  8. Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Robert Nisticò

    Full Text Available Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS and its mouse model, experimental autoimmune encephalomyelitis (EAE. In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP induction was favored over long-term depression (LTD in EAE, as shown by a significant rightward shift in the frequency-synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS.

  9. Linking neuronal ensembles by associative synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Qi Yuan

    Full Text Available Synchronized activity in ensembles of neurons recruited by excitatory afferents is thought to contribute to the coding information in the brain. However, the mechanisms by which neuronal ensembles are generated and modified are not known. Here we show that in rat hippocampal slices associative synaptic plasticity enables ensembles of neurons to change by incorporating neurons belonging to different ensembles. Associative synaptic plasticity redistributes the composition of different ensembles recruited by distinct inputs such as to specifically increase the similarity between the ensembles. These results show that in the hippocampus, the ensemble of neurons recruited by a given afferent projection is fluid and can be rapidly and persistently modified to specifically include neurons from different ensembles. This linking of ensembles may contribute to the formation of associative memories.

  10. Synaptic Plasticity, Dementia and Alzheimer Disease.

    Science.gov (United States)

    Skaper, Stephen D; Facci, Laura; Zusso, Morena; Giusti, Pietro

    2017-01-13

    Neuroplasticity is not only shaped by learning and memory but is also a mediator of responses to neuron attrition and injury (compensatory plasticity). As an ongoing process it reacts to neuronal cell activity and injury, death, and genesis, which encompasses the modulation of structural and functional processes of axons, dendrites, and synapses. The range of structural elements that comprise plasticity includes long-term potentiation (a cellular correlate of learning and memory), synaptic efficacy and remodelling, synaptogenesis, axonal sprouting and dendritic remodelling, and neurogenesis and recruitment. Degenerative diseases of the human brain continue to pose one of biomedicine's most intractable problems. Research on human neurodegeneration is now moving from descriptive to mechanistic analyses. At the same time, it is increasing apparent that morphological lesions traditionally used by neuropathologists to confirm post-mortem clinical diagnosis might furnish us with an experimentally tractable handle to understand causative pathways. Consider the aging-dependent neurodegenerative disorder Alzheimer's disease (AD) which is characterised at the neuropathological level by deposits of insoluble amyloid b-peptide (Ab) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. We now appreciate that mild cognitive impairment in early AD may be due to synaptic dysfunction caused by accumulation of non-fibrillar, oligomeric Ab, occurring well in advance of evident widespread synaptic loss and neurodegeneration. Soluble Ab oligomers can adversely affect synaptic structure and plasticity at extremely low concentrations, although the molecular substrates by which synaptic memory mechanisms are disrupted remain to be fully elucidated. The dendritic spine constitutes a primary locus of excitatory synaptic transmission in the mammalian central nervous system. These structures protruding from dendritic shafts

  11. Filamentary Switching: Synaptic Plasticity through Device Volatility

    CERN Document Server

    La Barbera, Selina; Alibart, Fabien

    2015-01-01

    Replicating the computational functionalities and performances of the brain remains one of the biggest challenges for the future of information and communication technologies. Such an ambitious goal requires research efforts from the architecture level to the basic device level (i.e., investigating the opportunities offered by emerging nanotechnologies to build such systems). Nanodevices, or, more precisely, memory or memristive devices, have been proposed for the implementation of synaptic functions, offering the required features and integration in a single component. In this paper, we demonstrate that the basic physics involved in the filamentary switching of electrochemical metallization cells can reproduce important biological synaptic functions that are key mechanisms for information processing and storage. The transition from short- to long-term plasticity has been reported as a direct consequence of filament growth (i.e., increased conductance) in filamentary memory devices. In this paper, we show tha...

  12. Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain

    Directory of Open Access Journals (Sweden)

    Christian Bonansco

    2016-01-01

    Full Text Available Synaptic plasticity is the capacity generated by experience to modify the neural function and, thereby, adapt our behaviour. Long-term plasticity of glutamatergic and GABAergic transmission occurs in a concerted manner, finely adjusting the excitatory-inhibitory (E/I balance. Imbalances of E/I function are related to several neurological diseases including epilepsy. Several evidences have demonstrated that astrocytes are able to control the synaptic plasticity, with astrocytes being active partners in synaptic physiology and E/I balance. Here, we revise molecular evidences showing the epileptic stage as an abnormal form of long-term brain plasticity and propose the possible participation of astrocytes to the abnormal increase of glutamatergic and decrease of GABAergic neurotransmission in epileptic networks.

  13. Recent advances in understanding synaptic abnormalities in Rett syndrome [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Michael Johnston

    2015-12-01

    Full Text Available Rett syndrome is an extremely disabling X-linked nervous system disorder that mainly affects girls in early childhood and causes autism-like behavior, severe intellectual disability, seizures, sleep disturbances, autonomic instability, and other disorders due to mutations in the MeCP2 (methyl CpG-binding protein 2 transcription factor. The disorder targets synapses and synaptic plasticity and has been shown to disrupt the balance between glutamate excitatory synapses and GABAergic inhibitory synapses. In fact, it can be argued that Rett syndrome is primarily a disorder of synaptic plasticity and that agents that can correct this imbalance may have beneficial effects on brain development. This review briefly summarizes the link between disrupted synaptic plasticity mechanisms and Rett syndrome and early clinical trials that aim to target these abnormalities to improve the outcome for these severely disabled children.

  14. Nicotinic mechanisms influencing synaptic plasticity in the hippocampus

    Institute of Scientific and Technical Information of China (English)

    Andon Nicholas PLACZEK; Tao A ZHANG; John Anthony DANI

    2009-01-01

    Nicotinic acetylcholine receptors (nAChRs) are expressed throughout the hippocampus, and nicotinic signaling plays an important role in neuronal function. In the context of learning and memory related behaviors associated with hippocampal function, a potentially significant feature of nAChR activity is the impact it has on synaptic plasticity. Synaptic plasticity in hippocampal neurons has long been considered a contributing cellular mechanism of learning and memory. These same kinds of cellular mechanisms are a factor in the development of nicotine addiction. Nicotinic signaling has been demonstrated by in vitro studies to affect synaptic plasticity in hippocampal neurons via multiple steps, and the signaling has also been shown to evoke synaptic plasticity in vivo. This review focuses on the nAChRs subtypes that contribute to hippocampal synaptic plasticity at the cellular and circuit level. It also considers nicotinic influences over long-term changes in the hippocampus that may contribute to addiction.

  15. Cellular and molecular bases of memory: synaptic and neuronal plasticity.

    Science.gov (United States)

    Wang, J H; Ko, G Y; Kelly, P T

    1997-07-01

    Discoveries made during the past decade have greatly improved our understanding of how the nervous system functions. This review article examines the relation between memory and the cellular mechanisms of neuronal and synaptic plasticity in the central nervous system. Evidence indicating that activity-dependent short- and long-term changes in strength of synaptic transmission are important for memory processes is examined. Focus is placed on one model of synaptic plasticity called long-term potentiation, and its similarities with memory processes are illustrated. Recent studies show that the regulation of synaptic strength is bidirectional (e.g., synaptic potentiation or depression). Mechanisms involving intracellular signaling pathways that regulate synaptic strength are described, and the specific roles of calcium, protein kinases, protein phosphatases, and retrograde messengers are emphasized. Evidence suggests that changes in synaptic ultrastructure, dendritic ultrastructure, and neuronal gene expression may also contribute to mechanisms of synaptic plasticity. Also discussed are recent findings about postsynaptic mechanisms that regulate short-term synaptic facilitation and neuronal burst-pattern activity, as well as evidence about the subcellular location (presynaptic or postsynaptic) of mechanisms involved in long-term synaptic plasticity.

  16. GAP-43 in synaptic plasticity: molecular perspectives

    Directory of Open Access Journals (Sweden)

    Holahan MR

    2015-06-01

    Full Text Available Matthew R HolahanDepartment of Neuroscience, Carleton University, Ottawa, ON, CanadaAbstract: The growth-associated protein, GAP-43 (also known as F1, neuromodulin, B-50, participates in the developmental regulation of axonal growth and neural network formation via protein kinase C-mediated regulation of cytoskeletal elements. Transgenic overexpression of GAP-43 can result in the formation of new synapses, neurite outgrowth, and synaptogenesis after injury. In a number of adult mammalian species, GAP-43 has been implicated in the regulation of synaptic transmission and plasticity, such as long-term potentiation, drug sensitization, and changes in memory processes. This review examines the molecular and biochemical attributes of GAP-43, its distribution in the central nervous system, subcellular localization, role in neurite outgrowth and development, and functions related to plasticity, such as those occurring during long-term potentiation, memory formation, and drug sensitization.Keywords: GAP-43, protein kinase C, axons, development, regeneration, long-term potentiation, memory

  17. Spikes Synchronization in Neural Networks with Synaptic Plasticity

    CERN Document Server

    Borges, Rafael R; Batista, Antonio M; Caldas, Iberê L; Borges, Fernando S; Lameu, Ewandson L

    2015-01-01

    In this paper, we investigated the neural spikes synchronisation in a neural network with synaptic plasticity and external perturbation. In the simulations the neural dynamics is described by the Hodgkin Huxley model considering chemical synapses (excitatory) among neurons. According to neural spikes synchronisation is expected that a perturbation produce non synchronised regimes. However, in the literature there are works showing that the combination of synaptic plasticity and external perturbation may generate synchronised regime. This article describes the effect of the synaptic plasticity on the synchronisation, where we consider a perturbation with a uniform distribution. This study is relevant to researches of neural disorders control.

  18. Synaptic plasticity: Building memories to last.

    Science.gov (United States)

    Thompson, S M

    2000-03-23

    A series of recent studies has provided long-awaited direct evidence that enduring changes in synaptic strength, presumably underlying the formation of persistent memories, may be encoded in a lasting form as a change in synaptic structure.

  19. Pannexin 1 Regulates Bidirectional Hippocampal Synaptic Plasticity in Adult Mice

    Directory of Open Access Journals (Sweden)

    Alvaro O. Ardiles

    2014-10-01

    Full Text Available The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR composition of GluN2 subunits. Pannexin 1 (Panx1, a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP, it remains unknown whether these channels also modulate long-term depression (LTD or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory.

  20. Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice

    Science.gov (United States)

    Ardiles, Alvaro O.; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M.; Palacios, Adrian G.; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C.; Martínez, Agustín D.

    2014-01-01

    The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory. PMID:25360084

  1. The impact of synapsins on synaptic plasticity and cognitive behaviors

    Institute of Scientific and Technical Information of China (English)

    Lin ZHANG; Zhong-Xin ZHAO

    2006-01-01

    Synapsins are a family of phosphoproteins specifically associated with the cytoplasmic surface of the synaptic vesicle membrane, appearing to regulate neurotransmitter release, the formation and maintenance of synaptic contacts.They could induce the change of the synaptic plasticity to regulate various adaptation reactions, and change the cognitive behaviors. So we presume that if some cognitive behavior are damaged, synapsins would be changed as well. This gives us a new recognition of better diagnosis and therapy of cognitive disorder desease.

  2. Astrocytes Mediate In Vivo Cholinergic-Induced Synaptic Plasticity

    OpenAIRE

    2012-01-01

    In vivo and in vitro studies reveal that astrocytes, classically considered supportive cells for neurons, regulate synaptic plasticity in the mouse hippocampus and are directly involved in information storage.

  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. Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Anubhuti Goel

    Full Text Available Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca(2+-permeable AMPA receptors (CP-AMPARs. However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1 subunit at the serine 845 (S845 site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants, which is a substrate of cAMP-dependent kinase (PKA, show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

  5. Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity.

    Science.gov (United States)

    Goel, Anubhuti; Xu, Linda W; Snyder, Kevin P; Song, Lihua; Goenaga-Vazquez, Yamila; Megill, Andrea; Takamiya, Kogo; Huganir, Richard L; Lee, Hey-Kyoung

    2011-03-31

    Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca(2+)-permeable AMPA receptors (CP-AMPARs). However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1) subunit at the serine 845 (S845) site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants), which is a substrate of cAMP-dependent kinase (PKA), show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

  6. Mapping homeostatic synaptic plasticity using cable properties of dendrites.

    Science.gov (United States)

    Queenan, B N; Lee, K J; Tan, H; Huganir, R L; Vicini, S; Pak, D T S

    2016-02-19

    When chronically silenced, cortical and hippocampal neurons homeostatically upregulate excitatory synaptic function. However, the subcellular position of such changes on the dendritic tree is not clear. We exploited the cable-filtering properties of dendrites to derive a parameter, the dendritic filtering index (DFI), to map the spatial distribution of synaptic currents. Our analysis indicates that young rat cortical neurons globally scale AMPA receptor-mediated currents, while mature hippocampal neurons do not, revealing distinct homeostatic strategies between brain regions and developmental stages. The DFI presents a useful tool for mapping the dendritic origin of synaptic currents and the location of synaptic plasticity changes.

  7. Cellular and molecular connections between sleep and synaptic plasticity.

    Science.gov (United States)

    Benington, Joel H; Frank, Marcos G

    2003-02-01

    The hypothesis that sleep promotes learning and memory has long been a subject of active investigation. This hypothesis implies that sleep must facilitate synaptic plasticity in some way, and recent studies have provided evidence for such a function. Our knowledge of both the cellular neurophysiology of sleep states and of the cellular and molecular mechanisms underlying synaptic plasticity has expanded considerably in recent years. In this article, we review findings in these areas and discuss possible mechanisms whereby the neurophysiological processes characteristic of sleep states may serve to facilitate synaptic plasticity. We address this issue first on the cellular level, considering how activation of T-type Ca(2+) channels in nonREM sleep may promote either long-term depression or long-term potentiation, as well as how cellular events of REM sleep may influence these processes. We then consider how synchronization of neuronal activity in thalamocortical and hippocampal-neocortical networks in nonREM sleep and REM sleep could promote differential strengthening of synapses according to the degree to which activity in one neuron is synchronized with activity in other neurons in the network. Rather than advocating one specific cellular hypothesis, we have intentionally taken a broad approach, describing a range of possible mechanisms whereby sleep may facilitate synaptic plasticity on the cellular and/or network levels. We have also provided a general review of evidence for and against the hypothesis that sleep does indeed facilitate learning, memory, and synaptic plasticity.

  8. Synaptic plasticity functions in an organic electrochemical transistor

    Science.gov (United States)

    Gkoupidenis, Paschalis; Schaefer, Nathan; Strakosas, Xenofon; Fairfield, Jessamyn A.; Malliaras, George G.

    2015-12-01

    Synaptic plasticity functions play a crucial role in the transmission of neural signals in the brain. Short-term plasticity is required for the transmission, encoding, and filtering of the neural signal, whereas long-term plasticity establishes more permanent changes in neural microcircuitry and thus underlies memory and learning. The realization of bioinspired circuits that can actually mimic signal processing in the brain demands the reproduction of both short- and long-term aspects of synaptic plasticity in a single device. Here, we demonstrate the implementation of neuromorphic functions similar to biological memory, such as short- to long-term memory transition, in non-volatile organic electrochemical transistors (OECTs). Depending on the training of the OECT, the device displays either short- or long-term plasticity, therefore, exhibiting non von Neumann characteristics with merged processing and storing functionalities. These results are a first step towards the implementation of organic-based neuromorphic circuits.

  9. Circuit reactivation dynamically regulates synaptic plasticity in neocortex

    Science.gov (United States)

    Kruskal, Peter B.; Li, Lucy; Maclean, Jason N.

    2013-10-01

    Circuit reactivations involve a stereotyped sequence of neuronal firing and have been behaviourally linked to memory consolidation. Here we use multiphoton imaging and patch-clamp recording, and observe sparse and stereotyped circuit reactivations that correspond to UP states within active neurons. To evaluate the effect of the circuit on synaptic plasticity, we trigger a single spike-timing-dependent plasticity (STDP) pairing once per circuit reactivation. The pairings reliably fall within a particular epoch of the circuit sequence and result in long-term potentiation. During reactivation, the amplitude of plasticity significantly correlates with the preceding 20-25 ms of membrane depolarization rather than the depolarization at the time of pairing. This circuit-dependent plasticity provides a natural constraint on synaptic potentiation, regulating the inherent instability of STDP in an assembly phase-sequence model. Subthreshold voltage during endogenous circuit reactivations provides a critical informative context for plasticity and facilitates the stable consolidation of a spatiotemporal sequence.

  10. Cross-modal synaptic plasticity in adult primary sensory cortices.

    Science.gov (United States)

    Lee, Hey-Kyoung; Whitt, Jessica L

    2015-12-01

    Sensory loss leads to widespread adaptation of brain circuits to allow an organism to navigate its environment with its remaining senses, which is broadly referred to as cross-modal plasticity. Such adaptation can be observed even in the primary sensory cortices, and falls into two distinct categories: recruitment of the deprived sensory cortex for processing the remaining senses, which we term 'cross-modal recruitment', and experience-dependent refinement of the spared sensory cortices referred to as 'compensatory plasticity.' Here we will review recent studies demonstrating that cortical adaptation to sensory loss involves LTP/LTD and homeostatic synaptic plasticity. Cross-modal synaptic plasticity is observed in adults, hence cross-modal sensory deprivation may be an effective way to promote plasticity in adult primary sensory cortices.

  11. Molecular mechanisms of synaptic plasticity and memory.

    Science.gov (United States)

    Elgersma, Y; Silva, A J

    1999-04-01

    To unravel the molecular and cellular bases of learning and memory is one of the most ambitious goals of modern science. The progress of recent years has not only brought us closer to understanding the molecular mechanisms underlying stable, long-lasting changes in synaptic strength, but it has also provided further evidence that these mechanisms are required for memory formation.

  12. Dysregulated Expression of Neuregulin-1 by Cortical Pyramidal Neurons Disrupts Synaptic Plasticity

    Directory of Open Access Journals (Sweden)

    Amit Agarwal

    2014-08-01

    Full Text Available Neuregulin-1 (NRG1 gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an “optimal” level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect.

  13. Energy Efficient Sparse Connectivity from Imbalanced Synaptic Plasticity Rules.

    Directory of Open Access Journals (Sweden)

    João Sacramento

    2015-06-01

    Full Text Available It is believed that energy efficiency is an important constraint in brain evolution. As synaptic transmission dominates energy consumption, energy can be saved by ensuring that only a few synapses are active. It is therefore likely that the formation of sparse codes and sparse connectivity are fundamental objectives of synaptic plasticity. In this work we study how sparse connectivity can result from a synaptic learning rule of excitatory synapses. Information is maximised when potentiation and depression are balanced according to the mean presynaptic activity level and the resulting fraction of zero-weight synapses is around 50%. However, an imbalance towards depression increases the fraction of zero-weight synapses without significantly affecting performance. We show that imbalanced plasticity corresponds to imposing a regularising constraint on the L1-norm of the synaptic weight vector, a procedure that is well-known to induce sparseness. Imbalanced plasticity is biophysically plausible and leads to more efficient synaptic configurations than a previously suggested approach that prunes synapses after learning. Our framework gives a novel interpretation to the high fraction of silent synapses found in brain regions like the cerebellum.

  14. Formation and maintenance of neuronal assemblies through synaptic plasticity.

    Science.gov (United States)

    Litwin-Kumar, Ashok; Doiron, Brent

    2014-11-14

    The architecture of cortex is flexible, permitting neuronal networks to store recent sensory experiences as specific synaptic connectivity patterns. However, it is unclear how these patterns are maintained in the face of the high spike time variability associated with cortex. Here we demonstrate, using a large-scale cortical network model, that realistic synaptic plasticity rules coupled with homeostatic mechanisms lead to the formation of neuronal assemblies that reflect previously experienced stimuli. Further, reverberation of past evoked states in spontaneous spiking activity stabilizes, rather than erases, this learned architecture. Spontaneous and evoked spiking activity contains a signature of learned assembly structures, leading to testable predictions about the effect of recent sensory experience on spike train statistics. Our work outlines requirements for synaptic plasticity rules capable of modifying spontaneous dynamics and shows that this modification is beneficial for stability of learned network architectures.

  15. Corticosterone alters AMPAR mobility and facilitates bidirectional synaptic plasticity

    NARCIS (Netherlands)

    Martin, S.; Henley, J.M.; Holman, D.; Zhou, M.; Wiegert, O.; van Spronsen, M.; Joëls, M.; Hoogenraad, C.C.; Krugers, H.J.

    2009-01-01

    Background: The stress hormone corticosterone has the ability both to enhance and suppress synaptic plasticity and learning and memory processes. However, until today there is very little known about the molecular mechanism that underlies the bidirectional effects of stress and corticosteroid hormon

  16. Corticosterone alters AMPAR mobility and facilitates bidirectional synaptic plasticity

    NARCIS (Netherlands)

    S. Martin (Stéphane); J.M. Henley (Jeremy); D. Holman (David); M. Zhou (Ming); O. Wiegert (Olof); M. van Spronsena (Myrrhe); M. Joëls (Marian); C.C. Hoogenraad (Casper); H.J. Krugers (Harmen)

    2009-01-01

    textabstractBackground: The stress hormone corticosterone has the ability both to enhance and suppress synaptic plasticity and learning and memory processes. However, until today there is very little known about the molecular mechanism that underlies the bidirectional effects of stress and corticost

  17. Frequency dependent changes in NMDAR-dependent synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Arvind eKumar

    2011-09-01

    Full Text Available The NMDAR-dependent synaptic plasticity is thought to mediate several forms of learning, and can be induced by spike trains containing a small number of spikes occurring with varying rates and timing, as well as with oscillations. We computed the influence of these variables on the plasticity induced at a single NMDAR containing synapse using a reduced model that was analytically tractable, and these findings were confirmed using detailed, multi-compartment model. In addition to explaining diverse experimental results about the rate and timing dependence of synaptic plasticity, the model made several novel and testable predictions. We found that there was a preferred frequency for inducing long-term potentiation (LTP such that higher frequency stimuli induced lesser LTP, decreasing as 1/f when the number of spikes in the stimulus was kept fixed. Among other things, the preferred frequency for inducing LTP varied as a function of the distance of the synapse from the soma. In fact, same stimulation frequencies could induce LTP or LTD depending on the dendritic location of the synapse. Next, we found that rhythmic stimuli induced greater plasticity then irregular stimuli. Furthermore, brief bursts of spikes significantly expanded the timing dependence of plasticity. Finally, we found that in the ~5-15Hz frequency range both rate- and timing-dependent plasticity mechanisms work synergistically to render the synaptic plasticity most sensitive to spike-timing. These findings provide computational evidence that oscillations can have a profound influence on the plasticity of an NMDAR-dependent synapse, and show a novel role for the dendritic morphology in this process.

  18. Stochastic synaptic plasticity with memristor crossbar arrays

    KAUST Repository

    Naous, Rawan

    2016-11-01

    Memristive devices have been shown to exhibit slow and stochastic resistive switching behavior under low-voltage, low-current operating conditions. Here we explore such mechanisms to emulate stochastic plasticity in memristor crossbar synapse arrays. Interfaced with integrate-and-fire spiking neurons, the memristive synapse arrays are capable of implementing stochastic forms of spike-timing dependent plasticity which parallel mean-rate models of stochastic learning with binary synapses. We present theory and experiments with spike-based stochastic learning in memristor crossbar arrays, including simplified modeling as well as detailed physical simulation of memristor stochastic resistive switching characteristics due to voltage and current induced filament formation and collapse. © 2016 IEEE.

  19. Amyloid-β as a modulator of synaptic plasticity.

    Science.gov (United States)

    Parihar, Mordhwaj S; Brewer, Gregory J

    2010-01-01

    Alzheimer's disease is associated with synapse loss, memory dysfunction, and pathological accumulation of amyloid-β (Aβ) in plaques. However, an exclusively pathological role for Aβ is being challenged by new evidence for an essential function of Aβ at the synapse. Aβ protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Aβ is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of Aβ at the synapse. At physiological levels, Aβ is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric Aβ40 and Aβ42 are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of Aβ are associated with synaptic failure and Alzheimer's disease pathology, possibly targeting the N-methyl-D-aspartic acid receptor through the nicotinic acetylcholine receptor, mitochondrial Aβ alcohol dehydrogenase, and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and Aβ independently decrease neuronal plasticity. Our laboratory has reported that Aβ, glutamate, and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein. This review examines the long-awaited functional impact of Aβ on synaptic plasticity.

  20. Neuropsin--a possible modulator of synaptic plasticity.

    Science.gov (United States)

    Shiosaka, Sadao; Ishikawa, Yasuyuki

    2011-09-01

    Accumulating evidence has suggested pivotal roles for neural proteases in development, maturation, aging, and cognitive functions. Among such proteases, neuropsin, a kallikrein gene-related (KLK) endoprotease, appears to have a significant plasticity function that has been analyzed primarily in the hippocampal Schaffer-collateral pathway. In this article, after reviewing the general features of neuropsin, its role in Schaffer-collateral synaptic plasticity is discussed in some detail. Enzymatically active neuropsin is necessary to establish the early phase of long-term potentiation (LTP). This type of LTP, which can be elicited by rather weak tetanic stimulation, is significant in synaptic late association between two independent hippocampal synapses. Neuropsin deficiency completely impaired the early phase of LTP, leading to the absence of late associativity. Associations between early and persistent-LTP synapses may be related to mammalian working memory and consequently integration in learning and memory.

  1. Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity

    OpenAIRE

    2016-01-01

    In the mammalian central nervous system, reactive oxygen species (ROS) generation is counterbalanced by antioxidant defenses. When large amounts of ROS accumulate, antioxidant mechanisms become overwhelmed and oxidative cellular stress may occur. Therefore, ROS are typically characterized as toxic molecules, oxidizing membrane lipids, changing the conformation of proteins, damaging nucleic acids, and causing deficits in synaptic plasticity. High ROS concentrations are associated with a declin...

  2. Coordinated Regulation of Synaptic Plasticity at Striatopallidal and Striatonigral Neurons Orchestrates Motor Control

    Directory of Open Access Journals (Sweden)

    Massimo Trusel

    2015-11-01

    Full Text Available The basal ganglia play a critical role in shaping motor behavior. For this function, the activity of medium spiny neurons (MSNs of the striatonigral and striatopallidal pathways must be integrated. It remains unclear whether the activity of the two pathways is primarily coordinated by synaptic plasticity mechanisms. Using a model of Parkinson’s disease, we determined the circuit and behavioral effects of concurrently regulating cell-type-specific forms of corticostriatal long-term synaptic depression (LTD by inhibiting small-conductance Ca2+-activated K+ channels (SKs of the dorsolateral striatum. At striatopallidal synapses, SK channel inhibition rescued the disease-linked deficits in endocannabinoid (eCB-dependent LTD. At striatonigral cells, inhibition of these channels counteracted a form of adenosine-mediated LTD by activating the ERK cascade. Interfering with eCB-, adenosine-, and ERK signaling in vivo alleviated motor abnormalities, which supports that synaptic modulation of striatal pathways affects behavior. Thus, our results establish a central role of coordinated synaptic plasticity at MSN subpopulations in motor control.

  3. A Model of Bidirectional Synaptic Plasticity: From Signaling Network to Channel Conductance

    Science.gov (United States)

    Castellani, Gastone C.; Quinlan, Elizabeth M.; Bersani, Ferdinando; Cooper, Leon N.; Shouval, Harel Z.

    2005-01-01

    In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of…

  4. The computational power of astrocyte mediated synaptic plasticity.

    Science.gov (United States)

    Min, Rogier; Santello, Mirko; Nevian, Thomas

    2012-01-01

    Research in the last two decades has made clear that astrocytes play a crucial role in the brain beyond their functions in energy metabolism and homeostasis. Many studies have shown that astrocytes can dynamically modulate neuronal excitability and synaptic plasticity, and might participate in higher brain functions like learning and memory. With the plethora of astrocyte mediated signaling processes described in the literature today, the current challenge is to identify, which of these processes happen under what physiological condition, and how this shapes information processing and, ultimately, behavior. To answer these questions will require a combination of advanced physiological, genetical, and behavioral experiments. Additionally, mathematical modeling will prove crucial for testing predictions on the possible functions of astrocytes in neuronal networks, and to generate novel ideas as to how astrocytes can contribute to the complexity of the brain. Here, we aim to provide an outline of how astrocytes can interact with neurons. We do this by reviewing recent experimental literature on astrocyte-neuron interactions, discussing the dynamic effects of astrocytes on neuronal excitability and short- and long-term synaptic plasticity. Finally, we will outline the potential computational functions that astrocyte-neuron interactions can serve in the brain. We will discuss how astrocytes could govern metaplasticity in the brain, how they might organize the clustering of synaptic inputs, and how they could function as memory elements for neuronal activity. We conclude that astrocytes can enhance the computational power of neuronal networks in previously unexpected ways.

  5. Ultradian corticosterone pulses balance glutamatergic transmission and synaptic plasticity.

    Science.gov (United States)

    Sarabdjitsingh, Ratna Angela; Jezequel, Julie; Pasricha, Natasha; Mikasova, Lenka; Kerkhofs, Amber; Karst, Henk; Groc, Laurent; Joëls, Marian

    2014-09-30

    The rodent adrenal hormone corticosterone (CORT) reaches the brain in hourly ultradian pulses, with a steep rise in amplitude before awakening. The impact of a single CORT pulse on glutamatergic transmission is well documented, but it remains poorly understood how consecutive pulses impact on glutamate receptor trafficking and synaptic plasticity. By using high-resolution imaging and electrophysiological approaches, we report that a single pulse of CORT to hippocampal networks causes synaptic enrichment of glutamate receptors and increased responses to spontaneously released glutamatergic vesicles, collectively abrogating the ability to subsequently induce synaptic long-term potentiation. Strikingly, a second pulse of CORT one hour after the first--mimicking ultradian pulses--completely normalizes all aspects of glutamate transmission investigated, restoring the plastic range of the synapse. The effect of the second pulse is precisely timed and depends on a nongenomic glucocorticoid receptor-dependent pathway. This normalizing effect through a sequence of CORT pulses--as seen around awakening--may ensure that hippocampal glutamatergic synapses remain fully responsive and able to encode new stress-related information when daily activities start.

  6. The computational power of astrocyte mediated synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Rogier eMin

    2012-11-01

    Full Text Available Research in the last two decades has made clear that astrocytes play a crucial role in the brain beyond their functions in energy metabolism and homeostasis. Many studies have shown that astrocytes can dynamically modulate neuronal excitability and synaptic plasticity, and might participate in higher brain functions like learning and memory. With the plethora of astrocyte-mediated signaling processes described in the literature today, the current challenge is to identify which of these processes happen under what physiological condition, and how this shapes information processing and, ultimately, behavior. To answer these questions will require a combination of advanced physiological, genetical and behavioral experiments. Additionally, mathematical modeling will prove crucial for testing predictions on the possible functions of astrocytes in neuronal networks, and to generate novel ideas as to how astrocytes can contribute to the complexity of the brain. Here, we aim to provide an outline of how astrocytes can interact with neurons. We do this by reviewing recent experimental literature on astrocyte-neuron interactions, discussing the dynamic effects of astrocytes on neuronal excitability and short- and long-term synaptic plasticity. Finally, we will outline the potential computational functions that astrocyte-neuron interactions can serve in the brain. We will discuss how astrocytes could govern metaplasticity in the brain, how they might organize the clustering of synaptic inputs, and how they could function as memory elements for neuronal activity. We conclude that astrocytes can enhance the computational power of neuronal networks in previously unexpected ways.

  7. Information processing and synaptic plasticity at hippocampal mossy fiber terminals

    Directory of Open Access Journals (Sweden)

    Alesya eEvstratova

    2014-02-01

    Full Text Available Granule cells of the dentate gyrus receive cortical information and they transform and transmit this code to the CA3 area via their axons, the mossy fibers. Structural and functional complexity of this network has been extensively studied at various organizational levels. This review is focused on the anatomical and physiological properties of the mossy fiber system. We will discuss the mechanism by which dentate granule cells process signals from single action potentials, short bursts and longer stimuli. Various parameters of synaptic interactions at different target cells such as quantal transmission, short- and long-term plasticity will be summarized. Different types of synaptic contacts formed by mossy fibers have unique sets of rules for information processing during different rates of granule cell activity. We will investigate the complex interactions between key determinants of information transfer between the dentate gyrus and the CA3 area of the hippocampus.

  8. Prenatal ethanol exposure alters synaptic plasticity in the dorsolateral striatum of rat offspring via changing the reactivity of dopamine receptor.

    Directory of Open Access Journals (Sweden)

    Rong Zhou

    Full Text Available Prenatal exposure to high-level ethanol (EtOH has been reported to produce hyperlocomotion in offspring. Previous studies have demonstrated synaptic plasticity in cortical afferent to the dorsolateral (DL striatum is involved in the pathogensis of hyperlocomotion. Here, prenatal EtOH-exposed rat offspring were used to investigate whether maternal EtOH exposure affected synaptic plasticity in the DL striatum. We found high-frequency stimulation (HFS induced a weaker long-term potentiation (LTP in EtOH rats than that in control rats at postnatal day (PD 15. The same protocol of HFS induced long-term depression (LTD in control group but still LTP in EtOH group at PD 30 or PD 40. Furthermore, enhancement of basal synaptic transmission accompanied by the decrease of pair-pulse facilitation (PPF was observed in PD 30 EtOH offspring. The perfusion with D1-type receptors (D1R antagonist SCH23390 recovered synaptic transmission and blocked the induction of abnormal LTP in PD 30 EtOH offspring. The perfusion with D2-type receptors (D2R agonist quinpirole reversed EtOH-induced LTP into D1R- and metabotropic glutamate receptor-dependent LTD. The data provide the functional evidence that prenatal ethanol exposure led to the persistent abnormal synaptic plasticity in the DL striatum via disturbing the balance between D1R and D2R.

  9. Microglia and Spinal Cord Synaptic Plasticity in Persistent Pain

    Directory of Open Access Journals (Sweden)

    Sarah Taves

    2013-01-01

    Full Text Available Microglia are regarded as macrophages in the central nervous system (CNS and play an important role in neuroinflammation in the CNS. Microglial activation has been strongly implicated in neurodegeneration in the brain. Increasing evidence also suggests an important role of spinal cord microglia in the genesis of persistent pain, by releasing the proinflammatory cytokines tumor necrosis factor-alpha (TNFα, Interleukine-1beta (IL-1β, and brain derived neurotrophic factor (BDNF. In this review, we discuss the recent findings illustrating the importance of microglial mediators in regulating synaptic plasticity of the excitatory and inhibitory pain circuits in the spinal cord, leading to enhanced pain states. Insights into microglial-neuronal interactions in the spinal cord dorsal horn will not only further our understanding of neural plasticity but may also lead to novel therapeutics for chronic pain management.

  10. Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease

    Directory of Open Access Journals (Sweden)

    G. D’Arcangelo

    2016-01-01

    Full Text Available Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1−/− mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1−/− mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1−/− mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia.

  11. Magnesium protects cognitive functions and synaptic plasticity in streptozotocin-induced sporadic Alzheimer's model.

    Directory of Open Access Journals (Sweden)

    Zhi-Peng Xu

    Full Text Available Alzheimer's disease (AD is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP, dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy.

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

    Science.gov (United States)

    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.

  13. In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Harry Pantazopoulos

    2016-01-01

    Full Text Available Rapidly emerging evidence implicates perineuronal nets (PNNs and extracellular matrix (ECM molecules that compose or interact with PNNs, in the pathophysiology of several psychiatric disorders. Studies on schizophrenia, autism spectrum disorders, mood disorders, Alzheimer’s disease, and epilepsy point to the involvement of ECM molecules such as chondroitin sulfate proteoglycans, Reelin, and matrix metalloproteases, as well as their cell surface receptors. In many of these disorders, PNN abnormalities have also been reported. In the context of the “quadripartite” synapse concept, that is, the functional unit composed of the pre- and postsynaptic terminals, glial processes, and ECM, and of the role that PNNs and ECM molecules play in regulating synaptic functions and plasticity, these findings resonate with one of the most well-replicated aspects of the pathology of psychiatric disorders, that is, synaptic abnormalities. Here we review the evidence for PNN/ECM-related pathology in these disorders, with particular emphasis on schizophrenia, and discuss the hypothesis that such pathology may significantly contribute to synaptic dysfunction.

  14. Emerging Links between Homeostatic Synaptic Plasticity and Neurological Disease

    Directory of Open Access Journals (Sweden)

    Dion eDickman

    2013-11-01

    Full Text Available Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases.

  15. Emerging links between homeostatic synaptic plasticity and neurological disease.

    Science.gov (United States)

    Wondolowski, Joyce; Dickman, Dion

    2013-11-21

    Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases.

  16. Wnts in adult brain: from synaptic plasticity to cognitive deficiencies

    Science.gov (United States)

    Oliva, Carolina A.; Vargas, Jessica Y.; Inestrosa, Nibaldo C.

    2013-01-01

    During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer’s disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts. PMID:24348327

  17. Astrocytes mediate in vivo cholinergic-induced synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Marta Navarrete

    2012-02-01

    Full Text Available Long-term potentiation (LTP of synaptic transmission represents the cellular basis of learning and memory. Astrocytes have been shown to regulate synaptic transmission and plasticity. However, their involvement in specific physiological processes that induce LTP in vivo remains unknown. Here we show that in vivo cholinergic activity evoked by sensory stimulation or electrical stimulation of the septal nucleus increases Ca²⁺ in hippocampal astrocytes and induces LTP of CA3-CA1 synapses, which requires cholinergic muscarinic (mAChR and metabotropic glutamate receptor (mGluR activation. Stimulation of cholinergic pathways in hippocampal slices evokes astrocyte Ca²⁺ elevations, postsynaptic depolarizations of CA1 pyramidal neurons, and LTP of transmitter release at single CA3-CA1 synapses. Like in vivo, these effects are mediated by mAChRs, and this cholinergic-induced LTP (c-LTP also involves mGluR activation. Astrocyte Ca²⁺ elevations and LTP are absent in IP₃R2 knock-out mice. Downregulating astrocyte Ca²⁺ signal by loading astrocytes with BAPTA or GDPβS also prevents LTP, which is restored by simultaneous astrocyte Ca²⁺ uncaging and postsynaptic depolarization. Therefore, cholinergic-induced LTP requires astrocyte Ca²⁺ elevations, which stimulate astrocyte glutamate release that activates mGluRs. The cholinergic-induced LTP results from the temporal coincidence of the postsynaptic activity and the astrocyte Ca²⁺ signal simultaneously evoked by cholinergic activity. Therefore, the astrocyte Ca²⁺ signal is necessary for cholinergic-induced synaptic plasticity, indicating that astrocytes are directly involved in brain storage information.

  18. Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity.

    Science.gov (United States)

    Erion, Joanna R; Wosiski-Kuhn, Marlena; Dey, Aditi; Hao, Shuai; Davis, Catherine L; Pollock, Norman K; Stranahan, Alexis M

    2014-02-12

    Adipose tissue is a known source of proinflammatory cytokines in obese humans and animal models, including the db/db mouse, in which obesity arises as a result of leptin receptor insensitivity. Inflammatory cytokines induce cognitive deficits across numerous conditions, but no studies have determined whether obesity-induced inflammation mediates synaptic dysfunction. To address this question, we used a treadmill training paradigm in which mice were exposed to daily training sessions or an immobile belt, with motivation achieved by delivery of compressed air on noncompliance. Treadmill training prevented hippocampal microgliosis, abolished expression of microglial activation markers, and also blocked the functional sensitization observed in isolated cells after ex vivo exposure to lipopolysaccharide. Reduced microglial reactivity with exercise was associated with reinstatement of hippocampus-dependent memory, reversal of deficits in long-term potentiation, and normalization of hippocampal dendritic spine density. Because treadmill training evokes broad responses not limited to the immune system, we next assessed whether directly manipulating adiposity through lipectomy and fat transplantation influences inflammation, cognition, and synaptic plasticity. Lipectomy prevents and fat transplantation promotes systemic and central inflammation, with associated alterations in cognitive and synaptic function. Levels of interleukin 1β (IL1β) emerged as a correlate of adiposity and cognitive impairment across both the treadmill and lipectomy studies, so we manipulated hippocampal IL1 signaling using intrahippocampal delivery of IL1 receptor antagonist (IL1ra). Intrahippocampal IL1ra prevented synaptic dysfunction, proinflammatory priming, and cognitive impairment. This pattern supports a central role for IL1-mediated neuroinflammation as a mechanism for cognitive deficits in obesity and diabetes.

  19. Presynaptic active zone density during development and synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Gwenaëlle L Clarke

    2012-02-01

    Full Text Available Neural circuits transmit information through synapses, and the efficiency of synaptic transmission is closely related to the density of presynaptic active zones, where synaptic vesicles are released. The goal of this review is to highlight recent insights into the molecular mechanisms that control the number of active zones per presynaptic terminal (active zone density during developmental and stimulus-dependent changes in synaptic efficacy. At the neuromuscular junctions (NMJs, the active zone density is preserved across species, remains constant during development, and is the same between synapses with different activities. However, the NMJ active zones are not always stable, as exemplified by the change in active zone density during acute experimental manipulation or as a result of aging. Therefore, a mechanism must exist to maintain its density. In the central nervous system (CNS, active zones have restricted maximal size, exist in multiple numbers in larger presynaptic terminals, and maintain a constant density during development. These findings suggest that active zone density in the CNS is also controlled. However, in contrast to the NMJ, active zone density in the CNS can also be increased, as observed in hippocampal synapses in response to synaptic plasticity. Although the numbers of known active zone proteins and protein interactions have increased, less is known about the mechanism that controls the number or spacing of active zones. The following molecules are known to control active zone density and will be discussed herein: extracellular matrix laminins and voltage-dependent calcium channels, amyloid precursor proteins, the small GTPase Rab3, an endocytosis mechanism including synaptojanin, cytoskeleton protein spectrins and β-adducin, and a presynaptic web including spectrins. The molecular mechanisms that organize the active zone density are just beginning to be elucidated.

  20. The Role of Short Term Synaptic Plasticity in Temporal Coding of Neuronal Networks

    Science.gov (United States)

    Chandrasekaran, Lakshmi

    2008-01-01

    Short term synaptic plasticity is a phenomenon which is commonly found in the central nervous system. It could contribute to functions of signal processing namely, temporal integration and coincidence detection by modulating the input synaptic strength. This dissertation has two parts. First, we study the effects of short term synaptic plasticity…

  1. Plasticity and mTOR: Towards Restoration of Impaired Synaptic Plasticity in mTOR-Related Neurogenetic Disorders

    Directory of Open Access Journals (Sweden)

    Tanjala T. Gipson

    2012-01-01

    Full Text Available Objective. To review the recent literature on the clinical features, genetic mutations, neurobiology associated with dysregulation of mTOR (mammalian target of rapamycin, and clinical trials for tuberous sclerosis complex (TSC, neurofibromatosis-1 (NF1 and fragile X syndrome (FXS, and phosphatase and tensin homolog hamartoma syndromes (PTHS, which are neurogenetic disorders associated with abnormalities in synaptic plasticity and mTOR signaling. Methods. Pubmed and Clinicaltrials.gov were searched using specific search strategies. Results/Conclusions. Although traditionally thought of as irreversible disorders, significant scientific progress has been made in both humans and preclinical models to understand how pathologic features of these neurogenetic disorders can be reduced or reversed. This paper revealed significant similarities among the conditions. Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features—autism, intellectual disability, cutaneous lesions, and tumors. Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well.

  2. Reelin Supplementation Enhances Cognitive Ability, Synaptic Plasticity, and Dendritic Spine Density

    Science.gov (United States)

    Rogers, Justin T.; Rusiana, Ian; Trotter, Justin; Zhao, Lisa; Donaldson, Erika; Pak, Daniel T.S.; Babus, Lenard W.; Peters, Melinda; Banko, Jessica L.; Chavis, Pascale; Rebeck, G. William; Hoe, Hyang-Sook; Weeber, Edwin J.

    2011-01-01

    Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive…

  3. Histone Deacetylase Inhibition Facilitates Massed Pattern-Induced Synaptic Plasticity and Memory

    Science.gov (United States)

    Pandey, Kiran; Sharma, Kaushik P.; Sharma, Shiv K.

    2015-01-01

    Massed training is less effective for long-term memory formation than the spaced training. The role of acetylation in synaptic plasticity and memory is now well established. However, the role of this important protein modification in synaptic plasticity induced by massed pattern of stimulation or memory induced by massed training is not well…

  4. Endocannabinoid system and synaptic plasticity: implications for emotional responses.

    Science.gov (United States)

    Viveros, María-Paz; Marco, Eva-María; Llorente, Ricardo; López-Gallardo, Meritxell

    2007-01-01

    The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long-term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms.

  5. Endocannabinoid System and Synaptic Plasticity: Implications for Emotional Responses

    Directory of Open Access Journals (Sweden)

    María-Paz Viveros

    2007-01-01

    Full Text Available The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long- term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms.

  6. Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism.

    Science.gov (United States)

    Takeuchi, Koichi; Gertner, Michael J; Zhou, Jing; Parada, Luis F; Bennett, Michael V L; Zukin, R Suzanne

    2013-03-19

    The phosphoinositide signaling system is a crucial regulator of neural development, cell survival, and plasticity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates phosphatidylinositol 3-kinase signaling and downstream targets. Nse-Cre Pten conditional knockout mice, in which Pten is ablated in granule cells of the dentate gyrus and pyramidal neurons of the hippocampal CA3, but not CA1, recapitulate many of the symptoms of humans with inactivating PTEN mutations, including progressive hypertrophy of the dentate gyrus and deficits in hippocampus-based social and cognitive behaviors. However, the impact of Pten loss on activity-dependent synaptic plasticity in this clinically relevant mouse model of Pten inactivation remains unclear. Here, we show that two phosphatidylinositol 3-kinase- and protein synthesis-dependent forms of synaptic plasticity, theta burst-induced long-term potentiation and metabotropic glutamate receptor (mGluR)-dependent long-term depression, are dysregulated at medial perforant path-to-dentate gyrus synapses of young Nse-Cre Pten conditional knockout mice before the onset of visible morphological abnormalities. In contrast, long-term potentiation and mGluR-dependent long-term depression are normal at CA3-CA1 pyramidal cell synapses at this age. Our results reveal that deletion of Pten in dentate granule cells dysregulates synaptic plasticity, a defect that may underlie abnormal social and cognitive behaviors observed in humans with Pten inactivating mutations and potentially other autism spectrum disorders.

  7. Adenosine gates synaptic plasticity at hippocampal mossy fiber synapses

    Science.gov (United States)

    Moore, Kimberly A.; Nicoll, Roger A.; Schmitz, Dietmar

    2003-11-01

    The release properties of synapses in the central nervous system vary greatly, not only across anatomically distinct types of synapses but also among the same class of synapse. This variation manifests itself in large part by differences in the probability of transmitter release, which affects such activity-dependent presynaptic forms of plasticity as paired-pulse facilitation and frequency facilitation. This heterogeneity in presynaptic function reflects differences in the intrinsic properties of the synaptic terminal and the activation of presynaptic neurotransmitter receptors. Here we show that the unique presynaptic properties of the hippocampal mossy fiber synapse are largely imparted onto the synapse by the continuous local action of extracellular adenosine at presynaptic A1 adenosine receptors, which maintains a low basal probability of transmitter release.

  8. Traumatic brain injury impairs synaptic plasticity in hippocampus in rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Bao-liang; CHEN Xin; TAN Tao; YANG Zhuo; CARLOS Dayao; JIANG Rong-cai; ZHANG Jian-ning

    2011-01-01

    Background Traumatic brain injury (TBl) often causes cognitive deficits and remote symptomatic epilepsy.Hippocampal regional excitability is associated with the cognitive function. However, little is known about injury-induced neuronal loss and subsequent alterations of hippocampal regional excitability. The present study was designed to determine whether TBl may impair the cellular circuit in the hippocampus.Methods Forty male Wistar rats were randomized into control (n=20) and TBl groups (n=20). Long-term potentiation,extracellular input/output curves, and hippocampal parvalbumin-immunoreactive and cholecystokinin-immunoreactive interneurons were compared between the two groups.Results TBI resulted in a significantly increased excitability in the dentate gyrus (DG), but a significantly decreased excitability in the cornu ammonis 1 (CA1) area. Using design-based stereological injury procedures, we induced interneuronal loss in the DG and CA3 subregions in the hippocampus, but not in the CA1 area.Conclusions TBl leads to the impairment of hippocampus synaptic plasticity due to the changing of interneuronal interaction. The injury-induced disruption of synaptic efficacy within the hippocampal circuit may underlie the observed cognitive deficits and symptomatic epilepsy.

  9. Pannexin1 stabilizes synaptic plasticity and is needed for learning.

    Directory of Open Access Journals (Sweden)

    Nora Prochnow

    Full Text Available Pannexin 1 (Panx1 represents a class of vertebrate membrane channels, bearing significant sequence homology with the invertebrate gap junction proteins, the innexins and more distant similarities in the membrane topologies and pharmacological sensitivities with gap junction proteins of the connexin family. In the nervous system, cooperation among pannexin channels, adenosine receptors, and K(ATP channels modulating neuronal excitability via ATP and adenosine has been recognized, but little is known about the significance in vivo. However, the localization of Panx1 at postsynaptic sites in hippocampal neurons and astrocytes in close proximity together with the fundamental role of ATP and adenosine for CNS metabolism and cell signaling underscore the potential relevance of this channel to synaptic plasticity and higher brain functions. Here, we report increased excitability and potently enhanced early and persistent LTP responses in the CA1 region of acute slice preparations from adult Panx1(-/- mice. Adenosine application and N-methyl-D-aspartate receptor (NMDAR-blocking normalized this phenotype, suggesting that absence of Panx1 causes chronic extracellular ATP/adenosine depletion, thus facilitating postsynaptic NMDAR activation. Compensatory transcriptional up-regulation of metabotropic glutamate receptor 4 (grm4 accompanies these adaptive changes. The physiological modification, promoted by loss of Panx1, led to distinct behavioral alterations, enhancing anxiety and impairing object recognition and spatial learning in Panx1(-/- mice. We conclude that ATP release through Panx1 channels plays a critical role in maintaining synaptic strength and plasticity in CA1 neurons of the adult hippocampus. This result provides the rationale for in-depth analysis of Panx1 function and adenosine based therapies in CNS disorders.

  10. Plasticity resembling spike-timing dependent synaptic plasticity: the evidence in human cortex

    Directory of Open Access Journals (Sweden)

    Florian Müller-Dahlhaus

    2010-07-01

    Full Text Available Spike-timing dependent plasticity (STDP has been studied extensively in a variety of animal models during the past decade but whether it can be studied at the systems level of the human cortex has been a matter of debate. Only recently newly developed non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS have made it possible to induce and assess timing dependent plasticity in conscious human subjects. This review will present a critical synopsis of these experiments, which suggest that several of the principal characteristics and molecular mechanisms of TMS-induced plasticity correspond to those of STDP as studied at a cellular level. TMS combined with a second phasic stimulation modality can induce bidirectional long-lasting changes in the excitability of the stimulated cortex, whose polarity depends on the order of the associated stimulus-evoked events within a critical time window of tens of milliseconds. Pharmacological evidence suggests an NMDA receptor mediated form of synaptic plasticity. Studies in human motor cortex demonstrated that motor learning significantly modulates TMS-induced timing dependent plasticity, and, conversely, may be modulated bidirectionally by prior TMS-induced plasticity, providing circumstantial evidence that long-term potentiation-like mechanisms may be involved in motor learning. In summary, convergent evidence is being accumulated for the contention that it is now possible to induce STDP-like changes in the intact human central nervous system by means of TMS to study and interfere with synaptic plasticity in neural circuits in the context of behaviour such as learning and memory.

  11. Spike-Timing–Dependent Synaptic Plasticity and Synaptic Democracy in Dendrites

    Science.gov (United States)

    Gidon, Albert; Segev, Idan

    2009-01-01

    We explored in a computational study the effect of dendrites on excitatory synapses undergoing spike-timing–dependent plasticity (STDP), using both cylindrical dendritic models and reconstructed dendritic trees. We show that even if the initial strength, gpeak, of distal synapses is augmented in a location independent manner, the efficacy of distal synapses diminishes following STDP and proximal synapses would eventually dominate. Indeed, proximal synapses always win over distal synapses following linear STDP rule, independent of the initial synaptic strength distribution in the dendritic tree. This effect is more pronounced as the dendritic cable length increases but it does not depend on the dendritic branching structure. Adding a small multiplicative component to the linear STDP rule, whereby already strong synapses tend to be less potentiated than depressed (and vice versa for weak synapses) did partially “save” distal synapses from “dying out.” Another successful strategy for balancing the efficacy of distal and proximal synapses following STDP is to increase the upper bound for the synaptic conductance (gmax) with distance from the soma. We conclude by discussing an experiment for assessing which of these possible strategies might actually operate in dendrites. PMID:19357339

  12. Spike-timing-dependent synaptic plasticity and synaptic democracy in dendrites.

    Science.gov (United States)

    Gidon, Albert; Segev, Idan

    2009-06-01

    We explored in a computational study the effect of dendrites on excitatory synapses undergoing spike-timing-dependent plasticity (STDP), using both cylindrical dendritic models and reconstructed dendritic trees. We show that even if the initial strength, g(peak), of distal synapses is augmented in a location independent manner, the efficacy of distal synapses diminishes following STDP and proximal synapses would eventually dominate. Indeed, proximal synapses always win over distal synapses following linear STDP rule, independent of the initial synaptic strength distribution in the dendritic tree. This effect is more pronounced as the dendritic cable length increases but it does not depend on the dendritic branching structure. Adding a small multiplicative component to the linear STDP rule, whereby already strong synapses tend to be less potentiated than depressed (and vice versa for weak synapses) did partially "save" distal synapses from "dying out." Another successful strategy for balancing the efficacy of distal and proximal synapses following STDP is to increase the upper bound for the synaptic conductance (g(max)) with distance from the soma. We conclude by discussing an experiment for assessing which of these possible strategies might actually operate in dendrites.

  13. Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex

    Science.gov (United States)

    Kuhn, Marion; Wolf, Elias; Maier, Jonathan G.; Mainberger, Florian; Feige, Bernd; Schmid, Hanna; Bürklin, Jan; Maywald, Sarah; Mall, Volker; Jung, Nikolai H.; Reis, Janine; Spiegelhalder, Kai; Klöppel, Stefan; Sterr, Annette; Eckert, Anne; Riemann, Dieter; Normann, Claus; Nissen, Christoph

    2016-01-01

    Sleep is ubiquitous in animals and humans, but its function remains to be further determined. The synaptic homeostasis hypothesis of sleep–wake regulation proposes a homeostatic increase in net synaptic strength and cortical excitability along with decreased inducibility of associative synaptic long-term potentiation (LTP) due to saturation after sleep deprivation. Here we use electrophysiological, behavioural and molecular indices to non-invasively study net synaptic strength and LTP-like plasticity in humans after sleep and sleep deprivation. We demonstrate indices of increased net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential and EEG theta activity) and decreased LTP-like plasticity (paired associative stimulation induced change in motor-evoked potential and memory formation) after sleep deprivation. Changes in plasma BDNF are identified as a potential mechanism. Our study indicates that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans. PMID:27551934

  14. Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex.

    Science.gov (United States)

    Kuhn, Marion; Wolf, Elias; Maier, Jonathan G; Mainberger, Florian; Feige, Bernd; Schmid, Hanna; Bürklin, Jan; Maywald, Sarah; Mall, Volker; Jung, Nikolai H; Reis, Janine; Spiegelhalder, Kai; Klöppel, Stefan; Sterr, Annette; Eckert, Anne; Riemann, Dieter; Normann, Claus; Nissen, Christoph

    2016-08-23

    Sleep is ubiquitous in animals and humans, but its function remains to be further determined. The synaptic homeostasis hypothesis of sleep-wake regulation proposes a homeostatic increase in net synaptic strength and cortical excitability along with decreased inducibility of associative synaptic long-term potentiation (LTP) due to saturation after sleep deprivation. Here we use electrophysiological, behavioural and molecular indices to non-invasively study net synaptic strength and LTP-like plasticity in humans after sleep and sleep deprivation. We demonstrate indices of increased net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential and EEG theta activity) and decreased LTP-like plasticity (paired associative stimulation induced change in motor-evoked potential and memory formation) after sleep deprivation. Changes in plasma BDNF are identified as a potential mechanism. Our study indicates that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans.

  15. Fructose consumption reduces hippocampal synaptic plasticity underlying cognitive performance

    Science.gov (United States)

    Cisternas, Pedro; Salazar, Paulina; Serrano, Felipe G.; Montecinos-Oliva, Carla; Arredondo, Sebastián B.; Varela-Nallar, Lorena; Barja, Salesa; Vio, Carlos P.; Gomez-Pinilla, Fernando; Inestrosa, Nibaldo C.

    2017-01-01

    Metabolic syndrome (MetS) is a global epidemic, which involves a spectrum of metabolic disorders comprising diabetes and obesity. The impact of MetS on the brain is becoming to be a concern, however, the poor understanding of mechanisms involved has limited the development of therapeutic strategies. We induced a MetS-like condition by exposing mice to fructose feeding for 7 weeks. There was a dramatic deterioration in the capacity of the hippocampus to sustain synaptic plasticity in the forms of long-term potentiation (LTP) and long-term depression (LTD). Mice exposed to fructose showed a reduction in the number of contact zones and the size of postsynaptic densities (PSDs) in the hippocampus, as well as a decrease in hippocampal neurogenesis. There was an increase in lipid peroxidation likely associated with a deficiency in plasma membrane excitability. Consistent with an overall hippocampal dysfunction, there was a subsequent decrease in hippocampal dependent learning and memory performance, i.e., spatial learning and episodic memory. Most of the pathological sequel of MetS in the brain was reversed three month after discontinue fructose feeding. These results are novel to show that MetS triggers a cascade of molecular events, which disrupt hippocampal functional plasticity, and specific aspects of learning and memory function. The overall information raises concerns about the risk imposed by excessive fructose consumption on the pathology of neurological disorders. PMID:26300486

  16. Abnormal Changes of Synaptic Excitability in Migraine with Aura

    DEFF Research Database (Denmark)

    Siniatchkin, Michael; Sendacki, Mascha; Moeller, Friederike

    2012-01-01

    Migraine patients are characterized by altered cortical excitability and information processing between attacks. The relationship between these abnormalities is still poorly understood. In this study, visual evoked potentials (VEP) and proton magnetic resonance spectroscopy were recorded simultan...

  17. Cross-talk induces bifurcations in nonlinear models of synaptic plasticity.

    Science.gov (United States)

    Elliott, Terry

    2012-02-01

    Linear models of synaptic plasticity provide a useful starting-point for examining the dynamics of neuronal development and learning, but their inherent problems are well known. Models of synaptic plasticity that embrace the demands of biological realism are therefore typically nonlinear. Viewed from a more abstract perspective, nonlinear models of synaptic plasticity are a subset of nonlinear dynamical systems. As such, they may therefore exhibit bifurcations under the variation of control parameters, including noise and errors in synaptic updates. One source of noise or error is the cross-talk that occurs during otherwise Hebbian plasticity. Under cross-talk, stimulation of a set of synapses can induce or modify plasticity in adjacent, unstimulated synapses. Here, we analyze two nonlinear models of developmental synaptic plasticity and a model of independent component analysis in the presence of a simple model of cross-talk. We show that cross-talk does indeed induce bifurcations in these models, entirely destroying their ability to acquire either developmentally or learning-related patterns of fixed points. Importantly, the critical level of cross-talk required to induce bifurcations in these models is very sensitive to the statistics of the afferents' activities and the number of afferents synapsing on a postsynaptic cell. In particular, the critical level can be made arbitrarily small. Because bifurcations are inevitable in nonlinear models, our results likely apply to many nonlinear models of synaptic plasticity, although the precise details vary by model. Hence, many nonlinear models of synaptic plasticity are potentially fatally compromised by the toxic influence of cross-talk and other sources of noise and errors more generally. We conclude by arguing that biologically realistic models of synaptic plasticity must be robust against noise-induced bifurcations and that biological systems may have evolved strategies to circumvent their possible dangers.

  18. Effects of changes in glucose concentration on synaptic plasticity in hippocampal slices

    NARCIS (Netherlands)

    Gispen, W.H.; Kamal, A.; Spoelstra, K.; Biessels, G.J.; Urban, I.J.A.

    1999-01-01

    The effects of a low or high concentration of glucose in the perfusion medium on synaptic activity and plasticity were studied in hippocampal slices from rats. Low-glucose medium depressed the field excitatory post-synaptic potentials (fEPSP) significantly, whereas high-glucose medium had little eff

  19. 5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders

    OpenAIRE

    Lucia eCiranna; Maria Vincenza Catania

    2014-01-01

    Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT trans...

  20. Synaptic plasticity, AMPA-R trafficking, and Ras-MAPK signaling

    Institute of Scientific and Technical Information of China (English)

    Yun GU; Ruth L STORNETTA

    2007-01-01

    Synaptic modification of transmission is a general phenomenon expressed at al-most every excitatory synapse in the mammalian brain. Over the last three decades,much has been discovered about the cellular, synaptic, molecular, and signalingmechanisms responsible for controlling synaptic transmission and plasticity. Here,we present a brief review of these mechanisms with emphasis on the currentunderstanding of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid recep-tor (AMPA-R) trafficking and Ras-mitogen-activated protein kinase (MAPK)signaling events involved in controlling synaptic transmission.

  1. Bidirectional Synaptic Structural Plasticity after Chronic Cocaine Administration Occurs through Rap1 Small GTPase Signaling.

    Science.gov (United States)

    Cahill, Michael E; Bagot, Rosemary C; Gancarz, Amy M; Walker, Deena M; Sun, HaoSheng; Wang, Zi-Jun; Heller, Elizabeth A; Feng, Jian; Kennedy, Pamela J; Koo, Ja Wook; Cates, Hannah M; Neve, Rachael L; Shen, Li; Dietz, David M; Nestler, Eric J

    2016-02-03

    Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a primary brain reward region, are seen at early versus late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce "metaplasticity" in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner.

  2. Interplay of multiple synaptic plasticity features in filamentary memristive devices for neuromorphic computing

    Science.gov (United States)

    La Barbera, Selina; Vincent, Adrien F.; Vuillaume, Dominique; Querlioz, Damien; Alibart, Fabien

    2016-12-01

    Bio-inspired computing represents today a major challenge at different levels ranging from material science for the design of innovative devices and circuits to computer science for the understanding of the key features required for processing of natural data. In this paper, we propose a detail analysis of resistive switching dynamics in electrochemical metallization cells for synaptic plasticity implementation. We show how filament stability associated to joule effect during switching can be used to emulate key synaptic features such as short term to long term plasticity transition and spike timing dependent plasticity. Furthermore, an interplay between these different synaptic features is demonstrated for object motion detection in a spike-based neuromorphic circuit. System level simulation presents robust learning and promising synaptic operation paving the way to complex bio-inspired computing systems composed of innovative memory devices.

  3. Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

    Science.gov (United States)

    Tan, Ji-Wei; Duan, Ting-Ting; Zhou, Qi-Xin; Ding, Ze-Yang; Jing, Liang; Cao, Jun; Wang, Li-Ping; Mao, Rong-Rong; Xu, Lin

    2015-07-01

    Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood.

  4. Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine

    Science.gov (United States)

    Martella, Giuseppina; Tassone, Annalisa; Sciamanna, Giuseppe; Platania, Paola; Cuomo, Dario; Viscomi, Maria Teresa; Bonsi, Paola; Cacci, Emanuele; Biagioni, Stefano; Usiello, Alessandro; Bernardi, Giorgio; Sharma, Nutan

    2009-01-01

    DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M1 receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M2/M4 receptor knockout mice, in which an increased striatal acetylcholine level has been

  5. A neuromorphic implementation of multiple spike-timing synaptic plasticity rules for large-scale neural networks

    Science.gov (United States)

    Wang, Runchun M.; Hamilton, Tara J.; Tapson, Jonathan C.; van Schaik, André

    2015-01-01

    We present a neuromorphic implementation of multiple synaptic plasticity learning rules, which include both Spike Timing Dependent Plasticity (STDP) and Spike Timing Dependent Delay Plasticity (STDDP). We present a fully digital implementation as well as a mixed-signal implementation, both of which use a novel dynamic-assignment time-multiplexing approach and support up to 226 (64M) synaptic plasticity elements. Rather than implementing dedicated synapses for particular types of synaptic plasticity, we implemented a more generic synaptic plasticity adaptor array that is separate from the neurons in the neural network. Each adaptor performs synaptic plasticity according to the arrival times of the pre- and post-synaptic spikes assigned to it, and sends out a weighted or delayed pre-synaptic spike to the post-synaptic neuron in the neural network. This strategy provides great flexibility for building complex large-scale neural networks, as a neural network can be configured for multiple synaptic plasticity rules without changing its structure. We validate the proposed neuromorphic implementations with measurement results and illustrate that the circuits are capable of performing both STDP and STDDP. We argue that it is practical to scale the work presented here up to 236 (64G) synaptic adaptors on a current high-end FPGA platform. PMID:26041985

  6. A neuromorphic implementation of multiple spike-timing synaptic plasticity rules for large-scale neural networks.

    Science.gov (United States)

    Wang, Runchun M; Hamilton, Tara J; Tapson, Jonathan C; van Schaik, André

    2015-01-01

    We present a neuromorphic implementation of multiple synaptic plasticity learning rules, which include both Spike Timing Dependent Plasticity (STDP) and Spike Timing Dependent Delay Plasticity (STDDP). We present a fully digital implementation as well as a mixed-signal implementation, both of which use a novel dynamic-assignment time-multiplexing approach and support up to 2(26) (64M) synaptic plasticity elements. Rather than implementing dedicated synapses for particular types of synaptic plasticity, we implemented a more generic synaptic plasticity adaptor array that is separate from the neurons in the neural network. Each adaptor performs synaptic plasticity according to the arrival times of the pre- and post-synaptic spikes assigned to it, and sends out a weighted or delayed pre-synaptic spike to the post-synaptic neuron in the neural network. This strategy provides great flexibility for building complex large-scale neural networks, as a neural network can be configured for multiple synaptic plasticity rules without changing its structure. We validate the proposed neuromorphic implementations with measurement results and illustrate that the circuits are capable of performing both STDP and STDDP. We argue that it is practical to scale the work presented here up to 2(36) (64G) synaptic adaptors on a current high-end FPGA platform.

  7. Downregulation of caveolin-1 contributes to the synaptic plasticity deficit in the hippocampus of aged rats*******

    Institute of Scientific and Technical Information of China (English)

    Yang Liu; Zhanhua Liang; Jing Liu; Wei Zou; Xiaoyan Li; Yachen Wang; Lijia An

    2013-01-01

    Caveolin-1 is involved in the regulation of synaptic plasticity, but the relationship between its pression and cognitive function during aging remains controversial. To explore the relationship be-tween synaptic plasticity in the aging process and changes in learning and memory, we examined caveolin-1 expression in the hippocampus, cortex and cerebel um of rats at different ages. We also examined the relationship between the expression of caveolin-1 and synaptophysin, a marker of synaptic plasticity. Hippocampal caveolin-1 and synaptophysin expression in aged (22-24 month old) rats was significantly lower than that in young (1 month old) and adult (4 months old) rats. pression levels of both proteins were significantly greater in the cortex of aged rats than in that of young or adult rats, and levels were similar between the three age groups in the cerebel um. Linear regression analysis revealed that hippocampal expression of synaptophysin was associated with memory and learning abilities. Moreover, synaptophysin expression correlated positively with caveolin-1 expression in the hippocampus, cortex and cerebel um. These results confirm that caveolin-1 has a regulatory effect on synaptic plasticity, and suggest that the downregulation of hippocampal caveolin-1 expression causes a decrease in synaptic plasticity during physiological aging.

  8. Plasticity of inhibitory synaptic network interactions in the lateral amygdala upon fear conditioning in mice.

    Science.gov (United States)

    Szinyei, Csaba; Narayanan, Rajeevan T; Pape, Hans-Christian

    2007-02-01

    After fear conditioning, plastic changes of excitatory synaptic transmission occur in the amygdala. Fear-related memory also involves the GABAergic system, although no influence on inhibitory synaptic transmission is known. In the present study we assessed the influence of Pavlovian fear conditioning on the plasticity of GABAergic synaptic interactions in the lateral amygdala (LA) in brain slices prepared from fear-conditioned, pseudo-trained and naïve adult mice. Theta-burst tetanization of thalamic afferent inputs to the LA evoked an input-specific potentiation of inhibitory postsynaptic responses in projection neurons; the cortical input was unaffected. Philanthotoxin (10 microM), an antagonist of Ca2+-permeable AMPA receptors, disabled this plastic phenomenon. Surgical isolation of the LA, extracellular application of a GABA(B) receptor antagonist (CGP 55845A, 10 microM) or an NMDA receptor antagonist (APV, 50 microM), or intracellular application of BAPTA (10 mM), did not influence the plasticity. The plasticity also showed as a potentiation of monosynaptic excitatory responses in putative GABAergic interneurons. Pavlovian fear conditioning, but not pseudo-conditioning, resulted in a significant reduction in this potentiation that was evident 24 h after training. Two weeks after training, the potentiation returned to control levels. In conclusion, a reduction in potentiation of inhibitory synaptic interactions occurs in the LA and may contribute to a shift in synaptic balance towards excitatory signal flow during the processes of fear-memory acquisition or consolidation.

  9. Altered synaptic plasticity in Tourette's syndrome and its relationship to motor skill learning.

    Directory of Open Access Journals (Sweden)

    Valerie Cathérine Brandt

    Full Text Available Gilles de la Tourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics that can be considered motor responses to preceding inner urges. It has been shown that Tourette patients have inferior performance in some motor learning tasks and reduced synaptic plasticity induced by transcranial magnetic stimulation. However, it has not been investigated whether altered synaptic plasticity is directly linked to impaired motor skill acquisition in Tourette patients. In this study, cortical plasticity was assessed by measuring motor-evoked potentials before and after paired associative stimulation in 14 Tourette patients (13 male; age 18-39 and 15 healthy controls (12 male; age 18-33. Tic and urge severity were assessed using the Yale Global Tic Severity Scale and the Premonitory Urges for Tics Scale. Motor learning was assessed 45 minutes after inducing synaptic plasticity and 9 months later, using the rotary pursuit task. On average, long-term potentiation-like effects in response to the paired associative stimulation were present in healthy controls but not in patients. In Tourette patients, long-term potentiation-like effects were associated with more and long-term depression-like effects with less severe urges and tics. While motor learning did not differ between patients and healthy controls 45 minutes after inducing synaptic plasticity, the learning curve of the healthy controls started at a significantly higher level than the Tourette patients' 9 months later. Induced synaptic plasticity correlated positively with motor skills in healthy controls 9 months later. The present study confirms previously found long-term improvement in motor performance after paired associative stimulation in healthy controls but not in Tourette patients. Tourette patients did not show long-term potentiation in response to PAS and also showed reduced levels of motor skill consolidation after 9 months compared to healthy controls. Moreover

  10. Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Zhang, Hua; Liu, Jie; Sun, Suya; Pchitskaya, Ekaterina; Popugaeva, Elena; Bezprozvanny, Ilya

    2015-01-01

    Alzheimer's disease (AD) and aging result in impaired ability to store memories, but the cellular mechanisms responsible for these defects are poorly understood. Presenilin 1 (PS1) mutations are responsible for many early-onset familial AD (FAD) cases. The phenomenon of hippocampal long-term potentiation (LTP) is widely used in studies of memory formation and storage. Recent data revealed long-term LTP maintenance (L-LTP) is impaired in PS1-M146V knock-in (KI) FAD mice. To understand the basis for this phenomenon, in the present study we analyzed structural synaptic plasticity in hippocampal cultures from wild type (WT) and KI mice. We discovered that exposure to picrotoxin induces formation of mushroom spines in both WT and KI cultures, but the maintenance of mushroom spines is impaired in KI neurons. This maintenance defect can be explained by an abnormal firing pattern during the consolidation phase of structural plasticity in KI neurons. Reduced frequency of neuronal firing in KI neurons is caused by enhanced calcium-induced calcium release (CICR), enhanced activity of calcium-activated potassium channels, and increased afterhyperpolarization. As a result, "consolidation" pattern of neuronal activity converted to "depotentiation" pattern of neuronal activity in KI neurons. Consistent with this model, we demonstrated that pharmacological inhibitors of CICR (dantrolene), of calcium-activated potassium channels (apamin), and of calcium-dependent phosphatase calcineurin (FK506) are able to rescue structural plasticity defects in KI neurons. Furthermore, we demonstrate that incubation with dantrolene or apamin also rescued L-LTP defects in KI hippocampal slices, suggesting a role for a similar mechanism. This proposed mechanism may be responsible for memory defects in AD but also for age-related memory decline.

  11. Pain-related synaptic plasticity in spinal dorsal horn neurons: role of CGRP

    Directory of Open Access Journals (Sweden)

    Willis William D

    2006-09-01

    Full Text Available Abstract Background The synaptic and cellular mechanisms of pain-related central sensitization in the spinal cord are not fully understood yet. Calcitonin gene-related peptide (CGRP has been identified as an important molecule in spinal nociceptive processing and ensuing behavioral responses, but its contribution to synaptic plasticity, cellular mechanisms and site of action in the spinal cord remain to be determined. Here we address the role of CGRP in synaptic plasticity in the spinal dorsal horn in a model of arthritic pain. Results Whole-cell current- and voltage-clamp recordings were made from substantia gelatinosa (SG neurons in spinal cord slices from control rats and arthritic rats (> 6 h postinjection of kaolin/carrageenan into the knee. Monosynaptic excitatory postsynaptic currents (EPSCs were evoked by electrical stimulation of afferents in the dorsal root near the dorsal root entry zone. Neurons in slices from arthritic rats showed increased synaptic transmission and excitability compared to controls. A selective CGRP1 receptor antagonist (CGRP8-37 reversed synaptic plasticity in neurons from arthritic rats but had no significant effect on normal transmission. CGRP facilitated synaptic transmission in the arthritis pain model more strongly than under normal conditions where both facilitatory and inhibitory effects were observed. CGRP also increased neuronal excitability. Miniature EPSC analysis suggested a post- rather than pre-synaptic mechanism of CGRP action. Conclusion This study is the first to show synaptic plasticity in the spinal dorsal horn in a model of arthritic pain that involves a postsynaptic action of CGRP on SG neurons.

  12. A neuromorphic implementation of multiple spike-timing synaptic plasticity rules for large-scale neural networks

    Directory of Open Access Journals (Sweden)

    Runchun Mark Wang

    2015-05-01

    Full Text Available We present a neuromorphic implementation of multiple synaptic plasticity learning rules, which include both Spike Timing Dependent Plasticity (STDP and Spike Timing Dependent Delay Plasticity (STDDP. We present a fully digital implementation as well as a mixed-signal implementation, both of which use a novel dynamic-assignment time-multiplexing approach and support up to 2^26 (64M synaptic plasticity elements. Rather than implementing dedicated synapses for particular types of synaptic plasticity, we implemented a more generic synaptic plasticity adaptor array that is separate from the neurons in the neural network. Each adaptor performs synaptic plasticity according to the arrival times of the pre- and post-synaptic spikes assigned to it, and sends out a weighted and/or delayed pre-synaptic spike to the target synapse in the neural network. This strategy provides great flexibility for building complex large-scale neural networks, as a neural network can be configured for multiple synaptic plasticity rules without changing its structure. We validate the proposed neuromorphic implementations with measurement results and illustrate that the circuits are capable of performing both STDP and STDDP. We argue that it is practical to scale the work presented here up to 2^36 (64G synaptic adaptors on a current high-end FPGA platform.

  13. NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity.

    Science.gov (United States)

    Carroll, Reed C; Zukin, R Suzanne

    2002-11-01

    Dynamic regulation of synaptic efficacy is thought to play a crucial role in formation of neuronal connections and in experience-dependent modification of neural circuitry. The molecular and cellular mechanisms by which synaptic changes are triggered and expressed are the focus of intense interest. This articles reviews recent evidence that NMDA receptors undergo dynamically regulated targeting and trafficking, and that the physical transport of NMDA receptors in and out of the synaptic membrane contributes to several forms of long-lasting synaptic plasticity. The identification of targeting and internalization sequences in NMDA-receptor subunits has begun the unraveling of some mechanisms that underlie activity-dependent redistribution of NMDA receptors. Given that NMDA receptors are widely expressed throughout the CNS, regulation of NMDA-receptor trafficking provides a potentially important way to modulate efficacy of synaptic transmission.

  14. In vivo BDNF modulation of adult functional and morphological synaptic plasticity at hippocampal mossy fibers.

    Science.gov (United States)

    Gómez-Palacio-Schjetnan, Andrea; Escobar, Martha L

    2008-11-07

    Brain-derived neurotrophic factor (BDNF) has been proposed as a key regulator and mediator of long-term synaptic modifications related to learning and memory maintenance. Our previous studies show that application of high-frequency stimulation (HFS) sufficient to elicit LTP at the dentate gyrus (DG)-CA3 pathway produces mossy fiber structural modifications 7 days after tetanic stimulation. In the present study, we show that acute intrahippocampal microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the DG-CA3 projection of anesthetized adult rats. Furthermore, we show that BDNF functional modifications in synaptic efficacy are accompanied by a presynaptic structural long-lasting reorganization at the hippocampal mossy fiber pathway. These findings support the idea that BDNF plays an important role as synaptic messenger of activity-dependent synaptic plasticity in the adult mammalian brain, in vivo.

  15. Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity.

    Science.gov (United States)

    Edelmann, Elke; Lessmann, Volkmar; Brigadski, Tanja

    2014-01-01

    Overwhelming evidence collected since the early 1990's strongly supports the notion that BDNF is among the key regulators of synaptic plasticity in many areas of the mammalian central nervous system. Still, due to the extremely low expression levels of endogenous BDNF in most brain areas, surprisingly little data i) pinpointing pre- and postsynaptic release sites, ii) unraveling the time course of release, and iii) elucidating the physiological levels of synaptic activity driving this secretion are available. Likewise, our knowledge regarding pre- and postsynaptic effects of endogenous BDNF at the single cell level in mediating long-term potentiation still is sparse. Thus, our review will discuss the data currently available regarding synaptic BDNF secretion in response to physiologically relevant levels of activity, and will discuss how endogenously secreted BDNF affects synaptic plasticity, giving a special focus on spike timing-dependent types of LTP and on mossy fiber LTP. We will attempt to open up perspectives how the remaining challenging questions regarding synaptic BDNF release and action might be addressed by future experiments. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

  16. The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

    Science.gov (United States)

    Aarse, Janna; Herlitze, Stefan

    2016-01-01

    ABSTRACT Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF+/−). We show that whereas early‐LTD (BDNF, short‐term depression (BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF+/− mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF+/− mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus‐dependent memory. © 2015 The Authors

  17. Intracerebroventricular administration of ouabain alters synaptic plasticity and dopamine release in rat medial prefrontal cortex.

    Science.gov (United States)

    Sui, Li; Song, Xiao-Jin; Ren, Jie; Ju, Li-Hua; Wang, Yan

    2013-08-01

    Intracerebroventricular (ICV) administration of ouabain, a specific Na-K-ATPase inhibitor, in rats mimics the manic phenotypes of bipolar disorder and thus has been proposed as one of the best animal models of mania. Bipolar mania has been known to be associated with dysfunctions of medial prefrontal cortex (mPFC), a brain area critically involved in mental functions; however, the exact mechanism underlying these dysfunctions is not yet clear. The present study investigated synaptic transmission, synaptic plasticity, and dopamine release in Sprague-Dawley rat mPFC following ICV administration of ouabain (5 μl of 1 mM ouabain). The electrophysiological results demonstrated that ouabain depressed the short- and the long-term synaptic plasticity, represented by paired-pulse facilitation and long-term potentiation, respectively, in the mPFC. These ouabain-induced alterations in synaptic plasticity can be prevented by pre-treatment with lithium (intraperitoneal injection of 47.5 mg/kg lithium, twice a day, 7 days), which acts as an effective mood stabilizer in preventing mania. The electrochemical results demonstrated that ICV administration of ouabain enhanced dopamine release in the mPFC, which did not be affected by pre-treatment with lithium. These findings suggested that alterations in synaptic plasticity and dopamine release in the mPFC might underlie the dysfunctions of mPFC accompanied with ouabain administration-induced bipolar mania.

  18. Synaptic plasticity in the hippocampal area CA1-subiculum projection: implications for theories of memory.

    Science.gov (United States)

    O'Mara, S M; Commins, S; Anderson, M

    2000-01-01

    This paper reviews investigations of synaptic plasticity in the major, and underexplored, pathway from hippocampal area CA1 to the subiculum. This brain area is the major synaptic relay for the majority of hippocampal area CA1 neurons, making the subiculum the last relay of the hippocampal formation prior to the cortex. The subiculum thus has a very major role in mediating hippocampal-cortical interactions. We demonstrate that the projection from hippocampal area CA1 to the subiculum sustains plasticity on a number of levels. We show that this pathway is capable of undergoing both long-term potentiation (LTP) and paired-pulse facilitation (PPF, a short-term plastic effect). Although we failed to induce long-term depression (LTD) of this pathway with low-frequency stimulation (LFS) and two-pulse stimulation (TPS), both protocols can induce a "late-developing" potentiation of synaptic transmission. We further demonstrate that baseline synaptic transmission can be dissociated from paired-pulse stimulation of the same pathway; we also show that it is possible, using appropriate protocols, to change PPF to paired-pulse depression, thus revealing subtle and previously undescribed mechanisms which regulate short-term synaptic plasticity. Finally, we successfully recorded from individual subicular units in the freely-moving animal, and provide a description of the characteristics of such neurons in a pellet-chasing task. We discuss the implications of these findings in relation to theories of the biological consolidation of memory.

  19. Dynamic Control of Synaptic Adhesion and Organizing Molecules in Synaptic Plasticity

    Energy Technology Data Exchange (ETDEWEB)

    Rudenko, Gabby [Department of Pharmacology and Toxicology, Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, 301 University Boulevard Rm. 5.114B, Galveston, TX 77555, USA

    2017-01-01

    Synapses play a critical role in establishing and maintaining neural circuits, permitting targeted information transfer throughout the brain. A large portfolio of synaptic adhesion/organizing molecules (SAMs) exists in the mammalian brain involved in synapse development and maintenance. SAMs bind protein partners, formingtrans-complexes spanning the synaptic cleft orcis-complexes attached to the same synaptic membrane. SAMs play key roles in cell adhesion and in organizing protein interaction networks; they can also provide mechanisms of recognition, generate scaffolds onto which partners can dock, and likely take part in signaling processes as well. SAMs are regulated through a portfolio of different mechanisms that affect their protein levels, precise localization, stability, and the availability of their partners at synapses. Interaction of SAMs with their partners can further be strengthened or weakened through alternative splicing, competing protein partners, ectodomain shedding, or astrocytically secreted factors. Given that numerous SAMs appear altered by synaptic activity, in vivo, these molecules may be used to dynamically scale up or scale down synaptic communication. Many SAMs, including neurexins, neuroligins, cadherins, and contactins, are now implicated in neuropsychiatric and neurodevelopmental diseases, such as autism spectrum disorder, schizophrenia, and bipolar disorder and studying their molecular mechanisms holds promise for developing novel therapeutics.

  20. Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity

    NARCIS (Netherlands)

    Jaworski, J.; Kapitein, L.C.; Montenegro Gouveia, S.; Dortland, B.R.; Wulf, P.S.; Grigoriev, I.; Camera, P.; Spangler, S.A.; Di Stefano, P.; Demmers, J.; Krugers, H.; Defilippi, P.; Akhmanova, A.; Hoogenraad, C.C.

    2009-01-01

    Dendritic spines are the major sites of excitatory synaptic input, and their morphological changes have been linked to learning and memory processes. Here, we report that growing microtubule plus ends decorated by the microtubule tip-tracking protein EB3 enter spines and can modulate spine morpholog

  1. Late onset deficits in synaptic plasticity in the valproic acid rat model of autism

    Directory of Open Access Journals (Sweden)

    Henry Giles Stratten Martin

    2014-01-01

    Full Text Available Valproic acid (VPA is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP due to an up-regulation of NMDA receptor (NMDAR expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDA receptors during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general.

  2. Hippocampal testosterone relates to reference memory performance and synaptic plasticity in male rats

    Directory of Open Access Journals (Sweden)

    Kristina eSchulz

    2010-12-01

    Full Text Available Steroids are important neuromodulators influencing cognitive performance and synaptic plasticity. While the majority of literature concerns adrenal- and gonadectomized animals, very little is known about the natural endogenous release of hormones during learning. Therefore, we measured blood and brain (hippocampus, prefrontal cortex testosterone, estradiol, and corticosterone concentrations of intact male rats undergoing a spatial learning paradigm which is known to reinforce hippocampal plasticity. We found significant modulations of all investigated hormones over the training course. Corticosterone and testosterone were correlated manifold with behaviour, while estradiol expressed fewer correlations. In the recall session, testosterone was tightly coupled to reference memory performance, which is crucial for reinforcement of synaptic plasticity in the dentate gyrus. Intriguingly, prefrontal cortex and hippocampal levels related differentially to reference memory performance. Correlations of testosterone and corticosterone switched from unspecific activity to specific cognitive functions over training. Correspondingly, exogenous application of testosterone revealed different effects on synaptic and neuronal plasticity in trained versus untrained animals. While hippocampal long-term potentiation (LTP of the field excitatory postsynaptic potential (fEPSP was prolonged in untrained rats, both the fEPSP- and the population spike amplitude-LTP was impaired in trained rats. Behavioural performance was unaffected, but correlations of hippocampal field potentials with behaviour were decoupled in treated rats. The data provide important evidence that besides adrenal, also gonadal steroids play a mechanistic role in linking synaptic plasticity to cognitive performance.

  3. Astroglial calcium signaling displays short-term plasticity and adjusts synaptic efficacy

    Directory of Open Access Journals (Sweden)

    Jeremie eSibille

    2015-05-01

    Full Text Available Astrocytes are dynamic signaling brain elements able to sense neuronal inputs and to respond by complex calcium signals, which are thought to represent their excitability. Such signaling has been proposed to modulate, or not, neuronal activities ranging from basal synaptic transmission to epileptiform discharges. However, whether calcium signaling in astrocytes exhibits activity-dependent changes and acutely modulates short-term synaptic plasticity is currently unclear. We here show, using dual recordings of astroglial calcium signals and synaptic transmission, that calcium signaling in astrocytes displays, concomitantly to excitatory synapses, short-term plasticity in response to prolonged repetitive and tetanic stimulations of Schaffer collaterals. We also found that acute inhibition of calcium signaling in astrocytes by intracellular calcium chelation rapidly potentiates excitatory synaptic transmission and short-term plasticity of Shaffer collateral CA1 synapses, i.e. paired-pulse facilitation and responses to tetanic and prolonged repetitive stimulation. These data reveal that calcium signaling of astrocytes is plastic and down-regulates basal transmission and short-term plasticity of hippocampal CA1 glutamatergic synapses.

  4. Learning Structure of Sensory Inputs with Synaptic Plasticity Leads to Interference

    Directory of Open Access Journals (Sweden)

    Joseph eChrol-Cannon

    2015-08-01

    Full Text Available Synaptic plasticity is often explored as a form of unsupervised adaptationin cortical microcircuits to learn the structure of complex sensoryinputs and thereby improve performance of classification and prediction. The question of whether the specific structure of the input patterns is encoded in the structure of neural networks has been largely neglected. Existing studies that have analyzed input-specific structural adaptation have used simplified, synthetic inputs in contrast to complex and noisy patterns found in real-world sensory data.In this work, input-specific structural changes are analyzed forthree empirically derived models of plasticity applied to three temporal sensory classification tasks that include complex, real-world visual and auditory data. Two forms of spike-timing dependent plasticity (STDP and the Bienenstock-Cooper-Munro (BCM plasticity rule are used to adapt the recurrent network structure during the training process before performance is tested on the pattern recognition tasks.It is shown that synaptic adaptation is highly sensitive to specific classes of input pattern. However, plasticity does not improve the performance on sensory pattern recognition tasks, partly due to synaptic interference between consecutively presented input samples. The changes in synaptic strength produced by one stimulus are reversed by thepresentation of another, thus largely preventing input-specific synaptic changes from being retained in the structure of the network.To solve the problem of interference, we suggest that models of plasticitybe extended to restrict neural activity and synaptic modification to a subset of the neural circuit, which is increasingly found to be the casein experimental neuroscience.

  5. Shp2 in forebrain neurons regulates synaptic plasticity, locomotion, and memory formation in mice.

    Science.gov (United States)

    Kusakari, Shinya; Saitow, Fumihito; Ago, Yukio; Shibasaki, Koji; Sato-Hashimoto, Miho; Matsuzaki, Yasunori; Kotani, Takenori; Murata, Yoji; Hirai, Hirokazu; Matsuda, Toshio; Suzuki, Hidenori; Matozaki, Takashi; Ohnishi, Hiroshi

    2015-05-01

    Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K(+)-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation.

  6. Water maze learning and hippocampal synaptic plasticity in streptozotocin diabetic rats: effects of insulin treatment

    NARCIS (Netherlands)

    Gispen, W.H.; Biessels, G.J.; Kamal, A.; Urban, I.J.A.; Spruijt, B.M.; Erkelens, D.W.

    1998-01-01

    Streptozotocin-diabetic rats express deficits in water maze learning and hippocampal synaptic plasticity. The present study examined whether these deficits could be prevented and/or reversed with insulin treatment. In addition, the water maze learning deficit in diabetic rats was further characteriz

  7. SRC Inhibition Reduces NR2B Surface Expression and Synaptic Plasticity in the Amygdala

    Science.gov (United States)

    Sinai, Laleh; Duffy, Steven; Roder, John C.

    2010-01-01

    The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src…

  8. 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.

  9. The transformation of synaptic to system plasticity in motor output from the sacral cord of the adult mouse.

    Science.gov (United States)

    Jiang, Mingchen C; Elbasiouny, Sherif M; Collins, William F; Heckman, C J

    2015-09-01

    Synaptic plasticity is fundamental in shaping the output of neural networks. The transformation of synaptic plasticity at the cellular level into plasticity at the system level involves multiple factors, including behavior of local networks of interneurons. Here we investigate the synaptic to system transformation for plasticity in motor output in an in vitro preparation of the adult mouse spinal cord. System plasticity was assessed from compound action potentials (APs) in spinal ventral roots, which were generated simultaneously by the axons of many motoneurons (MNs). Synaptic plasticity was assessed from intracellular recordings of MNs. A computer model of the MN pool was used to identify the middle steps in the transformation from synaptic to system behavior. Two input systems that converge on the same MN pool were studied: one sensory and one descending. The two synaptic input systems generated very different motor outputs, with sensory stimulation consistently evoking short-term depression (STD) whereas descending stimulation had bimodal plasticity: STD at low frequencies but short-term facilitation (STF) at high frequencies. Intracellular and pharmacological studies revealed contributions from monosynaptic excitation and stimulus time-locked inhibition but also considerable asynchronous excitation sustained from local network activity. The computer simulations showed that STD in the monosynaptic excitatory input was the primary driver of the system STD in the sensory input whereas network excitation underlies the bimodal plasticity in the descending system. These results provide insight on the roles of plasticity in the monosynaptic and polysynaptic inputs converging on the same MN pool to overall motor plasticity.

  10. Suppression of synaptic plasticity by fullerenol in rat hippocampus in vitro

    Directory of Open Access Journals (Sweden)

    Wang XX

    2016-09-01

    Full Text Available Xin-Xing Wang,1,2,* Ying-Ying Zha,3,* Bo Yang,1 Lin Chen,1,2 Ming Wang1,2 1CAS Key Laboratory of Brain Function and Diseases, 2Auditory Research Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 3Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu, Anhui, People’s Republic of China *These authors contributed equally to this work Abstract: Fullerenol, a water-soluble fullerene derivative, has attracted much attention due to its bioactive properties, including the antioxidative properties and free radical scavenging ability. Due to its superior nature, fullerenol represents a promising diagnostic, therapeutic, and protective agent. Therefore, elucidation of the possible side effects of fullerenol is important in determining its potential role. In the present study, we investigated the acute effects of 5 µM fullerenol on synaptic plasticity in hippocampal brain slices of rats. Incubation with fullerenol for 20 minutes significantly decreased the peak of paired-pulse facilitation and long-term potentiation, indicating that fullerenol suppresses the short- and long-term synaptic plasticity of region I of hippocampus. We found that fullerenol depressed the activity and the expression of nitric oxide (NO synthase in hippocampus. In view of the important role of NO in synaptic plasticity, the inhibition of fullerenol on NO synthase may contribute to the suppression of synaptic plasticity. These findings may facilitate the evaluation of the side effects of fullerenol. Keywords: fullerenol, hippocampal slice, nitric oxide synthase, synaptic plasticity, oxidative stress

  11. Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats.

    Science.gov (United States)

    Ju, Ling-sha; Jia, Min; Sun, Jie; Sun, Xiao-ru; Zhang, Hui; Ji, Mu-huo; Yang, Jian-jun; Wang, Zhong-yun

    2016-02-01

    General anesthetics given to immature rodents cause delayed neurobehavioral abnormalities via incompletely understood mechanisms. DNA methylation, one of the epigenetic modifications, is essential for the modulation of hippocampal synaptic plasticity through regulating the related genes. Therefore, we investigated whether abnormalities in the hippocampal DNA methylation of synaptic plasticity-related genes are involved in neonatal sevoflurane exposure-induced cognitive impairments in rats. Male Sprague-Dawley rats were exposed to 3 % sevoflurane or 30 % oxygen/air for 2 h daily from postnatal day 7 (P7) to P9 and were treated with DNA methyltransferases (DNMTs) inhibitor 5-aza-2-deoxycytidine (5-AZA) or vehicle 1 h before the first sevoflurane exposure on P7. The rats were euthanized 1, 6, 24 h, and 30 days after the last sevoflurane exposure, and the brain tissues were harvested for biochemical analysis. Cognitive functions were evaluated by the open field, fear conditioning, and Morris water maze (MWM) tests on P39, P41-43, and P50-57, respectively. In the present study, repeated neonatal sevoflurane exposure resulted in hippocampus-dependent cognitive impairments as assessed by fear conditioning and MWM tests. The cognitive impairments were associated with the increased DNMTs and hypermethylation of brain-derived neurotrophic factor (BDNF) and Reelin genes, and subsequent down-regulation of BDNF and Reelin genes, which finally led to the decrease of dendritic spines in the hippocampal pyramidal neurons in adolescent rats. Notably, pretreatment with 5-AZA reversed these sevoflurane-induced abnormalities. In conclusion, our results suggest that hypermethylation of hippocampal BDNF and Reelin is involved in neonatal sevoflurane exposure-induced cognitive impairments.

  12. 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'.

  13. Self-organization of a recurrent network under ongoing synaptic plasticity.

    Science.gov (United States)

    Aoki, Takaaki

    2015-02-01

    We investigated the organization of a recurrent network under ongoing synaptic plasticity using a model of neural oscillators coupled by dynamic synapses. In this model, the coupling weights changed dynamically, depending on the timing between the oscillators. We determined the phase coupling function of the oscillator model, Γ(ϕ), using conductance-based neuron models. Furthermore, we examined the effects of the Fourier zero mode of Γ(ϕ), which has a critical role in the case of spike-time-dependent plasticity-organized recurrent networks. Heterogeneous layered clusters with different frequencies emerged from homogeneous populations as the Fourier zero mode increased. Our findings may provide new insights into the self-assembly mechanisms of neural networks related to synaptic plasticity.

  14. p140Cap regulates memory and synaptic plasticity through Src-mediated and citron-N-mediated actin reorganization.

    Science.gov (United States)

    Repetto, Daniele; Camera, Paola; Melani, Riccardo; Morello, Noemi; Russo, Isabella; Calcagno, Eleonora; Tomasoni, Romana; Bianchi, Federico; Berto, Gaia; Giustetto, Maurizio; Berardi, Nicoletta; Pizzorusso, Tommaso; Matteoli, Michela; Di Stefano, Paola; Missler, Markus; Turco, Emilia; Di Cunto, Ferdinando; Defilippi, Paola

    2014-01-22

    A major challenge in the neuroscience field is the identification of molecules and pathways that control synaptic plasticity and memory. Dendritic spines play a pivotal role in these processes, as the major sites of excitatory synapses in neuronal communication. Previous studies have shown that the scaffold protein p140Cap localizes into dendritic spines and that its knockdown negatively modulates spine shape in culture. However, so far, there is no information on its in vivo relevance. By using a knock-out mouse model, we here demonstrate that p140Cap is a key element for both learning and synaptic plasticity. Indeed, p140Cap(-/-) mice are impaired in object recognition test, as well as in LTP and in LTD measurements. The in vivo effects of p140Cap loss are presumably attenuated by noncell-autonomous events, since primary neurons obtained from p140Cap(-/-) mice show a strong reduction in number of mushroom spines and abnormal organization of synapse-associated F-actin. These phenotypes are most likely caused by a local reduction of the inhibitory control of RhoA and of cortactin toward the actin-depolymerizing factor cofilin. These events can be controlled by p140Cap through its capability to directly inhibit the activation of Src kinase and by its binding to the scaffold protein Citron-N. Altogether, our results provide new insight into how protein associated with dynamic microtubules may regulate spine actin organization through interaction with postsynaptic density components.

  15. Activity- and age-dependent GABAergic synaptic plasticity in the developing rat hippocampus.

    Science.gov (United States)

    Gubellini, P; Ben-Ari, Y; Gaïarsa, J L

    2001-12-01

    Activity-dependent plasticity of GABAergic synaptic transmission was investigated in rat hippocampal slices obtained between postnatal day (P) 0-15 using the whole-cell patch-clamp recording technique. Spontaneous GABA(A) receptor-mediated postsynaptic currents (sGABA(A)-PSCs) were isolated in the presence of ionotropic glutamate receptor antagonists. A conditioning protocol relevant to the physiological condition, consisting of repetitive depolarizing pulses (DPs) at 0.1 Hz, was able to induce long-lasting changes in both frequency and amplitude of sGABA(A)-PSCs between P0 and P8. Starting from P12, DPs were unable to induce any form of synaptic plasticity. The effects of DPs were tightly keyed to the frequency at which they were delivered. When delivered at a lower (0.05 Hz) or higher (1 Hz) frequency, DPs failed to induce any long-lasting change in the frequency or amplitude of sGABA(A)-PSCs. In two cases, DPs were able to activate sGABA(A)-PSCs in previously synaptically silent cells at P0-1. These results show that long-term changes in GABAergic synaptic activity can be induced during a restricted period of development by a conditioning protocol relevant to the physiological condition. It is suggested that such activity-induced modifications may represent a physiological mechanism for the functional maturation of GABAergic synaptic transmission.

  16. The Roles of Protein Expression in Synaptic Plasticity and Memory Consolidation

    Directory of Open Access Journals (Sweden)

    Tali eRosenberg

    2014-11-01

    Full Text Available The amount and availability of proteins are regulated by their synthesis, degradation, and transport. These processes can specifically, locally, and temporally regulate a protein or a population of proteins, thus affecting numerous biological processes in health and disease states. Accordingly, malfunction in the processes of protein turnover and localization underlies different neuronal diseases. However, as early as a century ago, it was recognized that there is a specific need for normal macromolecular synthesis in a specific fragment of the learning process, memory consolidation, which takes place minutes to hours following acquisition. Memory consolidation is the process by which fragile short-term memory is converted into stable long-term memory. It is accepted today that synaptic plasticity is a cellular mechanism of learning and memory processes. Interestingly, similar molecular mechanisms subserve both memory and synaptic plasticity consolidation. In this review, we survey the current view on the connection between memory consolidation processes and proteostasis, i.e., maintaining the protein contents at the neuron and the synapse. In addition, we describe the technical obstacles and possible new methods to determine neuronal proteostasis of synaptic function and better explain the process of memory and synaptic plasticity consolidation.

  17. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus.

    Science.gov (United States)

    Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V

    2010-06-30

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

  18. Correlation between synaptic plasticity, associated proteins, and rehabilitation training in a rat model of cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    Dan Yang; Qian Yu

    2008-01-01

    All motions provide sensory, motoric, and reflexive input to the central nervous system, as well as playing an important role in cerebral functional plasticity and compensation. Cerebral plasticity has become the theoretical basis of neurorehabilitation. Studies of cerebrovascular disease, in particular, demonstrate that regeneration is accompanied by multiple forms of plasticity, such as functional and structural, in different phases of stroke rehabilitation. This study was designed to measure synaptic plasticity and expression of associated proteins to analyze the effect of rehabilitation training on learning and memory in a rat model of cerebral infarction. Results suggest that rehabilitation training increases expression of nerve growth factor associated protein 43, brain-derived neurotrophic factor, and neural cell adhesion molecules, and also promotes cerebral functional plasticity.

  19. Learning-facilitated synaptic plasticity occurs in the intermediate hippocampus in association with spatial learning

    Directory of Open Access Journals (Sweden)

    Jana eKenney

    2013-10-01

    Full Text Available The dorsoventral axis of the hippocampus is differentiated into dorsal, intermediate and ventral parts. Whereas the dorsal part is believed to specialize in processing spatial information, the ventral may be equipped to process non-spatial information. The precise role of the intermediate hippocampus is unclear, although recent data suggests it is functionally distinct, at least from the dorsal hippocampus. Learning-facilitated synaptic plasticity describes the ability of hippocampal synapses to respond with robust synaptic plasticity (>24h when a spatial learning event is coupled with afferent stimulation that would normally not lead to a lasting plasticity response: In the dorsal hippocampus novel space facilitates robust expression of LTP, whereas novel spatial content facilitates LTD. We explored whether the intermediate hippocampus engages in this kind of synaptic plasticity in response to novel spatial experience.In freely moving rats, high-frequency stimulation at 200Hz (3 bursts of 15 stimuli elicited synaptic potentiation that lasted for at least 4h. Coupling of this stimulation with the exploration of a novel holeboard resulted in long-term potentiation (LTP that lasted for over 24h. Low frequency afferent stimulation (1Hz, 900 pulses resulted in short-term depression (STD that was significantly enhanced and prolonged by exposure to a novel large orientational (landmark cues, however LTD was not enabled. Exposure to a holeboard that included novel objects in the holeboard holes elicited a transient enhancement of STD of the population spike but not field EPSP, and also failed to facilitate the expression of LTD. Our data suggest that the intermediate dentate gyrus engages in processing of spatial information, but is functionally distinct to the dorsal dentate gyrus. This may in turn reflect their assumed different roles in synaptic information processing and memory formation.

  20. Learning-facilitated synaptic plasticity occurs in the intermediate hippocampus in association with spatial learning

    Science.gov (United States)

    Kenney, Jana; Manahan-Vaughan, Denise

    2013-01-01

    The dorsoventral axis of the hippocampus is differentiated into dorsal, intermediate, and ventral parts. Whereas the dorsal part is believed to specialize in processing spatial information, the ventral may be equipped to process non-spatial information. The precise role of the intermediate hippocampus is unclear, although recent data suggests it is functionally distinct, at least from the dorsal hippocampus. Learning-facilitated synaptic plasticity describes the ability of hippocampal synapses to respond with robust synaptic plasticity (>24 h) when a spatial learning event is coupled with afferent stimulation that would normally not lead to a lasting plasticity response: in the dorsal hippocampus novel space facilitates robust expression of long-term potentiation (LTP), whereas novel spatial content facilitates long-term depression (LTD). We explored whether the intermediate hippocampus engages in this kind of synaptic plasticity in response to novel spatial experience. In freely moving rats, high-frequency stimulation at 200 Hz (3 bursts of 15 stimuli) elicited synaptic potentiation that lasted for at least 4 h. Coupling of this stimulation with the exploration of a novel holeboard resulted in LTP that lasted for over 24 h. Low frequency afferent stimulation (1 Hz, 900 pulses) resulted in short-term depression (STD) that was significantly enhanced and prolonged by exposure to a novel large orientational (landmark) cues, however LTD was not enabled. Exposure to a holeboard that included novel objects in the holeboard holes elicited a transient enhancement of STD of the population spike (PS) but not field EPSP, and also failed to facilitate the expression of LTD. Our data suggest that the intermediate dentate gyrus engages in processing of spatial information, but is functionally distinct to the dorsal dentate gyrus. This may in turn reflect their assumed different roles in synaptic information processing and memory formation. PMID:24194716

  1. Consequences of Inhibiting Amyloid Precursor Protein Processing Enzymes on Synaptic Function and Plasticity

    Directory of Open Access Journals (Sweden)

    Hui Wang

    2012-01-01

    Full Text Available Alzheimer's disease (AD is a neurodegenerative disease, one of whose major pathological hallmarks is the accumulation of amyloid plaques comprised of aggregated β-amyloid (Aβ peptides. It is now recognized that soluble Aβ oligomers may lead to synaptic dysfunctions early in AD pathology preceding plaque deposition. Aβ is produced by a sequential cleavage of amyloid precursor protein (APP by the activity of β- and γ-secretases, which have been identified as major candidate therapeutic targets of AD. This paper focuses on how Aβ alters synaptic function and the functional consequences of inhibiting the activity of the two secretases responsible for Aβ generation. Abnormalities in synaptic function resulting from the absence or inhibition of the Aβ-producing enzymes suggest that Aβ itself may have normal physiological functions which are disrupted by abnormal accumulation of Aβ during AD pathology. This interpretation suggests that AD therapeutics targeting the β- and γ-secretases should be developed to restore normal levels of Aβ or combined with measures to circumvent the associated synaptic dysfunction(s in order to have minimal impact on normal synaptic function.

  2. Synaptic plasticity can produce and enhance direction selectivity.

    Directory of Open Access Journals (Sweden)

    Sean Carver

    2008-02-01

    Full Text Available The discrimination of the direction of movement of sensory images is critical to the control of many animal behaviors. We propose a parsimonious model of motion processing that generates direction selective responses using short-term synaptic depression and can reproduce salient features of direction selectivity found in a population of neurons in the midbrain of the weakly electric fish Eigenmannia virescens. The model achieves direction selectivity with an elementary Reichardt motion detector: information from spatially separated receptive fields converges onto a neuron via dynamically different pathways. In the model, these differences arise from convergence of information through distinct synapses that either exhibit or do not exhibit short-term synaptic depression--short-term depression produces phase-advances relative to nondepressing synapses. Short-term depression is modeled using two state-variables, a fast process with a time constant on the order of tens to hundreds of milliseconds, and a slow process with a time constant on the order of seconds to tens of seconds. These processes correspond to naturally occurring time constants observed at synapses that exhibit short-term depression. Inclusion of the fast process is sufficient for the generation of temporal disparities that are necessary for direction selectivity in the elementary Reichardt circuit. The addition of the slow process can enhance direction selectivity over time for stimuli that are sustained for periods of seconds or more. Transient (i.e., short-duration stimuli do not evoke the slow process and therefore do not elicit enhanced direction selectivity. The addition of a sustained global, synchronous oscillation in the gamma frequency range can, however, drive the slow process and enhance direction selectivity to transient stimuli. This enhancement effect does not, however, occur for all combinations of model parameters. The ratio of depressing and nondepressing synapses

  3. Temporal profiles of synaptic plasticity-related signals in adult mouse hippocampus with methotrexate treatment.

    Science.gov (United States)

    Yang, Miyoung; Kim, Juhwan; Kim, Sung-Ho; Kim, Joong-Sun; Shin, Taekyun; Moon, Changjong

    2012-07-25

    Methotrexate, which is used to treat many malignancies and autoimmune diseases, affects brain functions including hippocampal-dependent memory function. However, the precise mechanisms underlying methotrexate-induced hippocampal dysfunction are poorly understood. To evaluate temporal changes in synaptic plasticity-related signals, the expression and activity of N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, extracellular signal-regulated kinase 1/2, cAMP responsive element-binding protein, glutamate receptor 1, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor were examined in the hippocampi of adult C57BL/6 mice after methotrexate (40 mg/kg) intraperitoneal injection. Western blot analysis showed biphasic changes in synaptic plasticity-related signals in adult hippocampi following methotrexate treatment. N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, and glutamate receptor 1 were acutely activated during the early phase (1 day post-injection), while extracellular signal-regulated kinase 1/2 and cAMP responsive element-binding protein activation showed biphasic increases during the early (1 day post-injection) and late phases (7-14 days post-injection). Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression increased significantly during the late phase (7-14 days post-injection). Therefore, methotrexate treatment affects synaptic plasticity-related signals in the adult mouse hippocampus, suggesting that changes in synaptic plasticity-related signals may be associated with neuronal survival and plasticity-related cellular remodeling.

  4. Temporal profiles of synaptic plasticity-related signals in adult mouse hippocampus with methotrexate treatment

    Institute of Scientific and Technical Information of China (English)

    Miyoung Yang; Juhwan Kim; Sung-Ho Kim; Joong-Sun Kim; Taekyun Shin; Changjong Moon

    2012-01-01

    Methotrexate, which is used to treat many malignancies and autoimmune diseases, affects brain functions including hippocampal-dependent memory function. However, the precise mechanisms underlying methotrexate-induced hippocampal dysfunction are poorly understood. To evaluate temporal changes in synaptic plasticity-related signals, the expression and activity of N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, extracellular signal-regulated kinase 1/2, cAMP responsive element-binding protein, glutamate receptor 1, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor were examined in the hippocampi of adult C57BL/6 mice after methotrexate (40 mg/kg) intraperitoneal injection. Western blot analysis showed biphasic changes in synaptic plasticity-related signals in adult hippocampi following methotrexate treatment. N-methyl-D-aspartic acid receptor 1, cal-cium/calmodulin-dependent protein kinase II, and glutamate receptor 1 were acutely activated dur-ing the early phase (1 day post-injection), while extracellular signal-regulated kinase 1/2 and cAMP responsive element-binding protein activation showed biphasic increases during the early (1 day post-injection) and late phases (7-14 days post-injection). Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression increased significantly during the late phase (7-14 days post-injection). Therefore, methotrexate treatment affects synaptic plasticity-related signals in the adult mouse hippocampus, suggesting that changes in synaptic plasticity-related signals may be associated with neuronal survival and plasticity-related cellular remodeling.

  5. Questions About STDP as a General Model of Synaptic Plasticity

    Directory of Open Access Journals (Sweden)

    John Lisman

    2010-10-01

    Full Text Available According to spike-timing-dependent plasticity (STDP, the timing of the Na+ spike relative to the EPSP determines whether LTP or LTD will occur. Here, we review our reservations about STDP. Most investigations of this process have been done under conditions in which the spike is evoked by postsynaptic current injection. Under more realistic conditions, in which the spike is evoked by the EPSP, the results do not generally support STDP. For instance, low-frequency stimulation of a group of synapses can cause LTD, not the LTP predicted by the pre-before-post sequence in STDP; this is true regardless of whether or not the EPSP is large enough to produce a Na+ spike. With stronger or more frequent stimulation, LTP can be induced by the same pre-before-post timing, but in this case block of Na+ spikes does not necessarily prevent LTP induction. Thus, Na+ spikes may facilitate LTP and/or LTD under some conditions, but they are not necessary, a finding consistent with their small size relative to the EPSP in many parts of pyramidal cell dendrites. The nature of the dendritic depolarizing events that control bidirectional plasticity is of central importance to understanding neural function. There are several candidates, including backpropagating action potentials, but also dendritic Ca2+ spikes, the AMPA receptor-mediated EPSP, and NMDA receptor-mediated EPSPs or spikes. These often appear to be more important than the Na+ spike in providing the depolarization necessary for plasticity. We thus feel that it is premature to accept STDP-like processes as the major determinant of LTP/LTD.

  6. Striatal synaptic dysfunction and hippocampal plasticity deficits in the Hu97/18 mouse model of Huntington disease.

    Directory of Open Access Journals (Sweden)

    Karolina Kolodziejczyk

    Full Text Available Huntington disease (HD is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the gene (HTT encoding the huntingtin protein (HTT. This mutation leads to multiple cellular and synaptic alterations that are mimicked in many current HD animal models. However, the most commonly used, well-characterized HD models do not accurately reproduce the genetics of human disease. Recently, a new 'humanized' mouse model, termed Hu97/18, has been developed that genetically recapitulates human HD, including two human HTT alleles, no mouse Hdh alleles and heterozygosity of the HD mutation. Previously, behavioral and neuropathological testing in Hu97/18 mice revealed many features of HD, yet no electrophysiological measures were employed to investigate possible synaptic alterations. Here, we describe electrophysiological changes in the striatum and hippocampus of the Hu97/18 mice. At 9 months of age, a stage when cognitive deficits are fully developed and motor dysfunction is also evident, Hu97/18 striatal spiny projection neurons (SPNs exhibited small changes in membrane properties and lower amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs; however, release probability from presynaptic terminals was unaltered. Strikingly, these mice also exhibited a profound deficiency in long-term potentiation (LTP at CA3-to-CA1 synapses. In contrast, at 6 months of age we found only subtle alterations in SPN synaptic transmission, while 3-month old animals did not display any electrophysiologically detectable changes in the striatum and CA1 LTP was intact. Together, these data reveal robust, progressive deficits in synaptic function and plasticity in Hu97/18 mice, consistent with previously reported behavioral abnormalities, and suggest an optimal age (9 months for future electrophysiological assessment in preclinical studies of HD.

  7. Abnormal sensorimotor plasticity in migraine without aura patients.

    Science.gov (United States)

    Pierelli, Francesco; Iacovelli, Elisa; Bracaglia, Martina; Serrao, Mariano; Coppola, Gianluca

    2013-09-01

    The period between migraine attacks is characterized by paradoxical responses to repetitive sensory and transcranial magnetic stimulation (TMS). Abnormal long-term cortical functional plasticity may play a role and can be assessed experimentally by paired associative stimulation (PAS), in which somatosensory peripheral nerve stimuli are followed by TMS of the motor cortex. Changes in motor-evoked potential (MEP) amplitudes were recorded in 16 migraine without aura patients (MO) and 15 healthy volunteers (HV) before and after PAS, which consisted of 90 peripheral electrical right ulnar nerve stimulations and subsequent TMS pulses over the first dorsal interosseous (FDI) muscle activation site with a delay of 10 ms (excitability depressing) or 25 ms (excitability enhancing). As a control experiment of the 31 subjects studied, 8 (4 MO and 4 HV) also underwent PAS10 earlier, the recording of somatosensory high-frequency oscillations (HFOs) reflecting thalamocortical activation (early HFOs). Although PAS10 reduced MEP amplitudes in HV (-17.7%), it significantly increased amplitudes in MO (+35.9%). Although in HV MEP amplitudes were significantly potentiated (+55.1) after PAS25, only a slight, nonsignificant increase was observed in MO (+18.8%). In the control experiment, performed on 8 subjects pooled together, Pearson's correlation showed an inverse relationship between the percentage of MEP amplitude changes after PAS10 and early HFO amplitudes (r=-0.81; P=.01). Because we observed that the more deficient the long-term PAS-induced change, the more the thalamocortical activation decreased, we hypothesize that the abnormalities in long-term cortical plasticity observed in the interictal period between migraine episodes could be due to altered thalamic control.

  8. The AAA+ ATPase, Thorase Regulates AMPA Receptor-Dependent Synaptic Plasticity and Behavior

    Science.gov (United States)

    Zhang, Jianmin; Wang, Yue; Chi, Zhikai; Keuss, Matthew J.; Pai, Ying-Min Emily; Kang, Ho Chul; Shin, Jooho; Bugayenko, Artem; Wang, Hong; Xiong, Yulan; Pletnikov, Mikhail V.; Mattson, Mark P.; Dawson, Ted M.; Dawson, Valina L.

    2011-01-01

    SUMMARY The synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the regulation of synaptic activity reflected in the expression of long-term potentiation (LTP) and long-term depression (LTD). The cellular events underlying this important process in learning and memory are still being revealed. Here we describe and characterize the AAA+ ATPase, Thorase, that regulates the expression of surface AMPAR. In an ATPase-dependent manner Thorase mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex. Following genetic deletion of Thorase, the internalization of AMPAR is substantially reduced, leading to increased amplitudes of miniature excitatory postsynaptic currents, enhancement of LTP and elimination of LTD. These molecular events are expressed as deficits in learning and memory in Thorase null mice. This study identifies an AAA+ ATPase that plays a critical role in regulating the surface expression of AMPAR and thereby regulates synaptic plasticity and learning and memory. PMID:21496646

  9. Disturbance in Maternal Environment Leads to Abnormal Synaptic Instability during Neuronal Circuitry Development

    Science.gov (United States)

    Hatanaka, Yusuke; Kabuta, Tomohiro; Wada, Keiji

    2017-01-01

    Adverse maternal environment during gestation and lactation can have negative effects on the developing brain that persist into adulthood and result in behavioral impairment. Recent studies of human and animal models suggest epidemiological and experimental association between disturbances in maternal environments during brain development and the occurrence of neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, anxiety, depression, and neurodegenerative diseases. In this review, we summarize recent advances in understanding the effects of maternal metabolic and hormonal abnormalities on the developing brain by focusing on the dynamics of dendritic spine, an excitatory postsynaptic structure. We discuss the abnormal instability of dendritic spines that is common to developmental disorders and neurological diseases. We also introduce our recent studies that demonstrate how maternal obesity and hyperandrogenism leads to abnormal development of neuronal circuitry and persistent synaptic instability, which results in the loss of synapses. The aim of this review is to highlight the links between abnormal maternal environment, behavioral impairment in offspring, and the dendiric spine pathology of neuropsychiatric disorders.

  10. Hormetic effect of amyloid-beta peptide in hippocampal synaptic plasticity and memory

    Directory of Open Access Journals (Sweden)

    Daniela Puzzo

    2012-09-01

    Full Text Available Background: The term hormesis refers to a biphasic dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition represented by a J-shaped or U-shaped curve, depending on the parameter measured (Calabrese and Baldwin, Hum Exp Toxicol, 2002. Indeed, several, if not all, physiological molecules (i.e. glutamate, glucocorticoids, nitric oxide are likely to present a hormetic effect, exhibiting opposite effects at high or low concentrations. In the last few years, we have focused on amyloid-beta (A, a peptide widely known because it is produced in high amounts during Alzheimer’s disease (AD. A is considered a toxic fragment causing synaptic dysfunction and memory impairment (Selkoe, Science, 2002. However, the peptide is normally produced in the healthy brain and growing evidences indicate that it might have a physiologic function. Aim: Based on previous results showing that picomolar concentrations of A42 enhance synaptic plasticity and memory (Puzzo et al, J Neurosci, 2008 and that endogenous A is necessary for synaptic plasticity and memory (Puzzo et al, Ann Neurol, 2011, the aim of our study was to demonstrate the hormetic role of A in synaptic plasticity and memory. Methods: We used 3-month old wild type mice to analyze how synaptic plasticity, measured on hippocampal slices in vitro, and spatial reference memory were modified by treatment with different doses of A (from 2 pM to 20 μM. Results: We demonstrated that A has a hormetic effect (Puzzo et al, Neurobiol Aging, 2012 with low-doses (200 pM stimulating synaptic plasticity and memory and high-doses (≥ 200 nM inhibiting these processes. Conclusions: Our results suggest that, paradoxically, very low doses of A might serve to enhance memory at appropriate concentrations and conditions. These findings raise several issues when designing

  11. EPO induces changes in synaptic transmission and plasticity in the dentate gyrus of rats.

    Science.gov (United States)

    Almaguer-Melian, William; Mercerón-Martínez, Daymara; Delgado-Ocaña, Susana; Pavón-Fuentes, Nancy; Ledón, Nuris; Bergado, Jorge A

    2016-06-01

    Erythropoietin has shown wide physiological effects on the central nervous system in animal models of disease, and in healthy animals. We have recently shown that systemic EPO administration 15 min, but not 5 h, after daily training in a water maze is able to induce the recovery of spatial memory in fimbria-fornix chronic-lesioned animals, suggesting that acute EPO triggers mechanisms which can modulate the active neural plasticity mechanism involved in spatial memory acquisition in lesioned animals. Additionally, this EPO effect is accompanied by the up-regulation of plasticity-related early genes. More remarkably, this time-dependent effects on learning recovery could signify that EPO in nerve system modulate specific living-cellular processes. In the present article, we focus on the question if EPO could modulate the induction of long-term synaptic plasticity like LTP and LTD, which presumably could support our previous published data. Our results show that acute EPO peripheral administration 15 min before the induction of synaptic plasticity is able to increase the magnitude of the LTP (more prominent in PSA than fEPSP-Slope) to facilitate the induction of LTD, and to protect LTP from depotentiation. These findings showing that EPO modulates in vivo synaptic plasticity sustain the assumption that EPO can act not only as a neuroprotective substance, but is also able to modulate transient neural plasticity mechanisms and therefore to promote the recovery of nerve function after an established chronic brain lesion. According to these results, EPO could be use as a molecular tool for neurorestaurative treatments.

  12. Curcumin improves synaptic plasticity impairment induced by HIV-1gp120 V3 loop

    Institute of Scientific and Technical Information of China (English)

    Ling-ling Shen; Li-juan Yang; Ying Xu; Jun Dong; Ming-liang Jiang; Si-si Liu; Min-chun Cai; Zhong-qiu Hong; Li-qing Lin; Yan-yan Xing; Gui-lin Chen; Rui Pan

    2015-01-01

    Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extra-cellular microelectrode recording techniques, this study conifrmed that the gp120 V3 loop could suppress long-term potentiation in the rat hippocampal CA1 region and synaptic plasticity, and that curcumin could antagonize these inhibitory effects. Using a Fura-2/AM calcium ion probe, we found that curcumin resisted the effects of the gp120 V3 loop on hippocampal synaptosomes and decreased Ca2+concentration in synaptosomes. This effect of curcumin was identical to nimodipine, suggesting that curcumin improved the inhibitory effects of gp120 on synaptic plasticity, ameliorated damage caused to the central nervous system, and might be a potential neuroprotective drug.

  13. Curcumin improves synaptic plasticity impairment induced by HIV-1gp120 V3 loop

    Directory of Open Access Journals (Sweden)

    Ling-ling Shen

    2015-01-01

    Full Text Available Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extracellular microelectrode recording techniques, this study confirmed that the gp120 V3 loop could suppress long-term potentiation in the rat hippocampal CA1 region and synaptic plasticity, and that curcumin could antagonize these inhibitory effects. Using a Fura-2/AM calcium ion probe, we found that curcumin resisted the effects of the gp120 V3 loop on hippocampal synaptosomes and decreased Ca 2+ concentration in synaptosomes. This effect of curcumin was identical to nimodipine, suggesting that curcumin improved the inhibitory effects of gp120 on synaptic plasticity, ameliorated damage caused to the central nervous system, and might be a potential neuroprotective drug.

  14. P2Y Receptors in Synaptic Transmission and Plasticity: Therapeutic Potential in Cognitive Dysfunction

    Directory of Open Access Journals (Sweden)

    Segundo J. Guzman

    2016-01-01

    Full Text Available ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer’s disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states.

  15. Domestication of the dog from the wolf was promoted by enhanced excitatory synaptic plasticity: a hypothesis.

    Science.gov (United States)

    Li, Yan; Wang, Guo-Dong; Wang, Ming-Shan; Irwin, David M; Wu, Dong-Dong; Zhang, Ya-Ping

    2014-11-05

    Dogs shared a much closer relationship with humans than any other domesticated animals, probably due to their unique social cognitive capabilities, which were hypothesized to be a by-product of selection for tameness toward humans. Here, we demonstrate that genes involved in glutamate metabolism, which account partially for fear response, indeed show the greatest population differentiation by whole-genome comparison of dogs and wolves. However, the changing direction of their expression supports a role in increasing excitatory synaptic plasticity in dogs rather than reducing fear response. Because synaptic plasticity are widely believed to be cellular correlates of learning and memory, this change may alter the learning and memory abilities of ancient scavenging wolves, weaken the fear reaction toward humans, and prompt the initial interspecific contact.

  16. Thrombin regulation of synaptic transmission and plasticity: implications for health and disease.

    Directory of Open Access Journals (Sweden)

    Marina eBen Shimon

    2015-04-01

    Full Text Available Thrombin, a serine protease involved in the blood coagulation cascade has been shown to affect neural function following blood-brain barrier breakdown. However, several lines of evidence exist that thrombin is also expressed in the brain under physiological conditions, suggesting an involvement of thrombin in the regulation of normal brain functions. Here, we review ours’ as well as others' recent work on the role of thrombin in synaptic transmission and plasticity through direct or indirect activation of Protease-Activated Receptor-1 (PAR1. These studies propose a novel role of thrombin in synaptic plasticity, both in physiology as well as in neurological diseases associated with increased brain thrombin/PAR1 levels.

  17. Complement emerges as a masterful regulator of CNS homeostasis, neural synaptic plasticity and cognitive function.

    Science.gov (United States)

    Mastellos, Dimitrios C

    2014-11-01

    Growing evidence points to a previously elusive role of complement-modulated pathways in CNS development, neurogenesis and synaptic plasticity. Distinct complement effectors appear to play a multifaceted role in brain homeostasis by regulating synaptic pruning in the retinogeniculate system and sculpting functional neural circuits both in the developing and adult mammalian brain. A recent study by Perez-Alcazar et al. (2014) provides novel insights into this intricate interplay between complement and the dynamically regulated brain synaptic circuitry, by reporting that mice deficient in C3 exhibit enhanced hippocampus-dependent spatial learning and cognitive performance. This behavioral pattern is associated with an impact of C3 on the functional capacity of glutamatergic synapses, supporting a crucial role for complement in excitatory synapse elimination in the hippocampus. These findings add a fresh twist to this rapidly evolving research field, suggesting that discrete complement components may differentially modulate synaptic connectivity by wiring up with diverse neural effectors in different regions of the brain. The emerging role of complement in synaptogenesis and neural network plasticity opens new conceptual avenues for considering complement interception as a potential therapeutic modality for ameliorating progressive cognitive impairment in age-related, debilitating brain diseases with a prominent inflammatory signature.

  18. Localization of Presynaptic Plasticity Mechanisms Enables Functional Independence of Synaptic and Ectopic Transmission in the Cerebellum

    Directory of Open Access Journals (Sweden)

    Katharine L. Dobson

    2015-01-01

    Full Text Available In the cerebellar molecular layer parallel fibre terminals release glutamate from both the active zone and from extrasynaptic “ectopic” sites. Ectopic release mediates transmission to the Bergmann glia that ensheathe the synapse, activating Ca2+-permeable AMPA receptors and glutamate transporters. Parallel fibre terminals exhibit several forms of presynaptic plasticity, including cAMP-dependent long-term potentiation and endocannabinoid-dependent long-term depression, but it is not known whether these presynaptic forms of long-term plasticity also influence ectopic transmission to Bergmann glia. Stimulation of parallel fibre inputs at 16 Hz evoked LTP of synaptic transmission, but LTD of ectopic transmission. Pharmacological activation of adenylyl cyclase by forskolin caused LTP at Purkinje neurons, but only transient potentiation at Bergmann glia, reinforcing the concept that ectopic sites lack the capacity to express sustained cAMP-dependent potentiation. Activation of mGluR1 caused depression of synaptic transmission via retrograde endocannabinoid signalling but had no significant effect at ectopic sites. In contrast, activation of NMDA receptors suppressed both synaptic and ectopic transmission. The results suggest that the signalling mechanisms for presynaptic LTP and retrograde depression by endocannabinoids are restricted to the active zone at parallel fibre synapses, allowing independent modulation of synaptic transmission to Purkinje neurons and ectopic transmission to Bergmann glia.

  19. Low-frequency transcranial magnetic stimulation is beneficial for enhancing synaptic plasticity in the aging brain

    Directory of Open Access Journals (Sweden)

    Zhan-chi Zhang

    2015-01-01

    Full Text Available In the aging brain, cognitive function gradually declines and causes a progressive reduction in the structural and functional plasticity of the hippocampus. Transcranial magnetic stimulation is an emerging and novel neurological and psychiatric tool used to investigate the neurobiology of cognitive function. Recent studies have demonstrated that low-frequency transcranial magnetic stimulation (≤1 Hz ameliorates synaptic plasticity and spatial cognitive deficits in learning-impaired mice. However, the mechanisms by which this treatment improves these deficits during normal aging are still unknown. Therefore, the current study investigated the effects of transcranial magnetic stimulation on the brain-derived neurotrophic factor signal pathway, synaptic protein markers, and spatial memory behavior in the hippocampus of normal aged mice. The study also investigated the downstream regulator, Fyn kinase, and the downstream effectors, synaptophysin and growth-associated protein 43 (both synaptic markers, to determine the possible mechanisms by which transcranial magnetic stimulation regulates cognitive capacity. Transcranial magnetic stimulation with low intensity (110% average resting motor threshold intensity, 1 Hz increased mRNA and protein levels of brain-derived neurotrophic factor, tropomyosin receptor kinase B, and Fyn in the hippocampus of aged mice. The treatment also upregulated the mRNA and protein expression of synaptophysin and growth-associated protein 43 in the hippocampus of these mice. In conclusion, brain-derived neurotrophic factor signaling may play an important role in sustaining and regulating structural synaptic plasticity induced by transcranial magnetic stimulation in the hippocampus of aging mice, and Fyn may be critical during this regulation. These responses may change the structural plasticity of the aging hippocampus, thereby improving cognitive function.

  20. All About Running: Synaptic Plasticity, Growth Factors and Adult Hippocampal Neurogenesis

    OpenAIRE

    2013-01-01

    Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus ...

  1. Low-frequency transcranial magnetic stimulation is beneifcial for enhancing synaptic plasticity in the aging brain

    Institute of Scientific and Technical Information of China (English)

    Zhan-chi Zhang; Feng Luan; Chun-yan Xie; Dan-dan Geng; Yan-yong Wang; Jun Ma

    2015-01-01

    In the aging brain, cognitive function gradually declines and causes a progressive reduction in the structural and functional plasticity of the hippocampus. Transcranial magnetic stimulation is an emerging and novel neurological and psychiatric tool used to investigate the neurobiology of cognitive function. Recent studies have demonstrated that low-frequency transcranial magnetic stimulation (≤1 Hz) ameliorates synaptic plasticity and spatial cognitive deifcits in learning-im-paired mice. However, the mechanisms by which this treatment improves these deifcits during normal aging are still unknown. Therefore, the current study investigated the effects of tran-scranial magnetic stimulation on the brain-derived neurotrophic factor signal pathway, synaptic protein markers, and spatial memory behavior in the hippocampus of normal aged mice. The study also investigated the downstream regulator, Fyn kinase, and the downstream effectors, syn-aptophysin and growth-associated protein 43 (both synaptic markers), to determine the possible mechanisms by which transcranial magnetic stimulation regulates cognitive capacity. Transcra-nial magnetic stimulation with low intensity (110%average resting motor threshold intensity, 1 Hz) increased mRNA and protein levels of brain-derived neurotrophic factor, tropomyosin receptor kinase B, and Fyn in the hippocampus of aged mice. The treatment also upregulated the mRNA and protein expression of synaptophysin and growth-associated protein 43 in the hippo-campus of these mice. In conclusion, brain-derived neurotrophic factor signaling may play an important role in sustaining and regulating structural synaptic plasticity induced by transcranial magnetic stimulation in the hippocampus of aging mice, and Fyn may be critical during this reg-ulation. These responses may change the structural plasticity of the aging hippocampus, thereby improving cognitive function.

  2. DHA dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition

    OpenAIRE

    Wu, Aiguo; Ying, Zhe; Gomez-Pinilla, Fernando

    2008-01-01

    Omega-3 fatty acids (i.e., docosahexaenoic acid; DHA), similar to exercise, improve cognitive function, promote neuroplasticity, and protect against neurological lesion. In this study, we investigated a possible synergistic action between DHA dietary supplementation and voluntary exercise on modulating synaptic plasticity and cognition. Rats received DHA dietary supplementation (1.25% DHA) with or without voluntary exercise for 12 days. We found that the DHA-enriched diet significantly increa...

  3. Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain

    Science.gov (United States)

    Watson, Jake F; Ho, Hinze; Greger, Ingo H

    2017-01-01

    AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and are selectively recruited during activity-dependent plasticity to increase synaptic strength. A prerequisite for faithful signal transmission is the positioning and clustering of AMPARs at postsynaptic sites. The mechanisms underlying this positioning have largely been ascribed to the receptor cytoplasmic C-termini and to AMPAR-associated auxiliary subunits, both interacting with the postsynaptic scaffold. Here, using mouse organotypic hippocampal slices, we show that the extracellular AMPAR N-terminal domain (NTD), which projects midway into the synaptic cleft, plays a fundamental role in this process. This highly sequence-diverse domain mediates synaptic anchoring in a subunit-selective manner. Receptors lacking the NTD exhibit increased mobility in synapses, depress synaptic transmission and are unable to sustain long-term potentiation (LTP). Thus, synaptic transmission and the expression of LTP are dependent upon an AMPAR anchoring mechanism that is driven by the NTD. DOI: http://dx.doi.org/10.7554/eLife.23024.001 PMID:28290985

  4. BACE1 Is Necessary for Experience-Dependent Homeostatic Synaptic Plasticity in Visual Cortex

    Directory of Open Access Journals (Sweden)

    Emily Petrus

    2014-01-01

    Full Text Available Alzheimer’s disease (AD is the most common form of age-related dementia, which is thought to result from overproduction and/or reduced clearance of amyloid-beta (Aβ peptides. Studies over the past few decades suggest that Aβ is produced in an activity-dependent manner and has physiological relevance to normal brain functions. Similarly, physiological functions for β- and γ-secretases, the two key enzymes that produce Aβ by sequentially processing the amyloid precursor protein (APP, have been discovered over recent years. In particular, activity-dependent production of Aβ has been suggested to play a role in homeostatic regulation of excitatory synaptic function. There is accumulating evidence that activity-dependent immediate early gene Arc is an activity “sensor,” which acts upstream of Aβ production and triggers AMPA receptor endocytosis to homeostatically downregulate the strength of excitatory synaptic transmission. We previously reported that Arc is critical for sensory experience-dependent homeostatic reduction of excitatory synaptic transmission in the superficial layers of visual cortex. Here we demonstrate that mice lacking the major neuronal β-secretase, BACE1, exhibit a similar phenotype: stronger basal excitatory synaptic transmission and failure to adapt to changes in visual experience. Our results indicate that BACE1 plays an essential role in sensory experience-dependent homeostatic synaptic plasticity in the neocortex.

  5. Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity

    KAUST Repository

    Lemtiri-Chlieh, Fouad

    2011-12-19

    Background: Dendritic spines represent the postsynaptic component of the vast majority of excitatory synapses present in the mammalian forebrain. The ability of spines to rapidly alter their shape, size, number and receptor content in response to stimulation is considered to be of paramount importance during the development of synaptic plasticity. Indeed, long-term potentiation (LTP), widely believed to be a cellular correlate of learning and memory, has been repeatedly shown to induce both spine enlargement and the formation of new dendritic spines. In our studies, we focus on Kalirin-7 (Kal7), a Rho GDP/GTP exchange factor (Rho-GEF) localized to the postsynaptic density that plays a crucial role in the development and maintenance of dendritic spines both in vitro and in vivo. Previous studies have shown that mice lacking Kal7 (Kal7 KO) have decreased dendritic spine density in the hippocampus as well as focal hippocampal-dependent learning impairments.Results: We have performed a detailed electrophysiological characterization of the role of Kal7 in hippocampal synaptic plasticity. We show that loss of Kal7 results in impaired NMDA receptor-dependent LTP and long-term depression, whereas a NMDA receptor-independent form of LTP is shown to be normal in the absence of Kal7.Conclusions: These results indicate that Kal7 is an essential and selective modulator of NMDA receptor-dependent synaptic plasticity in the hippocampus. 2011 Lemtiri-Chlieh et al; licensee BioMed Central Ltd.

  6. Circadian clocks, rhythmic synaptic plasticity and the sleep-wake cycle in zebrafish.

    Science.gov (United States)

    Elbaz, Idan; Foulkes, Nicholas S; Gothilf, Yoav; Appelbaum, Lior

    2013-01-01

    The circadian clock and homeostatic processes are fundamental mechanisms that regulate sleep. Surprisingly, despite decades of research, we still do not know why we sleep. Intriguing hypotheses suggest that sleep regulates synaptic plasticity and consequently has a beneficial role in learning and memory. However, direct evidence is still limited and the molecular regulatory mechanisms remain unclear. The zebrafish provides a powerful vertebrate model system that enables simple genetic manipulation, imaging of neuronal circuits and synapses in living animals, and the monitoring of behavioral performance during day and night. Thus, the zebrafish has become an attractive model to study circadian and homeostatic processes that regulate sleep. Zebrafish clock- and sleep-related genes have been cloned, neuronal circuits that exhibit circadian rhythms of activity and synaptic plasticity have been studied, and rhythmic behavioral outputs have been characterized. Integration of this data could lead to a better understanding of sleep regulation. Here, we review the progress of circadian clock and sleep studies in zebrafish with special emphasis on the genetic and neuroendocrine mechanisms that regulate rhythms of melatonin secretion, structural synaptic plasticity, locomotor activity and sleep.

  7. Effects of repetitive transcranial magnetic stimulation on synaptic plasticity and apoptosis in vascular dementia rats.

    Science.gov (United States)

    Yang, Hui-Yun; Liu, Yang; Xie, Jia-Cun; Liu, Nan-Nan; Tian, Xin

    2015-03-15

    This study aims to determine whether low-frequency repetitive transcranial magnetic stimulation (rTMS) protects pyramidal cells from apoptosis and promotes hippocampal synaptic plasticity in a vascular dementia (VaD) rat model. Following establishment of a VaD rat model using two-vessel occlusion (2VO), learning and memory were evaluated via the Morris Water Maze (MWM), hippocampal CA1 neuron ultrastructure was examined via electron microscopy, and hippocampal synaptic plasticity was assessed by long-term potentiation (LTP). Western blot was used to detect the expression of N-methyl-d-aspartic acid receptor 1 (NMDAR1), Bcl-2, and Bax. Compared with VaD group, rats treated with low-frequency rTMS had reduced-escape latencies, increased swimming time in the target quadrant (PCA3-CA1 synapses was enhanced (P<0.05). Low-frequency rTMS significantly up-regulated NMDAR1 and Bcl-2 expression and down-regulated Bax expression. Low-frequency rTMS improves learning and memory, protects the synapse, and increases synaptic plasticity in VaD model rats. Increased Bcl-2 expression and reduced Bax expression may be a novel protective mechanism of low-frequency rTMS treatment for VaD.

  8. Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition.

    Science.gov (United States)

    Wu, A; Ying, Z; Gomez-Pinilla, F

    2008-08-26

    Omega-3 fatty acids (i.e. docosahexaenoic acid; DHA), similar to exercise, improve cognitive function, promote neuroplasticity, and protect against neurological lesion. In this study, we investigated a possible synergistic action between DHA dietary supplementation and voluntary exercise on modulating synaptic plasticity and cognition. Rats received DHA dietary supplementation (1.25% DHA) with or without voluntary exercise for 12 days. We found that the DHA-enriched diet significantly increased spatial learning ability, and these effects were enhanced by exercise. The DHA-enriched diet increased levels of pro-brain-derived neurotrophic factor (BDNF) and mature BDNF, whereas the additional application of exercise boosted the levels of both. Furthermore, the levels of the activated forms of CREB and synapsin I were incremented by the DHA-enriched diet with greater elevation by the concurrent application of exercise. While the DHA diet reduced hippocampal oxidized protein levels, a combination of a DHA diet and exercise resulted in a greater reduction rate. The levels of activated forms of hippocampal Akt and CaMKII were increased by the DHA-enriched diet, and with even greater elevation by a combination of diet and exercise. Akt and CaMKII signaling are crucial step by which BDNF exerts its action on synaptic plasticity and learning and memory. These results indicate that the DHA diet enhanced the effects of exercise on cognition and BDNF-related synaptic plasticity, a capacity that may be used to promote mental health and reduce risk of neurological disorders.

  9. Synaptic plasticity in medial vestibular nucleus neurons: comparison with computational requirements of VOR adaptation.

    Directory of Open Access Journals (Sweden)

    John R W Menzies

    Full Text Available BACKGROUND: Vestibulo-ocular reflex (VOR gain adaptation, a longstanding experimental model of cerebellar learning, utilizes sites of plasticity in both cerebellar cortex and brainstem. However, the mechanisms by which the activity of cortical Purkinje cells may guide synaptic plasticity in brainstem vestibular neurons are unclear. Theoretical analyses indicate that vestibular plasticity should depend upon the correlation between Purkinje cell and vestibular afferent inputs, so that, in gain-down learning for example, increased cortical activity should induce long-term depression (LTD at vestibular synapses. METHODOLOGY/PRINCIPAL FINDINGS: Here we expressed this correlational learning rule in its simplest form, as an anti-Hebbian, heterosynaptic spike-timing dependent plasticity interaction between excitatory (vestibular and inhibitory (floccular inputs converging on medial vestibular nucleus (MVN neurons (input-spike-timing dependent plasticity, iSTDP. To test this rule, we stimulated vestibular afferents to evoke EPSCs in rat MVN neurons in vitro. Control EPSC recordings were followed by an induction protocol where membrane hyperpolarizing pulses, mimicking IPSPs evoked by flocculus inputs, were paired with single vestibular nerve stimuli. A robust LTD developed at vestibular synapses when the afferent EPSPs coincided with membrane hyperpolarization, while EPSPs occurring before or after the simulated IPSPs induced no lasting change. Furthermore, the iSTDP rule also successfully predicted the effects of a complex protocol using EPSP trains designed to mimic classical conditioning. CONCLUSIONS: These results, in strong support of theoretical predictions, suggest that the cerebellum alters the strength of vestibular synapses on MVN neurons through hetero-synaptic, anti-Hebbian iSTDP. Since the iSTDP rule does not depend on post-synaptic firing, it suggests a possible mechanism for VOR adaptation without compromising gaze-holding and VOR

  10. A role for calcium-permeable AMPA receptors in synaptic plasticity and learning.

    Directory of Open Access Journals (Sweden)

    Brian J Wiltgen

    Full Text Available A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca(2+-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice. Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP that was independent of NMDARs and mediated by GluR2-lacking Ca(2+-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca(2+-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs.

  11. UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

    Directory of Open Access Journals (Sweden)

    Jiandong Sun

    2015-07-01

    Full Text Available Gated solely by activity-induced changes in intracellular calcium, small-conductance potassium channels (SKs are critical for a variety of functions in the CNS, from learning and memory to rhythmic activity and sleep. While there is a wealth of information on SK2 gating, kinetics, and Ca2+ sensitivity, little is known regarding the regulation of SK2 subcellular localization. We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and overexpression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function.

  12. On Analysis of Quantifying Learning Creativity Phenomenon Considering Brain Synaptic Plasticity

    Directory of Open Access Journals (Sweden)

    Hassan Mustafa

    2009-06-01

    Full Text Available Generally, Analysis of learning creativity phenomenon is an interesting and challenging issue associated with educational practice. Moreover, that phenomenon is tightly related to main human brain functions (Learning and Memory. So, creative individuals are characterized by their distinct capabilities in performing both brain functions. Additionally, educationalists as well as psychologists, for a long time ago and until recently, have been interesting in searching for quantitative investigation of that challenging issue. In the field of education, practical evaluation of learners' performance, -during tutoring session(s - may result in observation of creativity phenomenon. Herein, this work introduces an interdisciplinary novel approach concerned with analysis of quantifying learning creativity phenomenon. That is fulfilled by adopting Artificial Neural Networks modeling for realistic simulation of synaptic connectivity dynamics (equivalently, synaptic plasticity. By some details, presented work considered two main design parameters of Artificial Neural Networks. Namely they are, gain factor (of neuronal sigmoid activation function, and learning rate value. Both parameters Synaptic Plasticity inside the brain. Obviously, individuals characterized by various values of gain factor value as well as learning rate parameter are well relevant to quantify there learning creativity. Conclusively, obtained results motivate future research for systematical investigational study in depth considering the effect of congenital and/or hereditary factors on learning creativity phenomenon.

  13. Gene control of synaptic plasticity and memory formation: implications for diseases and therapeutic strategies.

    Science.gov (United States)

    Vaillend, C; Rampon, C; Davis, S; Laroche, S

    2002-11-01

    There has been nearly a century of interest in the idea that information is stored in the brain as changes in the efficacy of synaptic connections between neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular and molecular bases of learning and memory. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. Here we briefly review these mechanisms and illustrate with a few examples of animal models of neurological disorders how new knowledge about these mechanisms can provide valuable insights into identifying the mechanisms that go awry when memory is deficient, and how, in turn, characterisation of the dysfunctional mechanisms offers prospects to design and evaluate molecular and biobehavioural strategies for therapeutic prevention and rescue.

  14. Homer 1a gates the induction mechanism for endocannabinoid-mediated synaptic plasticity.

    Science.gov (United States)

    Roloff, Alan M; Anderson, Garret R; Martemyanov, Kirill A; Thayer, Stanley A

    2010-02-24

    At hippocampal excitatory synapses, endocannabinoids (eCBs) mediate two forms of retrograde synaptic inhibition that are induced by postsynaptic depolarization or activation of metabotropic glutamate receptors (mGluRs). The homer family of molecular scaffolds provides spatial organization to regulate postsynaptic signaling cascades, including those activated by mGluRs. Expression of the homer 1a (H1a) immediate-early gene produces a short homer protein that lacks the domain required for homer oligomerization, enabling it to uncouple homer assemblies. Here, we report that H1a differentially modulates two forms of eCB-mediated synaptic plasticity, depolarization-induced suppression of excitation (DSE) and metabotropic suppression of excitation (MSE). EPSCs were recorded from cultured hippocampal neurons and DSE evoked by a 15 s depolarization to 0 mV and MSE evoked by a type I mGluR agonist. Expression of H1a enhanced DSE and inhibited MSE at the same synapse. Many physiologically important stimuli initiate H1a expression including brain-derived neurotrophic factor (BDNF). Treating hippocampal cultures with BDNF increased transcription of H1a and uncoupled homer 1c-GFP (green fluorescent protein) clusters. BDNF treatment blocked MSE and enhanced DSE. Thus, physiological changes in H1a expression gate the induction pathway for eCB-mediated synaptic plasticity by uncoupling mGluR from eCB production.

  15. Mind Bomb-2 Regulates Hippocampus-dependent Memory Formation and Synaptic Plasticity.

    Science.gov (United States)

    Kim, Somi; Kim, TaeHyun; Lee, Hye-Ryeon; Kong, Young-Yun; Kaang, Bong-Kiun

    2015-11-01

    Notch signaling is a key regulator of neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-2 (Mib2) is an essential positive regulator of the Notch pathway, which acts in the Notch signal-sending cells. Therefore, genetic deletion of Mib2 in the mouse brain might help understand Notch signaling-mediated cell-cell interactions between neurons and their physiological function. Here we show that deletion of Mib2 in the mouse brain results in impaired hippocampal spatial memory and contextual fear memory. Accordingly, we found impaired hippocampal synaptic plasticity in Mib2 knock-out (KO) mice; however, basal synaptic transmission did not change at the Schaffer collateral-CA1 synapses. Using western blot analysis, we found that the level of cleaved Notch1 was lower in Mib2 KO mice than in wild type (WT) littermates after mild foot shock. Taken together, these data suggest that Mib2 plays a critical role in synaptic plasticity and spatial memory through the Notch signaling pathway.

  16. Impaired novelty acquisition and synaptic plasticity in congenital hyperammonemia caused by hepatic glutamine synthetase deficiency

    Science.gov (United States)

    Chepkova, Aisa N.; Sergeeva, Olga A.; Görg, Boris; Haas, Helmut L.; Klöcker, Nikolaj; Häussinger, Dieter

    2017-01-01

    Genetic defects in ammonia metabolism can produce irreversible damage of the developing CNS causing an impairment of cognitive and motor functions. We investigated alterations in behavior, synaptic plasticity and gene expression in the hippocampus and dorsal striatum of transgenic mice with systemic hyperammonemia resulting from conditional knockout of hepatic glutamine synthetase (LGS-ko). These mice showed reduced exploratory activity and delayed habituation to a novel environment. Field potential recordings from LGS-ko brain slices revealed significantly reduced magnitude of electrically-induced long-term potentiation (LTP) in both CA3-CA1 hippocampal and corticostriatal synaptic transmission. Corticostriatal but not hippocampal slices from LGS-ko brains demonstrated also significant alterations in long-lasting effects evoked by pharmacological activation of glutamate receptors. Real-time RT-PCR revealed distinct patterns of dysregulated gene expression in the hippocampus and striatum of LGS-ko mice: LGS-ko hippocampus showed significantly modified expression of mRNAs for mGluR1, GluN2B subunit of NMDAR, and A1 adenosine receptors while altered expression of mRNAs for D1 dopamine receptors, the M1 cholinoreceptor and the acetylcholine-synthetizing enzyme choline-acetyltransferase was observed in LGS-ko striatum. Thus, inborn systemic hyperammonemia resulted in significant deficits in novelty acquisition and disturbed synaptic plasticity in corticostriatal and hippocampal pathways involved in learning and goal-directed behavior. PMID:28067279

  17. A light-stimulated synaptic transistor with synaptic plasticity and memory functions based on InGaZnOx-Al2O3 thin film structure

    Science.gov (United States)

    Li, H. K.; Chen, T. P.; Liu, P.; Hu, S. G.; Liu, Y.; Zhang, Q.; Lee, P. S.

    2016-06-01

    In this work, a synaptic transistor based on the indium gallium zinc oxide (IGZO)-aluminum oxide (Al2O3) thin film structure, which uses ultraviolet (UV) light pulses as the pre-synaptic stimulus, has been demonstrated. The synaptic transistor exhibits the behavior of synaptic plasticity like the paired-pulse facilitation. In addition, it also shows the brain's memory behaviors including the transition from short-term memory to long-term memory and the Ebbinghaus forgetting curve. The synapse-like behavior and memory behaviors of the transistor are due to the trapping and detrapping processes of the holes, which are generated by the UV pulses, at the IGZO/Al2O3 interface and/or in the Al2O3 layer.

  18. Memory and synaptic plasticity are impaired by dysregulated hippocampal O-GlcNAcylation

    Science.gov (United States)

    Yang, Yong Ryoul; Song, Seungju; Hwang, Hongik; Jung, Jung Hoon; Kim, Su-Jeong; Yoon, Sora; Hur, Jin-Hoe; Park, Jae-Il; Lee, Cheol; Nam, Dougu; Seo, Young-Kyo; Kim, Joung-Hun; Rhim, Hyewhon; Suh, Pann-Ghill

    2017-01-01

    O-GlcNAcylated proteins are abundant in the brain and are associated with neuronal functions and neurodegenerative diseases. Although several studies have reported the effects of aberrant regulation of O-GlcNAcylation on brain function, the roles of O-GlcNAcylation in synaptic function remain unclear. To understand the effect of aberrant O-GlcNAcylation on the brain, we used Oga+/− mice which have an increased level of O-GlcNAcylation, and found that Oga+/− mice exhibited impaired spatial learning and memory. Consistent with this result, Oga+/− mice showed a defect in hippocampal synaptic plasticity. Oga heterozygosity causes impairment of both long-term potentiation and long-term depression due to dysregulation of AMPA receptor phosphorylation. These results demonstrate a role for hyper-O-GlcNAcylation in learning and memory. PMID:28368052

  19. Magnetic nanotherapeutics for dysregulated synaptic plasticity during neuroAIDS and drug abuse.

    Science.gov (United States)

    Sagar, Vidya; Atluri, Venkata Subba Rao; Pilakka-Kanthikeel, Sudheesh; Nair, Madhavan

    2016-05-23

    The human immunodeficiency virus (HIV) is a neurotropic virus. It induces neurotoxicity and subsequent brain pathologies in different brain cells. Addiction to recreational drugs remarkably affects the initiation of HIV infections and expedites the progression of acquired immunodeficiency syndrome (AIDS) associated neuropathogenesis. Symptoms of HIV-associated neurocognitive disorders (HAND) are noticed in many AIDS patients. At least 50 % of HIV diagnosed cases show one or other kind of neuropathological signs or symptoms during different stages of disease progression. In the same line, mild to severe neurological alterations are seen in at least 80 % autopsies of AIDS patients. Neurological illnesses weaken the connections between neurons causing significant altercations in synaptic plasticity. Synaptic plasticity alterations during HIV infection and recreational drug abuse are mediated by complex cellular phenomena involving changes in gene expression and subsequent loss of dendritic and spine morphology and physiology. New treatment strategies with ability to deliver drugs across blood-brain barrier (BBB) are being intensively investigated. In this context, magnetic nanoparticles (MNPs) based nanoformulations have shown significant potential for target specificity, drug delivery, drug release, and bioavailability of desired amount of drugs in non-invasive brain targeting. MNPs-based potential therapies to promote neuronal plasticity during HIV infection and recreational drug abuse are being developed.

  20. Role of immediate-early genes in synaptic plasticity and neuronal ensembles underlying the memory trace

    Directory of Open Access Journals (Sweden)

    Keiichiro eMinatohara

    2016-01-01

    Full Text Available In the brain, neuronal gene expression is dynamically changed in response to neuronal activity. In particular, the expression of immediate-early genes (IEGs such as egr-1, c-fos, and Arc is rapidly and selectively upregulated in subsets of neurons in specific brain regions associated with learning and memory formation. IEG expression has therefore been widely used as a molecular marker for neuronal populations that undergo plastic changes underlying formation of long-term memory. In recent years, optogenetic and pharmacogenetic studies of neurons expressing c-fos or Arc have revealed that, during learning, IEG-positive neurons encode and store information that is required for memory recall, suggesting that they may be involved in formation of the memory trace. However, despite accumulating evidence for the role of IEGs in synaptic plasticity, the molecular and cellular mechanisms associated with this process remain unclear. In this review, we first summarize recent literature concerning the role of IEG-expressing neuronal ensembles in organizing the memory trace. We then focus on the physiological significance of IEGs, especially Arc, in synaptic plasticity, and describe our hypotheses about the importance of Arc expression in various types of input-specific circuit reorganization. Finally, we offer perspectives on Arc function that would unveil the role of IEG-expressing neurons in the formation of memory traces in the hippocampus and other brain areas.

  1. The role of extracellular proteolysis in synaptic plasticity of the central nervous system 

    Directory of Open Access Journals (Sweden)

    Anna Konopka

    2012-11-01

    Full Text Available The extracellular matrix (ECM of the central nervous system has a specific structure and protein composition that are different from those in other organs. Today we know that the ECM not only provides physical scaffolding for the neurons and glia, but also actively modifies their functions. Over the last two decades, a growing body of research evidence has been collected, suggesting an important role of ECM proteolysis in synaptic plasticity of the brain. So far the majority of data concern two large families of proteases: the serine proteases and the matrix metalloproteinases. The members of these families are localized at the synapses, and are secreted into the extracellular space in an activity-dependent manner. The proteases remodel the local environment as well as influencing synapse structure and function. The structural modifications induced by proteases include shape and size changes, as well as synapse elimination, and synaptogenesis. The functional changes include modifications of receptor function in the postsynaptic part of the synapse, as well as the potentiation or depression of neurotransmitter secretion by the presynaptic site. The present review summarizes the current view on the role of extracellular proteolysis in the physiological synaptic plasticity underlying the phenomena of learning and memory, as well as in the pathological plasticity occurring during epileptogenesis or development of drug addiction. 

  2. Nucleolar integrity is required for the maintenance of long-term synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Kim D Allen

    Full Text Available Long-term memory (LTM formation requires new protein synthesis and new gene expression. Based on our work in Aplysia, we hypothesized that the rRNA genes, stimulation-dependent targets of the enzyme Poly(ADP-ribose polymerase-1 (PARP-1, are primary effectors of the activity-dependent changes in synaptic function that maintain synaptic plasticity and memory. Using electrophysiology, immunohistochemistry, pharmacology and molecular biology techniques, we show here, for the first time, that the maintenance of forskolin-induced late-phase long-term potentiation (L-LTP in mouse hippocampal slices requires nucleolar integrity and the expression of new rRNAs. The activity-dependent upregulation of rRNA, as well as L-LTP expression, are poly(ADP-ribosylation (PAR dependent and accompanied by an increase in nuclear PARP-1 and Poly(ADP ribose molecules (pADPr after forskolin stimulation. The upregulation of PARP-1 and pADPr is regulated by Protein kinase A (PKA and extracellular signal-regulated kinase (ERK--two kinases strongly associated with long-term plasticity and learning and memory. Selective inhibition of RNA Polymerase I (Pol I, responsible for the synthesis of precursor rRNA, results in the segmentation of nucleoli, the exclusion of PARP-1 from functional nucleolar compartments and disrupted L-LTP maintenance. Taken as a whole, these results suggest that new rRNAs (28S, 18S, and 5.8S ribosomal components--hence, new ribosomes and nucleoli integrity--are required for the maintenance of long-term synaptic plasticity. This provides a mechanistic link between stimulation-dependent gene expression and the new protein synthesis known to be required for memory consolidation.

  3. Chronic alcohol exposure alters behavioral and synaptic plasticity of the rodent prefrontal cortex.

    Directory of Open Access Journals (Sweden)

    Sven Kroener

    Full Text Available In the present study, we used a mouse model of chronic intermittent ethanol (CIE exposure to examine how CIE alters the plasticity of the medial prefrontal cortex (mPFC. In acute slices obtained either immediately or 1-week after the last episode of alcohol exposure, voltage-clamp recording of excitatory post-synaptic currents (EPSCs in mPFC layer V pyramidal neurons revealed that CIE exposure resulted in an increase in the NMDA/AMPA current ratio. This increase appeared to result from a selective increase in the NMDA component of the EPSC. Consistent with this, Western blot analysis of the postsynaptic density fraction showed that while there was no change in expression of the AMPA GluR1 subunit, NMDA NR1 and NRB subunits were significantly increased in CIE exposed mice when examined immediately after the last episode of alcohol exposure. Unexpectedly, this increase in NR1 and NR2B was no longer observed after 1-week of withdrawal in spite of a persistent increase in synaptic NMDA currents. Analysis of spines on the basal dendrites of layer V neurons revealed that while the total density of spines was not altered, there was a selective increase in the density of mushroom-type spines following CIE exposure. Examination of NMDA-receptor mediated spike-timing-dependent plasticity (STDP showed that CIE exposure was associated with altered expression of long-term potentiation (LTP. Lastly, behavioral studies using an attentional set-shifting task that depends upon the mPFC for optimal performance revealed deficits in cognitive flexibility in CIE exposed mice when tested up to 1-week after the last episode of alcohol exposure. Taken together, these observations are consistent with those in human alcoholics showing protracted deficits in executive function, and suggest these deficits may be associated with alterations in synaptic plasticity in the mPFC.

  4. A neuromorphic VLSI design for spike timing and rate based synaptic plasticity.

    Science.gov (United States)

    Rahimi Azghadi, Mostafa; Al-Sarawi, Said; Abbott, Derek; Iannella, Nicolangelo

    2013-09-01

    Triplet-based Spike Timing Dependent Plasticity (TSTDP) is a powerful synaptic plasticity rule that acts beyond conventional pair-based STDP (PSTDP). Here, the TSTDP is capable of reproducing the outcomes from a variety of biological experiments, while the PSTDP rule fails to reproduce them. Additionally, it has been shown that the behaviour inherent to the spike rate-based Bienenstock-Cooper-Munro (BCM) synaptic plasticity rule can also emerge from the TSTDP rule. This paper proposes an analogue implementation of the TSTDP rule. The proposed VLSI circuit has been designed using the AMS 0.35 μm CMOS process and has been simulated using design kits for Synopsys and Cadence tools. Simulation results demonstrate how well the proposed circuit can alter synaptic weights according to the timing difference amongst a set of different patterns of spikes. Furthermore, the circuit is shown to give rise to a BCM-like learning rule, which is a rate-based rule. To mimic an implementation environment, a 1000 run Monte Carlo (MC) analysis was conducted on the proposed circuit. The presented MC simulation analysis and the simulation result from fine-tuned circuits show that it is possible to mitigate the effect of process variations in the proof of concept circuit; however, a practical variation aware design technique is required to promise a high circuit performance in a large scale neural network. We believe that the proposed design can play a significant role in future VLSI implementations of both spike timing and rate based neuromorphic learning systems.

  5. BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

    DEFF Research Database (Denmark)

    Zhu, Dan; Li, Chenchen; Swanson, Andrew M

    2015-01-01

    levels of the canonical PSD component PSD-95 in the brain, which stems from protein destabilization. We determined that BAI1 prevents PSD-95 polyubiquitination and degradation through an interaction with murine double minute 2 (MDM2), the E3 ubiquitin ligase that regulates PSD-95 stability. Restoration...... of PSD-95 expression in hippocampal neurons in BAI1-deficient mice by viral gene therapy was sufficient to compensate for Bai1 loss and rescued deficits in synaptic plasticity. Together, our results reveal that interaction of BAI1 with MDM2 in the brain modulates PSD-95 levels and thereby regulates...

  6. Synaptic plasticity in a recurrent neural network for versatile and adaptive behaviors of a walking robot

    DEFF Research Database (Denmark)

    Grinke, Eduard; Tetzlaff, Christian; Wörgötter, Florentin

    2015-01-01

    mechanisms with plasticity, exteroceptive sensory feedback, and biomechanics. The neural mechanisms consist of adaptive neural sensory processing and modular neural locomotion control. The sensory processing is based on a small recurrent neural network consisting of two fully connected neurons. Online...... correlation-based learning with synaptic scaling is applied to adequately change the connections of the network. By doing so, we can effectively exploit neural dynamics (i.e., hysteresis effects and single attractors) in the network to generate different turning angles with short-term memory for a walking...

  7. Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization.

    Science.gov (United States)

    Lange, Maren D; Jüngling, Kay; Paulukat, Linda; Vieler, Marc; Gaburro, Stefano; Sosulina, Ludmila; Blaesse, Peter; Sreepathi, Hari K; Ferraguti, Francesco; Pape, Hans-Christian

    2014-08-01

    An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders.

  8. The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing

    Directory of Open Access Journals (Sweden)

    Ayla eAksoy Aksel

    2013-08-01

    Full Text Available In terms of its sub-regional differentiation, the hippocampal CA1 region receives cortical information directly via the perforant (temporoammonic path (pp-CA1 synapse and indirectly via the tri-synaptic pathway where the last relay station is the Schaffer collateral-CA1 synapse (Sc-CA1 synapse. Research to date on pp-CA1 synapses has been conducted predominantly in vitro and never in awake animals, but these studies hint that information processing at this synapse might be distinct to processing at the Sc-CA1 synapse. Here, we characterized synaptic properties and synaptic plasticity at the pp-CA1 synapse of freely behaving adult rats. We established that field excitatory postsynaptic potentials at the pp-CA1 have longer onset latencies and a shorter time-to-peak compared to the Sc-CA1 synapse. LTP (> 24h was successfully evoked by tetanic afferent stimulation of pp-CA1 synapses. Low frequency stimulation evoked synaptic depression at Sc-CA1 synapses, but did not elicit LTD at pp-CA1 synapses unless the Schaffer collateral afferents to the CA1 region had been severed. Paired-pulse responses also showed significant differences. Our data suggest that synaptic plasticity at the pp-CA1 synapse is distinct from the Sc-CA1 synapse and that this may reflect its specific role in hippocampal information processing.

  9. The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing

    Science.gov (United States)

    Aksoy-Aksel, Ayla; Manahan-Vaughan, Denise

    2013-01-01

    In terms of its sub-regional differentiation, the hippocampal CA1 region receives cortical information directly via the perforant (temporoammonic) path (pp-CA1 synapse) and indirectly via the tri-synaptic pathway where the last relay station is the Schaffer collateral-CA1 synapse (Sc-CA1 synapse). Research to date on pp-CA1 synapses has been conducted predominantly in vitro and never in awake animals, but these studies hint that information processing at this synapse might be distinct to processing at the Sc-CA1 synapse. Here, we characterized synaptic properties and synaptic plasticity at the pp-CA1 synapse of freely behaving adult rats. We observed that field excitatory postsynaptic potentials at the pp-CA1 synapse have longer onset latencies and a shorter time-to-peak compared to the Sc-CA1 synapse. LTP (>24 h) was successfully evoked by tetanic afferent stimulation of pp-CA1 synapses. Low frequency stimulation evoked synaptic depression at Sc-CA1 synapses, but did not elicit LTD at pp-CA1 synapses unless the Schaffer collateral afferents to the CA1 region had been severed. Paired-pulse responses also showed significant differences. Our data suggest that synaptic plasticity at the pp-CA1 synapse is distinct from the Sc-CA1 synapse and that this may reflect its specific role in hippocampal information processing. PMID:23986697

  10. Cocaine-evoked synaptic plasticity of excitatory transmission in the ventral tegmental area.

    Science.gov (United States)

    Lüscher, Christian

    2013-05-01

    Cocaine leads to a strong euphoria, which is at the origin of its recreational use. Past the acute effects, the drug leaves traces in the brain that persist long after it has been cleared from the body. These traces eventually shape behavior such that drug use may become compulsive and addiction develops. Here we discuss cocaine-evoked synaptic plasticity of glutamatergic transmission onto dopamine (DA) neurons of the ventral tegmental area (VTA) as one of the earliest traces after a first injection of cocaine. We review the literature that has examined the induction requirements as well as the expression mechanism of this form of plasticity and ask the question about its functional significance.

  11. Human-Specific Cortical Synaptic Connections and Their Plasticity: Is That What Makes Us Human?

    Science.gov (United States)

    Lourenço, Joana; Bacci, Alberto

    2017-01-01

    One outstanding difference between Homo sapiens and other mammals is the ability to perform highly complex cognitive tasks and behaviors, such as language, abstract thinking, and cultural diversity. How is this accomplished? According to one prominent theory, cognitive complexity is proportional to the repetition of specific computational modules over a large surface expansion of the cerebral cortex (neocortex). However, the human neocortex was shown to also possess unique features at the cellular and synaptic levels, raising the possibility that expanding the computational module is not the only mechanism underlying complex thinking. In a study published in PLOS Biology, Szegedi and colleagues analyzed a specific cortical circuit from live postoperative human tissue, showing that human-specific, very powerful excitatory connections between principal pyramidal neurons and inhibitory neurons are highly plastic. This suggests that exclusive plasticity of specific microcircuits might be considered among the mechanisms endowing the human neocortex with the ability to perform highly complex cognitive tasks. PMID:28103228

  12. Human synaptic plasticity gene expression profile and dendritic spine density changes in HIV-infected human CNS cells: role in HIV-associated neurocognitive disorders (HAND.

    Directory of Open Access Journals (Sweden)

    Venkata Subba Rao Atluri

    Full Text Available HIV-associated neurocognitive disorders (HAND is characterized by development of cognitive, behavioral and motor abnormalities, and occur in approximately 50% of HIV infected individuals. Our current understanding of HAND emanates mainly from HIV-1 subtype B (clade B, which is prevalent in USA and Western countries. However very little information is available on neuropathogenesis of HIV-1 subtype C (clade C that exists in Sub-Saharan Africa and Asia. Therefore, studies to identify specific neuropathogenic mechanisms associated with HAND are worth pursuing to dissect the mechanisms underlying this modulation and to prevent HAND particularly in clade B infection. In this study, we have investigated 84 key human synaptic plasticity genes differential expression profile in clade B and clade C infected primary human astrocytes by using RT(2 Profile PCR Array human Synaptic Plasticity kit. Among these, 31 and 21 synaptic genes were significantly (≥3 fold down-regulated and 5 genes were significantly (≥3 fold up-regulated in clade B and clade C infected cells, respectively compared to the uninfected control astrocytes. In flow-cytometry analysis, down-regulation of postsynaptic density and dendrite spine morphology regulatory proteins (ARC, NMDAR1 and GRM1 was confirmed in both clade B and C infected primary human astrocytes and SK-N-MC neuroblastoma cells. Further, spine density and dendrite morphology changes by confocal microscopic analysis indicates significantly decreased spine density, loss of spines and decreased dendrite diameter, total dendrite and spine area in clade B infected SK-N-MC neuroblastoma cells compared to uninfected and clade C infected cells. We have also observed that, in clade B infected astrocytes, induction of apoptosis was significantly higher than in the clade C infected astrocytes. In conclusion, this study suggests that down-regulation of synaptic plasticity genes, decreased dendritic spine density and induction of

  13. Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity.

    Science.gov (United States)

    Almonte, Antoine G; Qadri, Laura H; Sultan, Faraz A; Watson, Jennifer A; Mount, Daniel J; Rumbaugh, Gavin; Sweatt, J David

    2013-01-01

    Protease-activated receptor-1 (PAR1) is an unusual G-protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. Although previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1's contribution to normal brain function. Here, we used PAR1-/- mice to investigate the contribution of PAR1 function to memory formation and synaptic function. We demonstrate that PAR1-/- mice have deficits in hippocampus-dependent memory. We also show that while PAR1-/- mice have normal baseline synaptic transmission at Schaffer collateral-CA1 synapses, they exhibit severe deficits in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). Mounting evidence indicates that activation of PAR1 leads to potentiation of NMDAR-mediated responses in CA1 pyramidal cells. Taken together, this evidence and our data suggest an important role for PAR1 function in NMDAR-dependent processes subserving memory formation and synaptic plasticity.

  14. The Role of Histone Deacetylase 6 in Synaptic Plasticity and Memory

    Directory of Open Access Journals (Sweden)

    Sarah Perry

    2017-02-01

    Full Text Available Histone deacetylases (HDACs have been extensively studied as drug targets in neurodegenerative diseases, but less is known about their role in healthy neurons. We tested zinc-dependent HDACs using RNAi in Drosophila melanogaster and found memory deficits with RPD3 and HDAC6. We demonstrate that HDAC6 is required in both the larval and adult stages for normal olfactory memory retention. Neuronal expression of HDAC6 rescued memory deficits, and we demonstrate that the N-terminal deacetylase (DAC domain is required for this ability. This suggests that deacetylation of synaptic targets associated with the first DAC domain, such as the active-zone scaffold Bruchpilot, is required for memory retention. Finally, electrophysiological experiments at the neuromuscular junction reveal that HDAC6 mutants exhibit a partial block of homeostatic plasticity, suggesting that HDAC6 may be required for the stabilization of synaptic strength. The learning deficit we observe in HDAC6 mutants could be a behavioral consequence of these synaptic defects.

  15. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning.

    Science.gov (United States)

    Fritsch, Brita; Reis, Janine; Martinowich, Keri; Schambra, Heidi M; Ji, Yuanyuan; Cohen, Leonardo G; Lu, Bai

    2010-04-29

    Despite its increasing use in experimental and clinical settings, the cellular and molecular mechanisms underlying transcranial direct current stimulation (tDCS) remain unknown. Anodal tDCS applied to the human motor cortex (M1) improves motor skill learning. Here, we demonstrate in mouse M1 slices that DCS induces a long-lasting synaptic potentiation (DCS-LTP), which is polarity specific, NMDA receptor dependent, and requires coupling of DCS with repetitive low-frequency synaptic activation (LFS). Combined DCS and LFS enhance BDNF-secretion and TrkB activation, and DCS-LTP is absent in BDNF and TrkB mutant mice, suggesting that BDNF is a key mediator of this phenomenon. Moreover, the BDNF val66met polymorphism known to partially affect activity-dependent BDNF secretion impairs motor skill acquisition in humans and mice. Motor learning is enhanced by anodal tDCS, as long as activity-dependent BDNF secretion is in place. We propose that tDCS may improve motor skill learning through augmentation of synaptic plasticity that requires BDNF secretion and TrkB activation within M1.

  16. Regulation of Astroglia on Synaptic Plasticity in the CA1 Region of Rat Hippocampus

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The regulation of astroglia on synaptic plasticity in the CA1 region of rat hippocampus was examined. Rats were divided into three groups: the newly born (<24 h), the juvenile (28-30days) and the adult groups (90-100 days), with each group having 20 animals. The CA1 region of rat hippocampus was immunohistochemically and electron-microscopically examined, respectively,for the growth of astroglia and the ultrastructure of synapses. The high performance liquid chromatography was employed to determine the cholesterol content of rat hippocampus. In the newly-born rats, a large number of neurons were noted in the hippocampal CA1 region of the newly-born rats,and few astroglia and no synaptic structure were observed. In the juvenile group, a few astroglias and some immature synapses were found, which were less than those in adult rats (P<0.01). The cholesterol content was 2.92±0.03 mg/g, 11.20± 3.41 mg/g and 12.91 ± 1.25 mg/g for newly born, the juvenile and the adult groups, respectively, with the differences among them being statistically significant (P<0.01). Our study suggests that the astrocytes may play an important role in the synaptic formation and functional maturity of hippocampal neurons, which may be related to the secretion of cholesterol from astrocytes.

  17. A distance constrained synaptic plasticity model of C. elegans neuronal network

    Science.gov (United States)

    Badhwar, Rahul; Bagler, Ganesh

    2017-03-01

    Brain research has been driven by enquiry for principles of brain structure organization and its control mechanisms. The neuronal wiring map of C. elegans, the only complete connectome available till date, presents an incredible opportunity to learn basic governing principles that drive structure and function of its neuronal architecture. Despite its apparently simple nervous system, C. elegans is known to possess complex functions. The nervous system forms an important underlying framework which specifies phenotypic features associated to sensation, movement, conditioning and memory. In this study, with the help of graph theoretical models, we investigated the C. elegans neuronal network to identify network features that are critical for its control. The 'driver neurons' are associated with important biological functions such as reproduction, signalling processes and anatomical structural development. We created 1D and 2D network models of C. elegans neuronal system to probe the role of features that confer controllability and small world nature. The simple 1D ring model is critically poised for the number of feed forward motifs, neuronal clustering and characteristic path-length in response to synaptic rewiring, indicating optimal rewiring. Using empirically observed distance constraint in the neuronal network as a guiding principle, we created a distance constrained synaptic plasticity model that simultaneously explains small world nature, saturation of feed forward motifs as well as observed number of driver neurons. The distance constrained model suggests optimum long distance synaptic connections as a key feature specifying control of the network.

  18. Fragile X protein FMRP is required for homeostatic plasticity and regulation of synaptic strength by retinoic acid.

    Science.gov (United States)

    Soden, Marta E; Chen, Lu

    2010-12-15

    Homeostatic synaptic plasticity adjusts the strength of synapses during global changes in neural activity, thereby stabilizing the overall activity of neural networks. Suppression of synaptic activity increases synaptic strength by inducing synthesis of retinoic acid (RA), which activates postsynaptic synthesis of AMPA-type glutamate receptors (AMPARs) in dendrites and promotes synaptic insertion of newly synthesized AMPARs. Here, we show that fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates dendritic protein synthesis, is essential for increases in synaptic strength induced by RA or by blockade of neural activity in the mouse hippocampus. Although activity-dependent RA synthesis is maintained in Fmr1 knock-out neurons, RA-dependent dendritic translation of GluR1-type AMPA receptors is impaired. Intriguingly, FMRP is only required for the form of homeostatic plasticity that is dependent on both RA signaling and local protein synthesis. Postsynaptic expression of wild-type or mutant FMRP(I304N) in knock-out neurons reduced the total, surface, and synaptic levels of AMPARs, implying a role for FMRP in regulating AMPAR abundance. Expression of FMRP lacking the RGG box RNA-binding domain had no effect on AMPAR levels. Importantly, postsynaptic expression of wild-type FMRP, but not FMRP(I304N) or FMRPΔRGG, restored synaptic scaling when expressed in knock-out neurons. Together, these findings identify an unanticipated role for FMRP in regulating homeostatic synaptic plasticity downstream of RA. Our results raise the possibility that at least some of the symptoms of fragile X syndrome reflect impaired homeostatic plasticity and impaired RA signaling.

  19. G-Protein-Coupled Estrogen Receptor 1 Is Anatomically Positioned to Modulate Synaptic Plasticity in the Mouse Hippocampus

    OpenAIRE

    Elizabeth M. Waters; Thompson, Louisa I.; Patel, Parth; Gonzales, Andreina D.; Ye, Hector (Zhiyu); Filardo, Edward J.; Clegg, Deborah J.; Gorecka, Jolanta; Akama, Keith T.; McEwen, Bruce S.; Milner, Teresa A.

    2015-01-01

    Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors α and β, and synaptic levels in the rodent dorsal hippocampus. Here, we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and int...

  20. Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor

    OpenAIRE

    Yang, Hongwei; Zhang, Jian; Breyer, Richard M.; Chen, Chu

    2008-01-01

    Our laboratory demonstrated previously that PGE2-induced modulation of hippocampal synaptic transmission is via a presynaptic PGE2 EP2 receptor. However, little is known about whether the EP2 receptor is involved in hippocampal long-term synaptic plasticity and cognitive function. Here we show that long-term potentiation (LTP) at the hippocampal perforant path synapses was impaired in mice deficient in the EP2 (KO), while membrane excitability and passive properties in granule neurons were no...

  1. Frequency-dependent gating of synaptic transmission and plasticity by dopamine

    Directory of Open Access Journals (Sweden)

    Hiroshi T Ito

    2007-11-01

    Full Text Available The neurotransmitter dopamine (DA plays an important role in learning by enhancing the saliency of behaviorally relevant stimuli. How this stimulus selection is achieved on the cellular level, however, is not known. Here, in recordings from hippocampal slices, we show that DA acts specifically at the direct cortical input to hippocampal area CA1 (the temporoammonic (TA pathway to filter the excitatory drive onto pyramidal neurons based on the input frequency. During low-frequency patterns of stimulation, DA depressed excitatory TA inputs to both CA1 pyramidal neurons and local inhibitory GABAergic interneurons via presynaptic inhibition. In contrast, during high-frequency patterns of stimulation, DA potently facilitated the TA excitatory drive onto CA1 pyramidal neurons, owing to diminished feedforward inhibition. Analysis of DA's effects over a broad range of stimulus frequencies indicates that it acts as a high-pass filter, augmenting the response to high-frequency inputs while diminishing the impact of low-frequency inputs. These modulatory effects of DA exert a profound influence on activity-dependent forms of synaptic plasticity at both TA-CA1 and Schaffer-collateral (SC-CA1 synapses. Taken together, our data demonstrate that DA acts as a gate on the direct cortical input to the hippocampus, modulating information flow and synaptic plasticity in a frequency-dependent manner.

  2. Priming stimulation modifies synaptic plasticity in the perforant path of hippocampal slice in rat

    Institute of Scientific and Technical Information of China (English)

    Lian ZHANG; Hong-Mei XIAO; Yan-Xia ZHOU; Xiao-Ping LUO

    2006-01-01

    Objective The potential of all central nervous system synapses to exhibit long term potentiation (LTP) or long term depression (LTD) is subject to modulation by prior synaptic activity, a higher-order form of plasticity that has been termed metaplasticity. This study is designed to examine the plasticity and metaplasticity in the lateral perforant path of rat. Methods Field potential was measured with different priming and conditioning stimulation protocols. Results Ten-hertz priming, which does not affect basal synaptic transmission, caused a dramatic reduction in subsequent LTP at lateral perforant path synapses in vitro, and the reduced LTP lasted for at least 2 h. The LTD was unaffected. The reduction of LTP in the lateral perforant path was also readily induced by applying priming antidromically at the mossy fibers. Conclusion Priming with 10 Hz, which is within a frequency range observed during physiological activity, can cause potent,long-lasting inhibition of LTP, but not LTD. This form of metaplasticity adds a layer of complexity to the activity-dependent modification of synapses within the dentate gyrus.

  3. Dynamic impact of temporal context of Ca²⁺ signals on inhibitory synaptic plasticity.

    Science.gov (United States)

    Kawaguchi, Shin-Ya; Nagasaki, Nobuhiro; Hirano, Tomoo

    2011-01-01

    Neuronal activity-dependent synaptic plasticity, a basis for learning and memory, is tightly correlated with the pattern of increase in intracellular Ca(2+) concentration ([Ca(2+)](i)). Here, using combined application of electrophysiological experiments and systems biological simulation, we show that such a correlation dynamically changes depending on the context of [Ca(2+)](i) increase. In a cerebellar Purkinje cell, long-term potentiation of inhibitory GABA(A) receptor responsiveness (called rebound potentiation; RP) was induced by [Ca(2+)](i) increase in a temporally integrative manner through sustained activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, the RP establishment was canceled by coupling of two patterns of RP-inducing [Ca(2+)](i) increase depending on the temporal sequence. Negative feedback signaling by phospho-Thr305/306 CaMKII detected the [Ca(2+)](i) context, and assisted the feedforward inhibition of CaMKII through PDE1, resulting in the RP impairment. The [Ca(2+)](i) context-dependent dynamic regulation of synaptic plasticity might contribute to the temporal refinement of information flow in neuronal networks.

  4. Multiplicative gain modulation arising from inhibitory synaptic plasticity in the cerebellar nuclei

    Directory of Open Access Journals (Sweden)

    Dimitris Bampasakis

    2014-03-01

    Full Text Available Neurons use the rate of action potentials to encode sensory variables. This makes the output rate as a function of input, also known as input-output (I–O relationship, a core computational function in neuronal processing. The introduction, or increase, of a modulatory input, can transform this function in multiple ways: additive transformations result in a shift, and multiplicative transformations in a change of slope of the I–O relationship. This slope change is known as gain modulation, and it can implement important forms of neural computation such as coordinate transformations. Gain modulation can be found in a wide range of brain systems, including the cerebellum, where it can be enabled by synaptic plasticity at both excitatory and inhibitory synapses. We use a realistic, conductance based, multi-compartmental model of a cerebellar nucleus (CN neuron, to investigate the determinants of gain modulation mediated by synaptic plasticity. In particular, we are interested in the effect of short term depression (STD at the inhibitory synapse from Purkinje cells (PCs to CN neurons. Considering the inhibitory PC input as the driving input, we compare the I–O relationship of the CN neuron in the presence and absence of STD for 20 Hz of excitatory synaptic input from mossy fibers (MFs, and find that STD introduces a gain change, changing the slope of the I–O function. We then proceed to compare the transformation performed by the increase of the modulatory input from 20 to 50 Hz, in the presence and absence of STD. We find that the presence of STD in the inhibitory synapse introduces a multiplicative component in the transformation performed by the excitatory input, an effect that persists for different levels of STD, and various combinations of regularity and synchronicity in the input.

  5. Histone acetylation in the olfactory bulb of young rats facilitates aversive olfactory learning and synaptic plasticity.

    Science.gov (United States)

    Wang, Y-J; Okutani, F; Murata, Y; Taniguchi, M; Namba, T; Kaba, H

    2013-03-01

    Epigenetic mechanisms play an important role in memory formation and synaptic plasticity. Specifically, histone-associated heterochromatin undergoes changes in structure during the early stages of long-term memory formation. In keeping with the classical conditioning paradigm, young rats have been shown to exhibit aversion to an odor stimulus initially presented during foot shock. We previously showed that synaptic plasticity at the dendrodendritic synapses between mitral and granule cells in the olfactory bulb (OB) underlies this aversive olfactory learning. However, the epigenetic mechanisms involved are not well characterized. Therefore, we examined whether intrabulbar infusion of trichostatin A (TSA), a histone deacetylase inhibitor, facilitates olfactory learning in young rats. TSA infusion during odor-shock training enhanced a conditioned odor aversion in a dose-dependent manner and prolonged the learned aversion. Western blot and immunohistochemical analyses showed that the level of histone H4 acetylation significantly increased until 4 h after odor-shock training in both mitral and granule cells in the OB, whereas histone H3 acetylation returned to the control level at 2 h after the training. We also obtained evidence that TSA infusion elevated acetylation of histone H4 or H3. Furthermore, in vitro electrophysiological analysis using slices of the OB revealed that application of TSA significantly enhanced the long-term potentiation induced in synaptic transmission from mitral to granule cells at dendrodendritic synapses. Taken together, these results provide evidence that histone H4 and H3 acetylation in the OB is an epigenetic mechanism associated with aversive olfactory learning in young rats.

  6. Repetitive transcranial magnetic stimulation (rTMS) influences spatial cognition and modulates hippocampal structural synaptic plasticity in aging mice.

    Science.gov (United States)

    Ma, Jun; Zhang, Zhanchi; Kang, Lin; Geng, Dandan; Wang, Yanyong; Wang, Mingwei; Cui, Huixian

    2014-10-01

    Normal aging is characteristic with the gradual decline in cognitive function associated with the progressive reduction of structural and functional plasticity in the hippocampus. Repetitive transcranial magnetic stimulation (rTMS) has developed into a novel neurological and psychiatric tool that can be used to investigate the neurobiology of cognitive function. Recent studies have demonstrated that low-frequency rTMS (≤1Hz) affects synaptic plasticity in rats with vascular dementia (VaD), and it ameliorates the spatial cognitive ability in mice with Aβ1-42-mediated memory deficits, but there are little concerns about the effects of rTMS on normal aging related cognition and synaptic plasticity changes. Thus, the current study investigated the effects of rTMS on spatial memory behavior, neuron and synapse morphology in the hippocampus, and synaptic protein markers and brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) in normal aging mice, to illustrate the mechanisms of rTMS in regulating cognitive capacity. Relative to adult animals, aging caused hippocampal-dependent cognitive impairment, simultaneously inhibited the activation of the BDNF-TrkB signaling pathway, reduced the transcription and expression of synaptic protein markers: synaptophysin (SYN), growth associated protein 43 (GAP43) and post-synaptic density protein 95 (PSD95), as well as decreased synapse density and PSD (post-synaptic density) thickness. Interestingly, rTMS with low intensity (110% average resting motor threshold intensity, 1Hz, LIMS) triggered the activation of BDNF and TrkB, upregulated the level of synaptic protein markers, and increased synapse density and thickened PSD, and further reversed the spatial cognition dysfunction in aging mice. Conversely, high-intensity magnetic stimulation (150% average resting motor threshold intensity, 1Hz, HIMS) appeared to be detrimental, inducing thinning of PSDs, disordered synaptic structure, and a large number of

  7. Investigation of hippocampal synaptic transmission and plasticity in mice deficient in the actin-binding protein Drebrin

    Science.gov (United States)

    Willmes, Claudia G.; Mack, Till G. A.; Ledderose, Julia; Schmitz, Dietmar; Wozny, Christian; Eickholt, Britta J.

    2017-01-01

    The dynamic regulation of the actin cytoskeleton plays a key role in controlling the structure and function of synapses. It is vital for activity-dependent modulation of synaptic transmission and long-term changes in synaptic morphology associated with memory consolidation. Several regulators of actin dynamics at the synapse have been identified, of which a salient one is the postsynaptic actin stabilising protein Drebrin (DBN). It has been suggested that DBN modulates neurotransmission and changes in dendritic spine morphology associated with synaptic plasticity. Given that a decrease in DBN levels is correlated with cognitive deficits associated with ageing and dementia, it was hypothesised that DBN protein abundance instructs the integrity and function of synapses. We created a novel DBN deficient mouse line. Analysis of gross brain and neuronal morphology revealed no phenotype in the absence of DBN. Electrophysiological recordings in acute hippocampal slices and primary hippocampal neuronal cultures showed that basal synaptic transmission, and both long-term and homeostatic synaptic plasticity were unchanged, suggesting that loss of DBN is not sufficient in inducing synapse dysfunction. We propose that the overall lack of changes in synaptic function and plasticity in DBN deficient mice may indicate robust compensatory mechanisms that safeguard cytoskeleton dynamics at the synapse. PMID:28198431

  8. Spike timing regulation on the millisecond scale by distributed synaptic plasticity at the cerebellum input stage: a simulation study

    Directory of Open Access Journals (Sweden)

    Jesus A Garrido

    2013-05-01

    Full Text Available The way long-term synaptic plasticity regulates neuronal spike patterns is not completely understood. This issue is especially relevant for the cerebellum, which is endowed with several forms of long-term synaptic plasticity and has been predicted to operate as a timing and a learning machine. Here we have used a computational model to simulate the impact of multiple distributed synaptic weights in the cerebellar granular layer network. In response to mossy fiber bursts, synaptic weights at multiple connections played a crucial role to regulate spike number and positioning in granule cells. The weight at mossy fiber to granule cell synapses regulated the delay of the first spike and the weight at mossy fiber and parallel fiber to Golgi cell synapses regulated the duration of the time-window during which the first-spike could be emitted. Moreover, the weights of synapses controlling Golgi cell activation regulated the intensity of granule cell inhibition and therefore the number of spikes that could be emitted. First spike timing was regulated with millisecond precision and the number of spikes ranged from 0 to 3. Interestingly, different combinations of synaptic weights optimized either first-spike timing precision or spike number, efficiently controlling transmission and filtering properties. These results predict that distributed synaptic plasticity regulates the emission of quasi-digital spike patterns on the millisecond time scale and allows the cerebellar granular layer to flexibly control burst transmission along the mossy fiber pathway.

  9. 5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders.

    Science.gov (United States)

    Ciranna, Lucia; Catania, Maria Vincenza

    2014-01-01

    Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD.

  10. 5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders

    Directory of Open Access Journals (Sweden)

    Lucia eCiranna

    2014-08-01

    Full Text Available Serotonin type 7 receptors (5-HT7 are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD, including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD.

  11. Loss of catecholaminergic neuromodulation of persistent forms of hippocampal synaptic plasticity with increasing age

    Directory of Open Access Journals (Sweden)

    Hannah Twarkowski

    2016-09-01

    Full Text Available Neuromodulation by means of the catecholaminergic system is a key component of motivation-driven learning and behaviorally modulated hippocampal synaptic plasticity. In particular, dopamine acting on D1/D5 receptors and noradrenaline acting on beta-adrenergic receptors exert a very potent regulation of forms of hippocampal synaptic plasticity that last for very long-periods of time (>24h, and occur in conjunction with novel spatial learning. Antagonism of these receptors not only prevents long-term potentiation (LTP and long-term depression (LTD, but prevents the memory of the spatial event that, under normal circumstances, leads to the perpetuation of these plasticity forms. Spatial learning behavior that normally comes easily to rats, such as object-place learning and spatial reference learning, becomes increasingly impaired with aging. Middle-aged animals display aging-related deficits of specific, but not all, components of spatial learning, and one possibility is that this initial manifestation of decrements in learning ability that become manifest in middle-age relate to changes in motivation, attention and/or the regulation by neuromodulatory systems of these behavioral states.Here, we compared the regulation by dopaminergic D1/D5 and beta-adrenergic receptors of persistent LTP in young (2-4 month old and middle-aged (8-14 month old rats. We observed in young rats, that weak potentiation that typically lasts for ca. 2h could be strengthened into persistent (>24h LTP by pharmacological activation of either D1/D5 or beta-adrenergic receptors. By contrast, no such facilitation occurred in middle-aged rats. This difference was not related to an ostensible learning deficit: a facilitation of weak potentiation into LTP by spatial learning was possible both in young and middle-aged rats. It was also not directly linked to deficits in LTP: strong afferent stimulation resulted in equivalent LTP in both age groups. We postulate that this change in

  12. Loss of Catecholaminergic Neuromodulation of Persistent Forms of Hippocampal Synaptic Plasticity with Increasing Age

    Science.gov (United States)

    Twarkowski, Hannah; Manahan-Vaughan, Denise

    2016-01-01

    Neuromodulation by means of the catecholaminergic system is a key component of motivation-driven learning and behaviorally modulated hippocampal synaptic plasticity. In particular, dopamine acting on D1/D5 receptors and noradrenaline acting on beta-adrenergic receptors exert a very potent regulation of forms of hippocampal synaptic plasticity that last for very long-periods of time (>24 h), and occur in conjunction with novel spatial learning. Antagonism of these receptors not only prevents long-term potentiation (LTP) and long-term depression (LTD), but prevents the memory of the spatial event that, under normal circumstances, leads to the perpetuation of these plasticity forms. Spatial learning behavior that normally comes easily to rats, such as object-place learning and spatial reference learning, becomes increasingly impaired with aging. Middle-aged animals display aging-related deficits of specific, but not all, components of spatial learning, and one possibility is that this initial manifestation of decrements in learning ability that become apparent in middle-age relate to changes in motivation, attention and/or the regulation by neuromodulatory systems of these behavioral states. Here, we compared the regulation by dopaminergic D1/D5 and beta-adrenergic receptors of persistent LTP in young (2–4 month old) and middle-aged (8–14 month old) rats. We observed in young rats, that weak potentiation that typically lasts for ca. 2 h could be strengthened into persistent (>24 h) LTP by pharmacological activation of either D1/D5 or beta-adrenergic receptors. By contrast, no such facilitation occurred in middle-aged rats. This difference was not related to an ostensible learning deficit: a facilitation of weak potentiation into LTP by spatial learning was possible both in young and middle-aged rats. It was also not directly linked to deficits in LTP: strong afferent stimulation resulted in equivalent LTP in both age groups. We postulate that this change in

  13. Translational control by eIF2α kinases in long-lasting synaptic plasticity and long-term memory.

    Science.gov (United States)

    Trinh, Mimi A; Klann, Eric

    2013-10-01

    Although the requirement for new protein synthesis in synaptic plasticity and memory has been well established, recent genetic, molecular, electrophysiological, and pharmacological studies have broadened our understanding of the translational control mechanisms that are involved in these processes. One of the critical translational control points mediating general and gene-specific translation depends on the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) by four regulatory kinases. Here, we review the literature highlighting the important role for proper translational control via regulation of eIF2α phosphorylation by its kinases in long-lasting synaptic plasticity and long-term memory.

  14. Proteolytic regulation of synaptic plasticity in the mouse primary visual cortex: analysis of matrix metalloproteinase 9 deficient mice.

    Science.gov (United States)

    Kelly, Emily A; Russo, Amanda S; Jackson, Cory D; Lamantia, Cassandra E; Majewska, Ania K

    2015-01-01

    The extracellular matrix (ECM) is known to play important roles in regulating neuronal recovery from injury. The ECM can also impact physiological synaptic plasticity, although this process is less well understood. To understand the impact of the ECM on synaptic function and remodeling in vivo, we examined ECM composition and proteolysis in a well-established model of experience-dependent plasticity in the visual cortex. We describe a rapid change in ECM protein composition during Ocular Dominance Plasticity (ODP) in adolescent mice, and a loss of ECM remodeling in mice that lack the extracellular protease, matrix metalloproteinase-9 (MMP9). Loss of MMP9 also attenuated functional ODP following monocular deprivation (MD) and reduced excitatory synapse density and spine density in sensory cortex. While we observed no change in the morphology of existing dendritic spines, spine dynamics were altered, and MMP9 knock-out (KO) mice showed increased turnover of dendritic spines over a period of 2 days. We also analyzed the effects of MMP9 loss on microglia, as these cells are involved in extracellular remodeling and have been recently shown to be important for synaptic plasticity. MMP9 KO mice exhibited very limited changes in microglial morphology. Ultrastructural analysis, however, showed that the extracellular space surrounding microglia was increased, with concomitant increases in microglial inclusions, suggesting possible changes in microglial function in the absence of MMP9. Taken together, our results show that MMP9 contributes to ECM degradation, synaptic dynamics and sensory-evoked plasticity in the mouse visual cortex.

  15. Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits

    Science.gov (United States)

    Fried, Peter J.; Schilberg, Lukas; Brem, Anna-Katharine; Saxena, Sadhvi; Wong, Bonnie; Cypess, Aaron M.; Horton, Edward S.; Pascual-Leone, Alvaro

    2016-01-01

    Background Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer’s disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed. Objective Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition. Methods A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores. Results In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance. Conclusion Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions. PMID:27636847

  16. Strain-dependent variations in spatial learning and in hippocampal synaptic plasticity in the dentate gyrus of freely behaving rats

    Directory of Open Access Journals (Sweden)

    Denise eManahan-Vaughan

    2011-03-01

    Full Text Available Hippocampal synaptic plasticity is believed to comprise the cellular basis for spatial learning. Strain-dependent differences in synaptic plasticity in the CA1 region have been reported. However, it is not known whether these differences extend to other synapses within the trisynaptic circuit, although there is evidence for morphological variations within that path. We investigated whether Wistar and Hooded Lister (HL rat strains express differences in synaptic plasticity in the dentate gyrus in vivo. We also explored whether they exhibit differences in the ability to engage in spatial learning in an 8-arm radial maze. Basal synaptic transmission was stable over a 24h period in both rat strains, and the input-output relationship of both strains was not significantly different. Paired-pulse analysis revealed significantly less paired-pulse facilitation in the Hooded Lister strain when pulses were given 40-100 msec apart. Low frequency stimulation at 1Hz evoked long-term depression (>24h in Wistar and short-term depression (<2h in HL rats; 200Hz stimulation induced long-term potentiation (>24h in Wistar, and a transient, significantly smaller potentiation (<1h in HL rats, suggesting that HL rats have higher thresholds for expression of persistent synaptic plasticity. Training for 10d in an 8-arm radial maze revealed that HL rats master the working memory task faster than Wistar rats, although both strains show an equivalent performance by the end of the trial period. HL rats also perform more efficiently in a double working and reference memory task. On the other hand, Wistar rats show better reference memory performance on the final (8-10 days of training. Wistar rats were less active and more anxious than HL rats.These data suggest that strain-dependent variations in hippocampal synaptic plasticity occur in different hippocampal synapses. A clear correlation with differences in spatial learning is not evident however.

  17. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity.

    Science.gov (United States)

    Liu, Zhigang; Patil, Ishan Y; Jiang, Tianyi; Sancheti, Harsh; Walsh, John P; Stiles, Bangyan L; Yin, Fei; Cadenas, Enrique

    2015-01-01

    High-fat diet (HFD)-induced obesity is associated with insulin resistance, which may affect brain synaptic plasticity through impairment of insulin-sensitive processes underlying neuronal survival, learning, and memory. The experimental model consisted of 3 month-old C57BL/6J mice fed either a normal chow diet (control group) or a HFD (60% of calorie from fat; HFD group) for 12 weeks. This model was characterized as a function of time in terms of body weight, fasting blood glucose and insulin levels, HOMA-IR values, and plasma triglycerides. IRS-1/Akt pathway was assessed in primary hepatocytes and brain homogenates. The effect of HFD in brain was assessed by electrophysiology, input/output responses and long-term potentiation. HFD-fed mice exhibited a significant increase in body weight, higher fasting glucose- and insulin levels in plasma, lower glucose tolerance, and higher HOMA-IR values. In liver, HFD elicited (a) a significant decrease of insulin receptor substrate (IRS-1) phosphorylation on Tyr608 and increase of Ser307 phosphorylation, indicative of IRS-1 inactivation; (b) these changes were accompanied by inflammatory responses in terms of increases in the expression of NFκB and iNOS and activation of the MAP kinases p38 and JNK; (c) primary hepatocytes from mice fed a HFD showed decreased cellular oxygen consumption rates (indicative of mitochondrial functional impairment); this can be ascribed partly to a decreased expression of PGC1α and mitochondrial biogenesis. In brain, HFD feeding elicited (a) an inactivation of the IRS-1 and, consequentially, (b) a decreased expression and plasma membrane localization of the insulin-sensitive neuronal glucose transporters GLUT3/GLUT4; (c) a suppression of the ERK/CREB pathway, and (d) a substantial decrease in long-term potentiation in the CA1 region of hippocampus (indicative of impaired synaptic plasticity). It may be surmised that 12 weeks fed with HFD induce a systemic insulin resistance that impacts

  18. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Zhigang Liu

    Full Text Available High-fat diet (HFD-induced obesity is associated with insulin resistance, which may affect brain synaptic plasticity through impairment of insulin-sensitive processes underlying neuronal survival, learning, and memory. The experimental model consisted of 3 month-old C57BL/6J mice fed either a normal chow diet (control group or a HFD (60% of calorie from fat; HFD group for 12 weeks. This model was characterized as a function of time in terms of body weight, fasting blood glucose and insulin levels, HOMA-IR values, and plasma triglycerides. IRS-1/Akt pathway was assessed in primary hepatocytes and brain homogenates. The effect of HFD in brain was assessed by electrophysiology, input/output responses and long-term potentiation. HFD-fed mice exhibited a significant increase in body weight, higher fasting glucose- and insulin levels in plasma, lower glucose tolerance, and higher HOMA-IR values. In liver, HFD elicited (a a significant decrease of insulin receptor substrate (IRS-1 phosphorylation on Tyr608 and increase of Ser307 phosphorylation, indicative of IRS-1 inactivation; (b these changes were accompanied by inflammatory responses in terms of increases in the expression of NFκB and iNOS and activation of the MAP kinases p38 and JNK; (c primary hepatocytes from mice fed a HFD showed decreased cellular oxygen consumption rates (indicative of mitochondrial functional impairment; this can be ascribed partly to a decreased expression of PGC1α and mitochondrial biogenesis. In brain, HFD feeding elicited (a an inactivation of the IRS-1 and, consequentially, (b a decreased expression and plasma membrane localization of the insulin-sensitive neuronal glucose transporters GLUT3/GLUT4; (c a suppression of the ERK/CREB pathway, and (d a substantial decrease in long-term potentiation in the CA1 region of hippocampus (indicative of impaired synaptic plasticity. It may be surmised that 12 weeks fed with HFD induce a systemic insulin resistance that impacts

  19. Homeostatic Synaptic Plasticity Can Explain Post-traumatic Epileptogenesis in Chronically Isolated Neocortex

    Science.gov (United States)

    Houweling, Arthur R.; Bazhenov, Maxim; Timofeev, Igor; Steriade, Mircea; Sejnowski, Terrence J.

    2010-01-01

    Chronically isolated neocortex develops chronic hyperexcitability and focal epileptogenesis in a period of days to weeks. The mechanisms operating in this model of post-traumatic epileptogenesis are not well understood. We hypothesized that the spontaneous burst discharges recorded in chronically isolated neocortex result from homeostatic plasticity (a mechanism generally assumed to stabilize neuronal activity) induced by low neuronal activity after deafferentation. To test this hypothesis we constructed computer models of neocortex incorporating a biologically based homeostatic plasticity rule that operates to maintain firing rates. After deafferentation, homeostatic upregulation of excitatory synapses on pyramidal cells, either with or without concurrent downregulation of inhibitory synapses or upregulation of intrinsic excitability, initiated slowly repeating burst discharges that closely resembled the epileptiform burst discharges recorded in chronically isolated neocortex. These burst discharges lasted a few hundred ms, propagated at 1–3 cm/s and consisted of large (10–15 mV) intracellular depolarizations topped by a small number of action potentials. Our results support a role for homeostatic synaptic plasticity as a novel mechanism of post-traumatic epileptogenesis. PMID:15483049

  20. Sleep deprivation during a specific 3-hour time window post-training impairs hippocampal synaptic plasticity and memory

    OpenAIRE

    Prince, Toni-Moi; Wimmer, Mathieu; Choi, Jennifer; Havekes, Robbert; Aton, Sara; Abel, Ted

    2013-01-01

    Sleep deprivation disrupts hippocampal function and plasticity. In particular, long-term memory consolidation is impaired by sleep deprivation, suggesting that a specific critical period exists following learning during which sleep is necessary. To elucidate the impact of sleep deprivation on long-term memory consolidation and synaptic plasticity, long-term memory was assessed when mice were sleep deprived following training in the hippocampus-dependent object place recognition task. We found...

  1. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury.

    Science.gov (United States)

    Huie, J Russell; Stuck, Ellen D; Lee, Kuan H; Irvine, Karen-Amanda; Beattie, Michael S; Bresnahan, Jacqueline C; Grau, James W; Ferguson, Adam R

    2015-01-01

    Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity.

  2. Modulation of Rho GTPases rescues brain mitochondrial dysfunction, cognitive deficits and aberrant synaptic plasticity in female mice modeling Rett syndrome.

    Science.gov (United States)

    De Filippis, Bianca; Valenti, Daniela; Chiodi, Valentina; Ferrante, Antonella; de Bari, Lidia; Fiorentini, Carla; Domenici, Maria Rosaria; Ricceri, Laura; Vacca, Rosa Anna; Fabbri, Alessia; Laviola, Giovanni

    2015-06-01

    Rho GTPases are molecules critically involved in neuronal plasticity and cognition. We have previously reported that modulation of brain Rho GTPases by the bacterial toxin CNF1 rescues the neurobehavioral phenotype in MeCP2-308 male mice, a model of Rett syndrome (RTT). RTT is a rare X-linked neurodevelopmental disorder and a genetic cause of intellectual disability, for which no effective therapy is available. Mitochondrial dysfunction has been proposed to be involved in the mechanism of the disease pathogenesis. Here we demonstrate that modulation of Rho GTPases by CNF1 rescues the reduced mitochondrial ATP production via oxidative phosphorylation in the brain of MeCP2-308 heterozygous female mice, the condition which more closely recapitulates that of RTT patients. In RTT mouse brain, CNF1 also restores the alterations in the activity of the mitochondrial respiratory chain (MRC) complexes and of ATP synthase, the molecular machinery responsible for the majority of cell energy production. Such effects were achieved through the upregulation of the protein content of those MRC complexes subunits, which were defective in RTT mouse brain. Restored mitochondrial functionality was accompanied by the rescue of deficits in cognitive function (spatial reference memory in the Barnes maze), synaptic plasticity (long-term potentiation) and Tyr1472 phosphorylation of GluN2B, which was abnormally enhanced in the hippocampus of RTT mice. Present findings bring into light previously unknown functional mitochondrial alterations in the brain of female mice modeling RTT and provide the first evidence that RTT brain mitochondrial dysfunction can be rescued by modulation of Rho GTPases.

  3. 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.

  4. A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Takashi Nakano

    2010-02-01

    Full Text Available Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD, the combination with dopamine switches LTD to long-term potentiation (LTP, which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32, as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA, protein phosphatase 2A (PP2A, and the phosphorylation site at threonine 75 of DARPP-32 (Thr75 served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B-CK1 (casein kinase 1-Cdk5 (cyclin-dependent kinase 5-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP. The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The

  5. Chaos and Correlated Avalanches in Excitatory Neural Networks with Synaptic Plasticity

    Science.gov (United States)

    Pittorino, Fabrizio; Ibáñez-Berganza, Miguel; di Volo, Matteo; Vezzani, Alessandro; Burioni, Raffaella

    2017-03-01

    A collective chaotic phase with power law scaling of activity events is observed in a disordered mean field network of purely excitatory leaky integrate-and-fire neurons with short-term synaptic plasticity. The dynamical phase diagram exhibits two transitions from quasisynchronous and asynchronous regimes to the nontrivial, collective, bursty regime with avalanches. In the homogeneous case without disorder, the system synchronizes and the bursty behavior is reflected into a period doubling transition to chaos for a two dimensional discrete map. Numerical simulations show that the bursty chaotic phase with avalanches exhibits a spontaneous emergence of persistent time correlations and enhanced Kolmogorov complexity. Our analysis reveals a mechanism for the generation of irregular avalanches that emerges from the combination of disorder and deterministic underlying chaotic dynamics.

  6. Cbln1 is essential for synaptic integrity and plasticity in the cerebellum.

    Science.gov (United States)

    Hirai, Hirokazu; Pang, Zhen; Bao, Dashi; Miyazaki, Taisuke; Li, Leyi; Miura, Eriko; Parris, Jennifer; Rong, Yongqi; Watanabe, Masahiko; Yuzaki, Michisuke; Morgan, James I

    2005-11-01

    Cbln1 is a cerebellum-specific protein of previously unknown function that is structurally related to the C1q and tumor necrosis factor families of proteins. We show that Cbln1 is a glycoprotein secreted from cerebellar granule cells that is essential for three processes in cerebellar Purkinje cells: the matching and maintenance of pre- and postsynaptic elements at parallel fiber-Purkinje cell synapses, the establishment of the proper pattern of climbing fiber-Purkinje cell innervation, and induction of long-term depression at parallel fiber-Purkinje cell synapses. Notably, the phenotype of cbln1-null mice mimics loss-of-function mutations in the orphan glutamate receptor, GluR delta2, a gene selectively expressed in Purkinje neurons. Therefore, Cbln1 secreted from presynaptic granule cells may be a component of a transneuronal signaling pathway that controls synaptic structure and plasticity.

  7. Synchronization and long-time memory in neural networks with inhibitory hubs and synaptic plasticity

    Science.gov (United States)

    Bertolotti, Elena; Burioni, Raffaella; di Volo, Matteo; Vezzani, Alessandro

    2017-01-01

    We investigate the dynamical role of inhibitory and highly connected nodes (hub) in synchronization and input processing of leaky-integrate-and-fire neural networks with short term synaptic plasticity. We take advantage of a heterogeneous mean-field approximation to encode the role of network structure and we tune the fraction of inhibitory neurons fI and their connectivity level to investigate the cooperation between hub features and inhibition. We show that, depending on fI, highly connected inhibitory nodes strongly drive the synchronization properties of the overall network through dynamical transitions from synchronous to asynchronous regimes. Furthermore, a metastable regime with long memory of external inputs emerges for a specific fraction of hub inhibitory neurons, underlining the role of inhibition and connectivity also for input processing in neural networks.

  8. Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms.

    Science.gov (United States)

    Morikawa, H; Paladini, C A

    2011-12-15

    Although the roles of dopaminergic signaling in learning and behavior are well established, it is not fully understood how the activity of dopaminergic neurons is dynamically regulated under different conditions in a constantly changing environment. Dopamine neurons must integrate sensory, motor, and cognitive information online to inform the organism to pursue outcomes with the highest reward probability. In this article, we provide an overview of recent advances on the intrinsic, extrinsic (i.e., synaptic), and plasticity mechanisms controlling dopamine neuron activity, mostly focusing on mechanistic studies conducted using ex vivo brain slice preparations. We also hope to highlight some unresolved questions regarding information processing that takes place at dopamine neurons, thereby stimulating further investigations at different levels of analysis.

  9. Protective effect of tetrahydroxy stilbene glucoside on learning and memory by regulating synaptic plasticity

    Institute of Scientific and Technical Information of China (English)

    Hong-bo Luo; Yun Li; Zun-jing Liu; Li Cao; Zhi-qiang Zhang; Yong Wang; Xiao-yan Zhang; Zhao Liu; Xiang-qun Shi

    2016-01-01

    Damage to synaptic plasticity induced by neurotoxicity of amyloid-beta is regarded to be one of the pathological mechanisms of learning and memory disabilities in Alzheimer’s disease patients. This study assumed that the damage of amyloid-beta to learning and memory abilities was strongly associated with the changes in the Fyn/N-methyl-D-aspartate receptor 2B (NR2B) expression. An APP695V7171 transgenic mouse model of Alzheimer’s disease was used and treatment with tetrahydroxy-stilbene glucoside was administered intragas-trically. Results showed that intragastric administration of tetrahydroxy-stilbene glucoside improved the learning and memory abilities of the transgenic mice through increasing NR2B receptors and Fyn expression. It also reversed parameters for synaptic interface structure of gray type I. These ifndings indicate that tetrahydroxy stilbene glucoside has protective effects on the brain, and has prospects for its clinical application to improve the learning and memory abilities and treat Alzheimer’s disease.

  10. A novel fibroblast growth factor receptor family member promotes neuronal outgrowth and synaptic plasticity in aplysia.

    Science.gov (United States)

    Pollak, Daniela D; Minh, Bui Quang; Cicvaric, Ana; Monje, Francisco J

    2014-11-01

    Fibroblast Growth Factor (FGF) Receptors (FGFRs) regulate essential biological processes, including embryogenesis, angiogenesis, cellular growth and memory-related long-term synaptic plasticity. Whereas canonical FGFRs depend exclusively on extracellular Immunoglobulin (Ig)-like domains for ligand binding, other receptor types, including members of the tropomyosin-receptor-kinase (Trk) family, use either Ig-like or Leucine-Rich Repeat (LRR) motifs, or both. Little is known, however, about the evolutionary events leading to the differential incorporation of LRR domains into Ig-containing tyrosine kinase receptors. Moreover, although FGFRs have been identified in many vertebrate species, few reports describe their existence in invertebrates. Information about the biological relevance of invertebrate FGFRs and evolutionary divergences between them and their vertebrate counterparts is therefore limited. Here, we characterized ApLRRTK, a neuronal cell-surface protein recently identified in Aplysia. We unveiled ApLRRTK as the first member of the FGFRs family deprived of Ig-like domains that instead contains extracellular LRR domains. We describe that ApLRRTK exhibits properties typical of canonical vertebrate FGFRs, including promotion of FGF activity, enhancement of neuritic outgrowth and signaling via MAPK and the transcription factor CREB. ApLRRTK also enhanced the synaptic efficiency of neurons known to mediate in vivo memory-related defensive behaviors. These data reveal a novel molecular regulator of neuronal function in invertebrates, provide the first evolutionary linkage between LRR proteins and FGFRs and unveil an unprecedented mechanism of FGFR gene diversification in primeval central nervous systems.

  11. Different Compartments of Apical CA1 Dendrites Have Different Plasticity Thresholds for Expressing Synaptic Tagging and Capture

    Science.gov (United States)

    Sajikumar, Sreedharan; Korte, Martin

    2011-01-01

    The consolidation process from short- to long-term memory depends on the type of stimulation received from a specific neuronal network and on the cooperativity and associativity between different synaptic inputs converging onto a specific neuron. We show here that the plasticity thresholds for inducing LTP are different in proximal and distal…

  12. The role of astrocytic aquaporin-4 in synaptic plasticity and learning and memory

    Directory of Open Access Journals (Sweden)

    Jenny I. Szu

    2016-02-01

    Full Text Available Aquaporin-4 (AQP4 is the predominant water channel expressed by astrocytes in the central nervous system. AQP4 is widely expressed throughout the brain, especially at the blood-brain barrier where AQP4 is highly polarized to astrocytic foot processes in contact with blood vessels. The bidirectional water transport function of AQP4 suggests its role in cerebral water balance in the CNS. The regulation of AQP4 has been extensively investigated in various neuropathological conditions such as cerebral edema, epilepsy, and ischemia, however, the functional role of AQP4 in synaptic plasticity, learning, and memory is only beginning to be elucidated. In this review, we explore the current literature on AQP4 and its influence on LTP and LTD in the hippocampus as well as the potential relationship between AQP4 in learning and memory. We begin by discussing recent in vitro and in vivo studies using AQP4 knockout (KO and wild-type mice, in particular, the impairment of LTP and LTD observed in the hippocampus. Early evidence using AQP4 KO mice have suggested that impaired LTP and LTD is BDNF dependent. Others have indicated a possible link between defective LTP and the downregulation of glutamate transporter-1 which is rescued by chronic treatment of β-lactam antibiotic ceftriaxone. Furthermore, behavioral studies may shed some light into the functional role of AQP4 in learning and memory. AQP4 KO mice performances utilizing Morris water maze, object placement tests, and contextual fear conditioning proposed a specific role of AQP4 in memory consolidation. All together, these studies highlight the potential influence AQP4 may have on long term synaptic plasticity and memory.

  13. Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala.

    Directory of Open Access Journals (Sweden)

    Melissa S Monsey

    Full Text Available Epigenetic mechanisms, including histone acetylation and DNA methylation, have been widely implicated in hippocampal-dependent learning paradigms. Here, we have examined the role of epigenetic alterations in amygdala-dependent auditory Pavlovian fear conditioning and associated synaptic plasticity in the lateral nucleus of the amygdala (LA in the rat. Using Western blotting, we first show that auditory fear conditioning is associated with an increase in histone H3 acetylation and DNMT3A expression in the LA, and that training-related alterations in histone acetylation and DNMT3A expression in the LA are downstream of ERK/MAPK signaling. Next, we show that intra-LA infusion of the histone deacetylase (HDAC inhibitor TSA increases H3 acetylation and enhances fear memory consolidation; that is, long-term memory (LTM is enhanced, while short-term memory (STM is unaffected. Conversely, intra-LA infusion of the DNA methyltransferase (DNMT inhibitor 5-AZA impairs fear memory consolidation. Further, intra-LA infusion of 5-AZA was observed to impair training-related increases in H3 acetylation, and pre-treatment with TSA was observed to rescue the memory consolidation deficit induced by 5-AZA. In our final series of experiments, we show that bath application of either 5-AZA or TSA to amygdala slices results in significant impairment or enhancement, respectively, of long-term potentiation (LTP at both thalamic and cortical inputs to the LA. Further, the deficit in LTP following treatment with 5-AZA was observed to be rescued at both inputs by co-application of TSA. Collectively, these findings provide strong support that histone acetylation and DNA methylation work in concert to regulate memory consolidation of auditory fear conditioning and associated synaptic plasticity in the LA.

  14. Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala.

    Science.gov (United States)

    Monsey, Melissa S; Ota, Kristie T; Akingbade, Irene F; Hong, Ellie S; Schafe, Glenn E

    2011-01-01

    Epigenetic mechanisms, including histone acetylation and DNA methylation, have been widely implicated in hippocampal-dependent learning paradigms. Here, we have examined the role of epigenetic alterations in amygdala-dependent auditory Pavlovian fear conditioning and associated synaptic plasticity in the lateral nucleus of the amygdala (LA) in the rat. Using Western blotting, we first show that auditory fear conditioning is associated with an increase in histone H3 acetylation and DNMT3A expression in the LA, and that training-related alterations in histone acetylation and DNMT3A expression in the LA are downstream of ERK/MAPK signaling. Next, we show that intra-LA infusion of the histone deacetylase (HDAC) inhibitor TSA increases H3 acetylation and enhances fear memory consolidation; that is, long-term memory (LTM) is enhanced, while short-term memory (STM) is unaffected. Conversely, intra-LA infusion of the DNA methyltransferase (DNMT) inhibitor 5-AZA impairs fear memory consolidation. Further, intra-LA infusion of 5-AZA was observed to impair training-related increases in H3 acetylation, and pre-treatment with TSA was observed to rescue the memory consolidation deficit induced by 5-AZA. In our final series of experiments, we show that bath application of either 5-AZA or TSA to amygdala slices results in significant impairment or enhancement, respectively, of long-term potentiation (LTP) at both thalamic and cortical inputs to the LA. Further, the deficit in LTP following treatment with 5-AZA was observed to be rescued at both inputs by co-application of TSA. Collectively, these findings provide strong support that histone acetylation and DNA methylation work in concert to regulate memory consolidation of auditory fear conditioning and associated synaptic plasticity in the LA.

  15. Spinal motoneuron synaptic plasticity after axotomy in the absence of inducible nitric oxide synthase

    Directory of Open Access Journals (Sweden)

    Zanon Renata G

    2010-05-01

    Full Text Available Abstract Background Astrocytes play a major role in preserving and restoring structural and physiological integrity following injury to the nervous system. After peripheral axotomy, reactive gliosis propagates within adjacent spinal segments, influenced by the local synthesis of nitric oxide (NO. The present work investigated the importance of inducible nitric oxide synthase (iNOS activity in acute and late glial responses after injury and in major histocompatibility complex class I (MHC I expression and synaptic plasticity of inputs to lesioned alpha motoneurons. Methods In vivo analyses were carried out using C57BL/6J-iNOS knockout (iNOS-/- and C57BL/6J mice. Glial response after axotomy, glial MHC I expression, and the effects of axotomy on synaptic contacts were measured using immunohistochemistry and transmission electron microscopy. For this purpose, 2-month-old animals were sacrificed and fixed one or two weeks after unilateral sciatic nerve transection, and spinal cord sections were incubated with antibodies against classical MHC I, GFAP (glial fibrillary acidic protein - an astroglial marker, Iba-1 (an ionized calcium binding adaptor protein and a microglial marker or synaptophysin (a presynaptic terminal marker. Western blotting analysis of MHC I and nNOS expression one week after lesion were also performed. The data were analyzed using a two-tailed Student's t test for parametric data or a two-tailed Mann-Whitney U test for nonparametric data. Results A statistical difference was shown with respect to astrogliosis between strains at the different time points studied. Also, MHC I expression by iNOS-/- microglial cells did not increase at one or two weeks after unilateral axotomy. There was a difference in synaptophysin expression reflecting synaptic elimination, in which iNOS-/- mice displayed a decreased number of the inputs to alpha motoneurons, in comparison to that of C57BL/6J. Conclusion The findings herein indicate that i

  16. Morphological and functional abnormalities in mitochondria associated with synaptic degeneration in prion disease.

    Science.gov (United States)

    Sisková, Zuzana; Mahad, Don Joseph; Pudney, Carianne; Campbell, Graham; Cadogan, Mark; Asuni, Ayodeji; O'Connor, Vincent; Perry, Victor Hugh

    2010-09-01

    Synaptic and dendritic pathology is a well-documented component of prion disease. In common with other neurodegenerative diseases that contain an element of protein misfolding, little is known about the underlying mechanisms of synaptic degeneration. In particular, in prion disease the relationship between synaptic malfunction, degeneration, and mitochondria has been neglected. We investigated a wide range of mitochondrial parameters, including changes in mitochondrial density, inner membrane ultrastructure, functional properties and nature of mitochondrial DNA from hippocampal tissue of mice with prion disease, which have ongoing synaptic pathology. Our results indicate that despite a lack of detectable changes in either mitochondrial density or expression of the mitochondrial proteins, mitochondrial function was impaired when compared with age-matched control animals. We observed changes in mitochondrial inner membrane morphology and a reduction in the cytochrome c oxidase activity relative to a sustained level of mitochondrial proteins such as porin and individual, functionally important subunits of complex II and complex IV. These data support the idea that mitochondrial dysfunction appears to occur due to inhibition or modification of respiratory complex rather than deletions of mitochondrial DNA. Indeed, these changes were seen in the stratum radiatum where synaptic pathology is readily detected, indicating that mitochondrial function is impaired and could potentially contribute to or even initiate the synaptic pathology in prion disease.

  17. The Role of GluK4 in Synaptic Plasticity and Affective Behavior in Mice

    Science.gov (United States)

    Catches, Justin Samuel

    Kainate receptors (KARs) are glutamate-gated ion channels that signal through both ionotropic and metabotropic pathways (Contractor et al., 2011). Combinations of five KAR subunits (GluK1-5) form tetrameric receptors with GluK1, GluK2, and GluK3 able to form functional homomeric channels. The high-affinity subunits, GluK4 and GluK5, do not form homomeric channels but modify the properties of heteromeric receptors. Expression of the GluK4 receptor subunit in the forebrain is restricted to the CA3 region of the hippocampus and dentate gyrus regions where KARs modulate synaptic plasticity. In this study, ablation of Grik4, which encodes GluK4, in mice reduced KAR synaptic currents and altered activation properties of postsynaptic receptors but left two forms of presynaptic short-term plasticity intact. Disruption of both Grik4 and Grik5 caused complete loss of the postsynaptic ionotropic KAR current and impaired presynaptic frequency facilitation. Additionally, KAR surface expression was altered at pre- and postsynaptic sites at the MF synapse. Despite the loss of ionotropic signaling, KAR-mediated inhibition of the slow afterhyperpolarization current, which is dependent on metabotropic signaling, was intact in CA3 neurons. Long-term potentiation at the MF-CA3 synapse was reduced, likely through a loss of KAR modulation of excitability of the presynaptic MF axons. Genetic variants in the human GRIK4 gene alter the susceptibility for affective disorders (Bloss and Hunter, 2010). We found that ablation of Grik4 in mice resulted in reduced anxiety and an antidepressant-like phenotype. In the elevated zero-maze, a test for anxiety and risk taking behavior, and in two anxiogenic tests, marble-burying and novelty-induced suppression of feeding, anxiety-like behavior was consistently reduced in knockout animals. In the forced swim, a test of learned helplessness used to determine depression-like behavior, knockout mice demonstrated significantly less immobility suggesting

  18. Proteolytic Regulation of Synaptic Plasticity in the Mouse Primary Visual Cortex: Analysis of Matrix Metalloproteinase 9 Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Emily A Kelly

    2015-09-01

    Full Text Available The extracellular matrix (ECM is known to play important roles in regulating neuronal recovery from injury. The ECM can also impact physiological synaptic plasticity, although this process is less well understood. To understand the impact of the ECM on synaptic function and remodeling in vivo, we examined ECM composition and proteolysis in a well-established model of experience-dependent plasticity in the visual cortex. We describe a rapid change in ECM protein composition during ocular dominance plasticity in adolescent mice, and a loss of ECM remodeling in mice that lack the extracellular protease, matrix metalloproteinase-9 (MMP9. Loss of MMP9 also attenuated functional ocular dominance plasticity following monocular deprivation and reduced excitatory synapse density and spine density in sensory cortex. While we observed no change in the morphology of existing dendritic spines, spine dynamics were altered, and MMP9 knock-out (KO mice showed increased turnover of dendritic spines over a period of 2 days. We also analyzed the effects of MMP9 loss on microglia, as these cells are involved in extracellular remodeling and have been recently shown to be important for synaptic plasticity. MMP9 KO mice exhibited very limited changes in microglial morphology. Ultrastructural analysis, however, showed that the extracellular space surrounding microglia was increased, with concomitant increases in microglial inclusions, suggesting possible changes in microglial function in the absence of MMP9. Taken together, our results show that MMP9 contributes to ECM degradation, synaptic dynamics and sensory-evoked plasticity in the mouse visual cortex.

  19. Simulating the Effects of Short-Term Synaptic Plasticity on Postsynaptic Dynamics in the Globus Pallidus

    Directory of Open Access Journals (Sweden)

    Moran eBrody

    2013-08-01

    Full Text Available The rat globus pallidus (GP is one of the nuclei of the basal ganglia and plays an important role in a variety of motor and cognitive processes. In vivo studies have shown that repetitive stimulation evokes complex modulations of GP activity. In vitro and computational studies have suggested that short-term synaptic plasticity (STP could be one of the underlying mechanisms. The current study used simplified single compartment modeling to explore the possible effect of STP on the activity of GP neurons during low and high frequency stimulation. To do this we constructed a model of a GP neuron connected to a small network of neurons from the three major input sources to GP neurons: striatum (Str, subthalamic nucleus (STN and GP collaterals. All synapses were implemented with a kinetic model of STP. The in vitro recordings of responses to low frequency repetitive stimulation were highly reconstructed, including rate changes and locking to the stimulus. Mainly involved were fast forms of plasticity which have been found at these synapses. . The simulations were qualitatively compared to a data set previously recorded in vitro in our lab. Reconstructions of experimental responses to high frequency stimulation required adding slower forms of plasticity to the STN and GP collateral synapses, as well as adding metabotropic receptors to the STN-GP synapses. These finding suggest the existence of as yet unreported slower short-term dynamics in the GP. The computational model made additional predictions about GP activity during low and high frequency stimulation that may further our understanding of the mechanisms underlying repetative stimulation of the GP.

  20. The BDNF Val66Met polymorphism enhances glutamatergic transmission but diminishes activity-dependent synaptic plasticity in the dorsolateral striatum.

    Science.gov (United States)

    Jing, Deqiang; Lee, Francis S; Ninan, Ipe

    2017-01-01

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene disrupts the activity-dependent release of BDNF, which might underlie its involvement in several neuropsychiatric disorders. Consistent with the potential role of regulated release of BDNF in synaptic functions, earlier studies have demonstrated that the BDNF Val66Met polymorphism impairs NMDA receptor-mediated synaptic transmission and plasticity in the hippocampus, the medial prefrontal cortex and the central amygdala. However, it is unknown whether the BDNF Val66Met polymorphism affects synapses in the dorsal striatum, which depends on cortical afferents for BDNF. Electrophysiological experiments revealed an enhanced glutamatergic transmission in the dorsolateral striatum (DLS) of knock-in mice containing the variant polymorphism (BDNF(Met/Met)) compared to the wild-type (BDNF(Val/Val)) mice. This increase in glutamatergic transmission is mediated by a potentiation in glutamate release and NMDA receptor transmission in the medium spiny neurons without any alterations in non-NMDA receptor-mediated transmission. We also observed an impairment of synaptic plasticity, both long-term potentiation and depression in the DLS neurons, in BDNF(Met/Met) mice. Thus, the BDNF Val66Met polymorphism exerts an increase in glutamatergic transmission but impairs synaptic plasticity in the dorsal striatum, which might play a role in its effect on neuropsychiatric symptoms. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

  1. Streptavidin-conjugated CdSe/ZnS quantum dots impaired synaptic plasticity and spatial memory process

    Energy Technology Data Exchange (ETDEWEB)

    Gao Xiaoyan [Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf (Germany); Tang Mingliang [Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences (China); Li Zhifeng; Zha Yingying [University of Science and Technology of China, CAS Key Laboratory of Brain Function and Disease, and School of Life Sciences (China); Cheng Guosheng [Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences (China); Yin Shuting [Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf (Germany); Chen Jutao; Ruan Diyun; Chen Lin; Wang Ming, E-mail: wming@ustc.edu.cn [University of Science and Technology of China, CAS Key Laboratory of Brain Function and Disease, and School of Life Sciences (China)

    2013-04-15

    Studies reported that quantum dots (QDs), as a novel probe, demonstrated a promising future for in vivo imaging, but also showed potential toxicity. This study is mainly to investigate in vivo response in the central nervous system (CNS) after exposure to QDs in a rat model of synaptic plasticity and spatial memory. Adult rats were exposed to streptavidin-conjugated CdSe/ZnS QDs (Qdots 525, purchased from Molecular Probes Inc.) by intraperitoneal injection for 7 days, followed by behavioral, electrophysiological, and biochemical examinations. The electrophysiological results show that input/output (I/O) functions were increased, while the peak of paired-pulse reaction and long-term potentiation were decreased after QDs insult, indicating synaptic transmission was enhanced and synaptic plasticity in the hippocampus was impaired. Meanwhile, behavioral experiments provide the evidence that QDs could impair rats' spatial memory process. All the results present evidences of interference of synaptic transmission and plasticity in rat hippocampal dentate gyrus area by QDs insult and suggest potential adverse issues which should be considered in QDs applications.

  2. MicroRNA132 Modulates Short-Term Synaptic Plasticity but Not Basal Release Probability in Hippocampal Neurons

    OpenAIRE

    Lambert, Talley J.; Storm, Daniel R.; Sullivan, Jane M.

    2010-01-01

    MicroRNAs play important regulatory roles in a broad range of cellular processes including neuronal morphology and long-term synaptic plasticity. MicroRNA-132 (miR132) is a CREB-regulated miRNA that is induced by neuronal activity and neurotrophins, and plays a role in regulating neuronal morphology and cellular excitability. Little is known about the effects of miR132 expression on synaptic function. Here we show that overexpression of miR132 increases the paired-pulse ratio and decreases sy...

  3. Structural synaptic plasticity has high memory capacity and can explain graded amnesia, catastrophic forgetting, and the spacing effect.

    Directory of Open Access Journals (Sweden)

    Andreas Knoblauch

    Full Text Available Although already William James and, more explicitly, Donald Hebb's theory of cell assemblies have suggested that activity-dependent rewiring of neuronal networks is the substrate of learning and memory, over the last six decades most theoretical work on memory has focused on plasticity of existing synapses in prewired networks. Research in the last decade has emphasized that structural modification of synaptic connectivity is common in the adult brain and tightly correlated with learning and memory. Here we present a parsimonious computational model for learning by structural plasticity. The basic modeling units are "potential synapses" defined as locations in the network where synapses can potentially grow to connect two neurons. This model generalizes well-known previous models for associative learning based on weight plasticity. Therefore, existing theory can be applied to analyze how many memories and how much information structural plasticity can store in a synapse. Surprisingly, we find that structural plasticity largely outperforms weight plasticity and can achieve a much higher storage capacity per synapse. The effect of structural plasticity on the structure of sparsely connected networks is quite intuitive: Structural plasticity increases the "effectual network connectivity", that is, the network wiring that specifically supports storage and recall of the memories. Further, this model of structural plasticity produces gradients of effectual connectivity in the course of learning, thereby explaining various cognitive phenomena including graded amnesia, catastrophic forgetting, and the spacing effect.

  4. Synaptic plasticity in a recurrent neural network for versatile and adaptive behaviors of a walking robot

    Directory of Open Access Journals (Sweden)

    Eduard eGrinke

    2015-10-01

    Full Text Available Walking animals, like insects, with little neural computing can effectively perform complex behaviors. They can walk around their environment, escape from corners/deadlocks, and avoid or climb over obstacles. While performing all these behaviors, they can also adapt their movements to deal with an unknown situation. As a consequence, they successfully navigate through their complex environment. The versatile and adaptive abilities are the result of an integration of several ingredients embedded in their sensorimotor loop. Biological studies reveal that the ingredients include neural dynamics, plasticity, sensory feedback, and biomechanics. Generating such versatile and adaptive behaviors for a walking robot is a challenging task. In this study, we present a bio-inspired approach to solve this task. Specifically, the approach combines neural mechanisms with plasticity, sensory feedback, and biomechanics. The neural mechanisms consist of adaptive neural sensory processing and modular neural locomotion control. The sensory processing is based on a small recurrent network consisting of two fully connected neurons. Online correlation-based learning with synaptic scaling is applied to adequately change the connections of the network. By doing so, we can effectively exploit neural dynamics (i.e., hysteresis effects and single attractors in the network to generate different turning angles with short-term memory for a biomechanical walking robot. The turning information is transmitted as descending steering signals to the locomotion control which translates the signals into motor actions. As a result, the robot can walk around and adapt its turning angle for avoiding obstacles in different situations as well as escaping from sharp corners or deadlocks. Using backbone joint control embedded in the locomotion control allows the robot to climb over small obstacles. Consequently, it can successfully explore and navigate in complex environments.

  5. Muscarinic and nicotinic modulation of thalamo-prefrontal cortex synaptic plasticity [corrected] in vivo.

    Directory of Open Access Journals (Sweden)

    Lezio Soares Bueno-Junior

    Full Text Available The mediodorsal nucleus of the thalamus (MD is a rich source of afferents to the medial prefrontal cortex (mPFC. Dysfunctions in the thalamo-prefrontal connections can impair networks implicated in working memory, some of which are affected in Alzheimer disease and schizophrenia. Considering the importance of the cholinergic system to cortical functioning, our study aimed to investigate the effects of global cholinergic activation of the brain on MD-mPFC synaptic plasticity by measuring the dynamics of long-term potentiation (LTP and depression (LTD in vivo. Therefore, rats received intraventricular injections either of the muscarinic agonist pilocarpine (PILO; 40 nmol/µL, the nicotinic agonist nicotine (NIC; 320 nmol/µL, or vehicle. The injections were administered prior to either thalamic high-frequency (HFS or low-frequency stimulation (LFS. Test pulses were applied to MD for 30 min during baseline and 240 min after HFS or LFS, while field postsynaptic potentials were recorded in the mPFC. The transient oscillatory effects of PILO and NIC were monitored through recording of thalamic and cortical local field potentials. Our results show that HFS did not affect mPFC responses in vehicle-injected rats, but induced a delayed-onset LTP with distinct effects when applied following PILO or NIC. Conversely, LFS induced a stable LTD in control subjects, but was unable to induce LTD when applied after PILO or NIC. Taken together, our findings show distinct modulatory effects of each cholinergic brain activation on MD-mPFC plasticity following HFS and LFS. The LTP-inducing action and long-lasting suppression of cortical LTD induced by PILO and NIC might implicate differential modulation of thalamo-prefrontal functions under low and high input drive.

  6. Diversity of thalamorecipient spine morphology in cat visual cortex and its implication for synaptic plasticity.

    Science.gov (United States)

    da Costa, Nuno Maçarico

    2013-06-15

    A feature of spine synapses is the existence of a neck connecting the synapse on the spine head to the dendritic shaft. As with a cable, spine neck resistance (R(neck)) increases with increasing neck length and is inversely proportional to the cross-sectional area of the neck. A synaptic current entering a spine with a high R(neck) will lead to greater local depolarization in the spine head than would a similar input applied to a spine with a lower R(neck). This could make spines with high R(neck) more sensitive to plastic changes since voltage sensitive conductances, such as N-methyl-D-aspartic acid (NMDA) channels can be more easily activated. This hypothesis was tested using serial section electron microscopic reconstructions of thalamocortical spine synapses and spine necks located on spiny stellate cells and corticothalamic cells from area 17 of cats. Thalamic axons and corticothalamic neurons were labeled by injections of the tracer biotinylated dextran amine (BDA) in the dorsal lateral geniculate nucleus (dLGN) of anesthetized cats and spiny stellates were filled intracellularly in vivo with horseradish peroxidase. Twenty-eight labeled spines that formed synapses with dLGN boutons were collected from three spiny stellate and four corticothalamic cells and reconstructed in 3D from serial electron micrographs. Spine length, spine diameter, and the area of the postsynaptic density were measured from the 3D reconstructions and R(neck) of the spine was estimated. No correlation was found between the postsynaptic density size and the estimated spine R(neck). This suggests that forms of plasticity that lead to larger synapses are independent of spine neck resistance.

  7. Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses.

    Science.gov (United States)

    Royer, S; Paré, D

    2002-01-01

    Classical fear conditioning is believed to result from potentiation of conditioned synaptic inputs in the basolateral amygdala. That is, the conditioned stimulus would excite more neurons in the central nucleus and, via their projections to the brainstem and hypothalamus, evoke fear responses. However, much data suggests that extinction of fear responses does not depend on the reversal of these changes but on a parallel NMDA-dependent learning that competes with the first one. Because they control impulse traffic from the basolateral amygdala to the central nucleus, GABAergic neurons of the intercalated cell masses are ideally located to implement this second learning. Consistent with this hypothesis, the present study shows that low- and high-frequency stimulation of basolateral afferents respectively induce long-term depression (LTD) and potentiation (LTP) of responses in intercalated cells. Moreover, induction of LTP and LTD is prevented by application of an NMDA antagonist. To determine how these activity-dependent changes are expressed, we tested whether LTD and LTP induction are associated with modifications in paired-pulse facilitation, an index of transmitter release probability. Only LTP induction was associated with a change in paired-pulse facilitation. Depotentiation of previously potentiated synapses did not revert the modification in paired pulse facilitation, suggesting that LTP is associated with presynaptic alterations, but that LTD and depotentiation depend on postsynaptic changes. Taken together, our results suggest that basolateral synapses onto intercalated neurons can express NMDA-dependent LTP and LTD, consistent with the possibility that intercalated neurons are a critical locus of plasticity for the extinction of conditioned fear responses. Ultimately, these plastic events may prevent conditioned amygdala responses from exciting neurons of the central nucleus, and thus from evoking conditioned fear responses.

  8. Effects of decreased inhibition on synaptic plasticity and dendritic morphology in the juvenile prefrontal cortex

    Directory of Open Access Journals (Sweden)

    Xanthippi Konstantoudaki

    2014-03-01

    Full Text Available Excitation-inhibition balance is critical for maintaining proper functioning of the cerebral cortex, as evident from electrophysiological and modeling studies, and it is also important for animal behavior (Yizhar et al., 2011. In the cerebral cortex, excitation is provided by glutamate release from pyramidal neurons, while inhibition is provided by GABA release from several types of interneurons. Many neuropsychiatric disorders, such as epilepsy, anxiety, schizophrenia and autism exhibit an imbalance between the excitatory and inhibitory mechanisms of cortical circuits within key brain regions as prefrontal cortex or hippocampus, primarily through dysfunctions in the inhibitory system (Lewis, Volk, & Hashimoto, 2003; Marín, 2012 Given the significant role of GABAergic inhibition in shaping proper function of the cerebral cortex, we used a mouse model of developmentally decreased GABAergic inhibition in order to examine its effects in network properties, namely basal synaptic transmission, synaptic plasticity and dendritic morphology of pyramidal neurons. For our study, we used mice (postnatal day 20-30 in which the Rac1 protein was deleted from Nkx2.1-expressing neurons (Vidaki et al., 2012, (Rac1fl/flNkx2.1 +/cre referred as Rac1 KO mice, and heterozygous (Rac1+/flNkx2.1 +/cre or control (Rac1+/flNkx2.1 +/+ mice. The specific ablation of Rac1 protein from NKx2.1-expressing MGE-derived progenitors leads to a perturbation of their cell cycle exit resulting in decreased number of interneurons in the cortex(Vidaki et al, 2012. We prepared brain slices from the prefrontal cortex and recorded field excitatory postsynaptic potentials (fEPSPs from layer II neurons while stimulating axons in layer II. We find that the evoked fEPSPs are decreased in Rac1 KO mice compared to Rac1 heterozygous or control mice. This could suggest that the decreased GABAergic inhibition causes network alterations that result in reduced glutamatergic function. Furthermore

  9. Effect of Aggregated β-Amyloid (1-42 on Synaptic Plasticity of Hippocampal Dentate Gyrus Granule Cells in Vivo

    Directory of Open Access Journals (Sweden)

    Shirin Babri

    2012-12-01

    Full Text Available Introduction: Alzheimer’s disease (AD is a common neurodegenerative disorder in elderly people with an impairment of cognitive decline and memory loss. β-amyloid (Aβ as a potent neurotoxic peptide has a pivotal role in the pathogenesis of AD. This disease begins with impairment in synaptic functions before developing into later neuro­degeneration and neuronal loss. The aim of this study was to evaluate the synaptic plasticity and electrophysiological function of granule cells in hippocampal dentate gyrus (DG after intracerebroventricular (i.c.v. administration of aggregated Aβ (1-42 peptide in vivo. Methods: Animals were divided to control and Aβ (1-42 groups. Long-term potentia­tion (LTP in perforant path-DG synapses was assessed in order to investigate the effect of aggregated Aβ (1-42 on synaptic plasticity. Field excitatory post-synaptic potential (fEPSP slope and population spike (PS amplitude were measured. Results: Administration of Aβ (1-42 significantly decreased fEPSP slope and PS amplitude in Aβ (1-42 group comparing with the control group and had no effect on baseline activity of neurons. Conclusion: The present study indicates that administration of aggregated form of Aβ (1-42 into the lateral ventricle effectively inhibits LTP in granular cells of the DG in hippocampus in vivo.

  10. Synapse-specific stabilization of plasticity processes: the synaptic tagging and capture hypothesis revisited 10 years later.

    Science.gov (United States)

    Barco, Angel; Lopez de Armentia, Mikel; Alarcon, Juan M

    2008-01-01

    A decade ago, the synaptic tagging hypothesis was proposed to explain how newly synthesized plasticity products can be specifically targeted to active synapses. A growing number of studies have validated the seminal findings that gave rise to this model, as well as contributed to unveil and expand the range of mechanisms underlying late-associativity and neuronal computation. Here, we will review what it was learnt during this past decade regarding the cellular and molecular mechanisms underlying synaptic tagging and synaptic capture. The accumulated experimental evidence has widened the theoretical framework set by the synaptic tagging and capture (STC) model and introduced concepts that were originally considered part of alternative models for explaining synapse-specific long-term potentiation (LTP). As a result, we believe that the STC model, now improved and expanded with these new ideas and concepts, still represents the most compelling hypothesis to explain late-associativity in synapse-specific plasticity processes. We will also discuss the impact of this model in our view of the integrative capability of neurons and associative learning.

  11. p38 MAPK Inhibition Improves Synaptic Plasticity and Memory in Angiotensin II-dependent Hypertensive Mice

    Science.gov (United States)

    Dai, Hai-long; Hu, Wei-yuan; Jiang, Li-hong; Li, Le; Gaung, Xue-feng; Xiao, Zhi-cheng

    2016-01-01

    The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. p38 MAPK pathway plays an important role in hypertensive target organ damage. Activated p38 MAPK was seen in AD brain tissue. In this study, we found that long-term potentiation (LTP) of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive C57BL/6 mice. In vivo, using a p38 heterozygous knockdown mice (p38KI/+) model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38KI/+ hypertensive mice. In vitro, LTP was improved in hippocampal slices from C57BL/6 hypertensive mice by treatment with p38MAPK inhibitor SKF86002. Our data demonstrated that p38 MAPK may be a potential therapeutic target for hypertension-related cognitive dysfunction. PMID:27283322

  12. Short-term plasticity and modulation of synaptic transmission at mammalian inhibitory cholinergic olivocochlear synapses

    Directory of Open Access Journals (Sweden)

    Eleonora eKatz

    2014-12-01

    Full Text Available The organ of Corti, the mammalian sensory epithelium of the inner ear, has two types of mechanoreceptor cells, inner hair cells (IHCs and outer hair cells (OHCs. In this sensory epithelium, vibrations produced by sound waves are transformed into electrical signals. When depolarized by incoming sounds, IHCs release glutamate and activate auditory nerve fibers innervating them and OHCs, by virtue of their electromotile property, increase the amplification and fine tuning of sound signals. The medial olivocochlear (MOC system, an efferent feedback system, inhibits OHC activity and thereby reduces the sensitivity and sharp tuning of cochlear afferent fibers. During neonatal development, IHCs fire Ca2+ action potentials which evoke glutamate release promoting activity in the immature auditory system in the absence of sensory stimuli. During this period, MOC fibers also innervate IHCs and are thought to modulate their firing rate. Both the MOC-OHC and the MOC-IHC synapses are cholinergic, fast and inhibitory and mediated by the alpha9alpha10 nicotinic cholinergic receptor (nAChR coupled to the activation of calcium-activated potassium channels that hyperpolarize the hair cells.In this review we discuss the biophysical, functional and molecular data which demonstrate that at the synapses between MOC efferent fibers and cochlear hair cells, modulation of transmitter release as well as short-term synaptic plasticity mechanisms, operating both at the presynaptic terminal and at the postsynaptic hair-cell, determine the efficacy of these synapses and shape the hair cell response pattern.

  13. DCC Expression by Neurons Regulates Synaptic Plasticity in the Adult Brain

    Directory of Open Access Journals (Sweden)

    Katherine E. Horn

    2013-01-01

    Full Text Available The transmembrane protein deleted in colorectal cancer (DCC and its ligand, netrin-1, regulate synaptogenesis during development, but their function in the mature central nervous system is unknown. Given that DCC promotes cell-cell adhesion, is expressed by neurons, and activates proteins that signal at synapses, we hypothesized that DCC expression by neurons regulates synaptic function and plasticity in the adult brain. We report that DCC is enriched in dendritic spines of pyramidal neurons in wild-type mice, and we demonstrate that selective deletion of DCC from neurons in the adult forebrain results in the loss of long-term potentiation (LTP, intact long-term depression, shorter dendritic spines, and impaired spatial and recognition memory. LTP induction requires Src activation of NMDA receptor (NMDAR function. DCC deletion severely reduced Src activation. We demonstrate that enhancing NMDAR function or activating Src rescues LTP in the absence of DCC. We conclude that DCC activation of Src is required for NMDAR-dependent LTP and certain forms of learning and memory.

  14. Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity.

    Science.gov (United States)

    Kluge, Christian; Stoppel, Christian; Szinyei, Csaba; Stork, Oliver; Pape, Hans-Christian

    2008-04-01

    Somatostatin has been implicated in various cognitive and emotional functions, but its precise role is still poorly understood. Here, we have made use of mice with somatostatin deficiency, based upon genetic invalidation or pharmacologically induced depletion, and Pavlovian fear conditioning in order to address the contribution of the somatostatin system to associative fear memory. The results demonstrate an impairment of foreground and background contextual but not tone fear conditioning in mice with targeted ablation of the somatostatin gene. These deficits were associated with a decrease in long-term potentiation in the CA1 area of the hippocampus. Both the behavioral and the electrophysiological phenotypes were mimicked in wild-type mice through application of the somatostatin-depleting substance cysteamine prior to fear training, whereas no further deficits were observed upon application in the somatostatin null mutants. These results suggest that the somatostatin system plays a critical role in the acquisition of contextual fear memory, but not tone fear learning, and further highlights the role of hippocampal synaptic plasticity for information processing concerning contextual information.

  15. GABAergic synaptic transmission regulates calcium influx during spike-timing dependent plasticity

    Directory of Open Access Journals (Sweden)

    Trevor Balena

    2010-06-01

    Full Text Available Coincident pre- and postsynaptic activity of hippocampal neurons alters the strength of gamma-aminobutyric acid (GABAA-mediated inhibition through a Ca2+-dependent regulation of cation-chloride cotransporters. This long-term synaptic modulation is termed GABAergic spike-timing dependent plasticity (STDP. In the present study, we examined whether the properties of the GABAergic synapses themselves modulate the required postsynaptic Ca2+ influx during GABAergic STDP induction. To do this we first identified GABAergic synapses between cultured hippocampal neurons based on their relatively long decay time constants and their reversal potentials which lay close to the resting membrane potential. GABAergic STDP was then induced by coincidentally (± 1 ms firing the pre- and postsynaptic neurons at 5 Hz for 30 seconds, while postsynaptic Ca2+ was imaged with the Ca2+-sensitive fluorescent dye Fluo4-AM. In all cases, the induction of GABAergic STDP increased postsynaptic Ca2+ above resting levels. We further found that the magnitude of this increase correlated with the amplitude and polarity of the GABAergic postsynaptic current (GPSC; hyperpolarizing GPSCs reduced the Ca2+ influx in comparison to both depolarizing GPSCs, and postsynaptic neurons spiked alone. This relationship was influenced by both the driving force for Cl- and GABAA conductance (which had positive correlations with the Ca2+ influx. The spike-timing order during STDP induction did not influence the correlation between GPSC amplitude and Ca2+ influx, which is likely accounted for by the symmetrical GABAergic STDP window.

  16. Constitutive and Acquired Serotonin Deficiency Alters Memory and Hippocampal Synaptic Plasticity.

    Science.gov (United States)

    Fernandez, Sebastian P; Muzerelle, Aude; Scotto-Lomassese, Sophie; Barik, Jacques; Gruart, Agnès; Delgado-García, José M; Gaspar, Patricia

    2017-01-01

    Serotonin (5-HT) deficiency occurs in a number of brain disorders that affect cognitive function. However, a direct causal relationship between 5-HT hypo-transmission and memory and underlying mechanisms has not been established. We used mice with a constitutive depletion of 5-HT brain levels (Pet1KO mice) to analyze the contribution of 5-HT to different forms of learning and memory. Pet1KO mice exhibited a striking deficit in novel object recognition memory, a hippocampal-dependent task. No alterations were found in tasks for social recognition, procedural learning, or fear memory. Viral delivery of designer receptors exclusively activated by designer drugs was used to selectively silence the activity of 5-HT neurons in the raphe. Inhibition of 5-HT neurons in the median raphe, but not the dorsal raphe, was sufficient to impair object recognition in adult mice. In vivo electrophysiology in behaving mice showed that long-term potentiation in the hippocampus of 5-HT-deficient mice was altered, and administration of the 5-HT1A agonist 8-OHDPAT rescued the memory deficits. Our data suggest that hyposerotonergia selectively affects declarative hippocampal-dependent memory. Serotonergic projections from the median raphe are necessary to regulate object memory and hippocampal synaptic plasticity processes, through an inhibitory control mediated by 5-HT1A receptors.

  17. Short-term synaptic plasticity can enhance weak signal detectability in nonrenewal spike trains.

    Science.gov (United States)

    Lüdtke, Niklas; Nelson, Mark E

    2006-12-01

    We study the encoding of weak signals in spike trains with interspike interval (ISI) correlations and the signals' subsequent detection in sensory neurons. Motivated by the observation of negative ISI correlations in auditory and electrosensory afferents, we assess the theoretical performance limits of an individual detector neuron receiving a weak signal distributed across multiple afferent inputs. We assess the functional role of ISI correlations in the detection process using statistical detection theory and derive two sequential likelihood ratio detector models: one for afferents with renewal statistics; the other for afferents with negatively correlated ISIs. We suggest a mechanism that might enable sensory neurons to implicitly compute conditional probabilities of presynaptic spikes by means of short-term synaptic plasticity. We demonstrate how this mechanism can enhance a postsynaptic neuron's sensitivity to weak signals by exploiting the correlation structure of the input spike trains. Our model not only captures fundamental aspects of early electrosensory signal processing in weakly electric fish, but may also bear relevance to the mammalian auditory system and other sensory modalities.

  18. Neural Cell Adhesion Molecule-Associated Polysialic Acid Regulates Synaptic Plasticity and Learning by Restraining the Signaling through GluN2B-Containing NMDA Receptors

    Science.gov (United States)

    Kochlamazashvili, Gaga; Senkov, Oleg; Grebenyuk, Sergei; Robinson, Catrina; Xiao, Mei-Fang; Stummeyer, Katharina; Gerardy-Schahn, Rita; Engel, Andreas K.; Feig, Larry; Semyanov, Alexey; Suppiramaniam, Vishnu; Schachner, Melitta; Dityatev, Alexander

    2017-01-01

    The neural cell adhesion molecule (NCAM) is the predominant carrier of α2,8 polysialic acid (PSA) in the mammalian brain. Abnormalities in PSA and NCAM expression are associated with schizophrenia in humans and cause deficits in hippocampal synaptic plasticity and contextual fear conditioning in mice. Here, we show that PSA inhibits opening of recombinant NMDA receptors composed of GluN1/2B (NR1/NR2B) or GluN1/2A/2B (NR1/NR2A/NR2B) but not of GluN1/2A (NR1/NR2A) subunits. Deficits in NCAM/PSA increase GluN2B-mediated transmission and Ca2+ transients in the CA1 region of the hippocampus. In line with elevation of GluN2B-mediated transmission, defects in long-term potentiation in the CA1 region and contextual fear memory in NCAM/PSA-deficient mice are abrogated by application of a GluN2B-selective antagonist. Furthermore, treatment with the glutamate scavenger glutamic-pyruvic transaminase, ablation of Ras-GRF1 (a mediator of GluN2B signaling to p38 MAPK), or direct inhibition of hyperactive p38 MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38 MAPK signaling pathway. These findings implicate carbohydrates carried by adhesion molecules in modulating NMDA receptor signaling in the brain and demonstrate reversibility of cognitive deficits associated with ablation of a schizophrenia-related adhesion molecule. PMID:20237287

  19. Effects of exercise intensity on spatial memory performance and hippocampal synaptic plasticity in transient brain ischemic rats.

    Directory of Open Access Journals (Sweden)

    Pei-Cheng Shih

    Full Text Available Memory impairment is commonly noted in stroke survivors, and can lead to delay of functional recovery. Exercise has been proved to improve memory in adult healthy subjects. Such beneficial effects are often suggested to relate to hippocampal synaptic plasticity, which is important for memory processing. Previous evidence showed that in normal rats, low intensity exercise can improve synaptic plasticity better than high intensity exercise. However, the effects of exercise intensities on hippocampal synaptic plasticity and spatial memory after brain ischemia remain unclear. In this study, we investigated such effects in brain ischemic rats. The middle cerebral artery occlusion (MCAO procedure was used to induce brain ischemia. After the MCAO procedure, rats were randomly assigned to sedentary (Sed, low-intensity exercise (Low-Ex, or high-intensity exercise (High-Ex group. Treadmill training began from the second day post MCAO procedure, 30 min/day for 14 consecutive days for the exercise groups. The Low-Ex group was trained at the speed of 8 m/min, while the High-Ex group at the speed of 20 m/min. The spatial memory, hippocampal brain-derived neurotrophic factor (BDNF, synapsin-I, postsynaptic density protein 95 (PSD-95, and dendritic structures were examined to document the effects. Serum corticosterone level was also quantified as stress marker. Our results showed the Low-Ex group, but not the High-Ex group, demonstrated better spatial memory performance than the Sed group. Dendritic complexity and the levels of BDNF and PSD-95 increased significantly only in the Low-Ex group as compared with the Sed group in bilateral hippocampus. Notably, increased level of corticosterone was found in the High-Ex group, implicating higher stress response. In conclusion, after brain ischemia, low intensity exercise may result in better synaptic plasticity and spatial memory performance than high intensity exercise; therefore, the intensity is suggested to be

  20. Excitatory synaptic activity is associated with a rapid structural plasticity of inhibitory synapses on hippocampal CA1 pyramidal cells

    OpenAIRE

    Lushnikova, Irina; Skibo, Galina; Muller, Dominique; Nikonenko, Iryna

    2011-01-01

    Synaptic activity, such as long-term potentiation (LTP), has been shown to induce morphological plasticity of excitatory synapses on dendritic spines through the spine head and postsynaptic density (PSD) enlargement and reorganization. Much less, however, is known about activity-induced morphological modifications of inhibitory synapses. Using an in vitro model of rat organotypic hippocampal slice cultures and electron microscopy, we studied activity-related morphological changes of somatic i...

  1. IQGAP1: A microtubule-microfilament scaffolding protein with multiple roles in nerve cell development and synaptic plasticity.

    Science.gov (United States)

    Jausoro, Ignacio; Mestres, Iván; Remedi, Mónica; Sanchez, Mónica; Cáceres, Alfredo

    2012-11-01

    In this article, we review our current understanding of the biology of IQ domain-containing GTPase-Activating Protein 1, IQGAP1, a scaffolding protein with multiple binding partners, which is widely expressed among different cell types, including neurons, and capable of linking Rho-GTPase signaling with cytosleletal elements and environmental cues. Interestingly, a series of recent studies suggest that IQGAP family members have an important role in neuronal development, synaptic plasticity and nervous system disorders involving alterations in spine density.

  2. The sphingolipid receptor S1PR2 is a receptor for Nogo-a repressing synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Anissa Kempf

    2014-01-01

    Full Text Available Nogo-A is a membrane protein of the central nervous system (CNS restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR sphingosine 1-phosphate receptor 2 (S1PR2 as a Nogo-A-Δ20-specific receptor. Nogo-A-Δ20 binds S1PR2 on sites distinct from the pocket of the sphingolipid sphingosine 1-phosphate (S1P and signals via the G protein G13, the Rho GEF LARG, and RhoA. Deleting or blocking S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth and cell spreading. Blockade of S1PR2 strongly enhances long-term potentiation (LTP in the hippocampus of wild-type but not Nogo-A(-/- mice, indicating a repressor function of the Nogo-A/S1PR2 axis in synaptic plasticity. A similar increase in LTP was also observed in the motor cortex after S1PR2 blockade. We propose a novel signaling model in which a GPCR functions as a receptor for two structurally unrelated ligands, a membrane protein and a sphingolipid. Elucidating Nogo-A/S1PR2 signaling platforms will provide new insights into regulation of synaptic plasticity.

  3. Gastrin-releasing peptide facilitates glutamatergic transmission in the hippocampus and effectively prevents vascular dementia induced cognitive and synaptic plasticity deficits.

    Science.gov (United States)

    Yang, Jiajia; Yao, Yang; Wang, Ling; Yang, Chunxiao; Wang, Faqi; Guo, Jie; Wang, Zhiyun; Yang, Zhuo; Ming, Dong

    2017-01-01

    Neuronal gastrin-releasing peptide (GRP) has been proved to be an important neuromodulator in the brain and involved in a variety of neurological diseases. Whether GRP could attenuate cognition impairment induced by vascular dementia (VD) in rats, and the mechanism of synaptic plasticity and GRP's action on synaptic efficiency are still poorly understood. In this study, we first investigated the effects of GRP on glutamatergic transmission with patch-clamp recording. We found that acute application of GRP enhanced the excitatory synaptic transmission in hippocampal CA1 neurons via GRPR in a presynaptic mechanism. Secondly, we examined whether exogenous GRP or its analogue neuromedin B (NMB) could prevent VD-induced cognitive deficits and the mechanism of synaptic plasticity. By using Morris water maze, long-term potentiation (LTP) recording, western blot assay and immunofluorescent staining, we verified for the first time that GRP or NMB substantially improved the spatial learning and memory abilities in VD rats, restored the impaired synaptic plasticity and was able to elevate the expression of synaptic proteins, synaptophysin (SYP) and CaMKII, which play pivotal roles in synaptic plasticity. These results suggest that the facilitatory effects of GRP on glutamate release may contribute to its long-term action on synaptic efficacy which is essential in cognitive function. Our findings present a new entry point for a better understanding of physiological function of GRP and raise the possibility that GRPR agonists might ameliorate cognitive deficits associated with neurological diseases.

  4. Haploinsufficiency of the 22q11.2-microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium

    Science.gov (United States)

    Devaraju, Prakash; Yu, Jing; Eddins, Donnie; Mellado-Lagarde, Marcia M.; Earls, Laurie R.; Westmoreland, Joby J.; Quarato, Giovanni; Green, Douglas R.; Zakharenko, Stanislav S.

    2016-01-01

    Hemizygous deletion of a 1.5- to 3-megabase region on chromosome 22 causes 22q11.2 deletion syndrome (22q11DS), which constitutes one of the strongest genetic risks for schizophrenia. Mouse models of 22q11DS have abnormal short-term synaptic plasticity (STP) that contributes to working memory deficiencies similar to those in schizophrenia. We screened mutant mice carrying hemizygous deletions of 22q11DS genes and identified haploinsufficiency of Mrpl40 (mitochondrial large ribosomal subunit protein 40) as a contributor to abnormal STP. Two-photon imaging of the genetically encoded fluorescent calcium indicator GCaMP6, expressed in presynaptic cytosol or mitochondria, showed that Mrpl40 haploinsufficiency deregulates STP via impaired calcium extrusion from the mitochondrial matrix through the mitochondrial permeability transition pore. This led to abnormally high cytosolic calcium transients in presynaptic terminals and deficient working memory but did not affect long-term spatial memory. Thus, we propose that mitochondrial calcium deregulation is a novel pathogenic mechanism of cognitive deficiencies in schizophrenia. PMID:27184122

  5. Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice.

    Science.gov (United States)

    Cooper, Ayelet; Grigoryan, Gayane; Guy-David, Liora; Tsoory, Michael M; Chen, Alon; Reuveny, Eitan

    2012-02-14

    G protein-activated inwardly rectifying K+ channels (GIRK) generate slow inhibitory postsynaptic potentials in the brain via G(i/o) protein-coupled receptors. GIRK2, a GIRK subunit, is widely abundant in the brain and has been implicated in various functions and pathologies, such as learning and memory, reward, motor coordination, and Down syndrome. Down syndrome, the most prevalent cause of mental retardation, results from the presence of an extra maternal chromosome 21 (trisomy 21), which comprises the Kcnj6 gene (GIRK2). The present study examined the behaviors and cellular physiology properties in mice harboring a single trisomy of the Kcnj6 gene. Kcnj6 triploid mice exhibit deficits in hippocampal-dependent learning and memory, altered responses to rewards, hampered depotentiation, a form of excitatory synaptic plasticity, and have accentuated long-term synaptic depression. Collectively the findings suggest that triplication of Kcnj6 gene may play an active role in some of the abnormal neurological phenotypes found in Down syndrome.

  6. Differential regulation of BDNF, synaptic plasticity and sprouting in the hippocampal mossy fiber pathway of male and female rats.

    Science.gov (United States)

    Scharfman, Helen E; MacLusky, Neil J

    2014-01-01

    Many studies have described potent effects of BDNF, 17β-estradiol or androgen on hippocampal synapses and their plasticity. Far less information is available about the interactions between 17β-estradiol and BDNF in hippocampus, or interactions between androgen and BDNF in hippocampus. Here we review the regulation of BDNF in the mossy fiber pathway, a critical part of hippocampal circuitry. We discuss the emerging view that 17β-estradiol upregulates mossy fiber BDNF synthesis in the adult female rat, while testosterone exerts a tonic suppression of mossy fiber BDNF levels in the adult male rat. The consequences are interesting to consider: in females, increased excitability associated with high levels of BDNF in mossy fibers could improve normal functions of area CA3, such as the ability to perform pattern completion. However, memory retrieval may lead to anxiety if stressful events are recalled. Therefore, the actions of 17β-estradiol on the mossy fiber pathway in females may provide a potential explanation for the greater incidence of anxiety-related disorders and post-traumatic stress syndrome (PTSD) in women relative to men. In males, suppression of BDNF-dependent plasticity in the mossy fibers may be protective, but at the 'price' of reduced synaptic plasticity in CA3. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

  7. Synaptic plasticity in a recurrent neural network for versatile and adaptive behaviors of a walking robot.

    Science.gov (United States)

    Grinke, Eduard; Tetzlaff, Christian; Wörgötter, Florentin; Manoonpong, Poramate

    2015-01-01

    Walking animals, like insects, with little neural computing can effectively perform complex behaviors. For example, they can walk around their environment, escape from corners/deadlocks, and avoid or climb over obstacles. While performing all these behaviors, they can also adapt their movements to deal with an unknown situation. As a consequence, they successfully navigate through their complex environment. The versatile and adaptive abilities are the result of an integration of several ingredients embedded in their sensorimotor loop. Biological studies reveal that the ingredients include neural dynamics, plasticity, sensory feedback, and biomechanics. Generating such versatile and adaptive behaviors for a many degrees-of-freedom (DOFs) walking robot is a challenging task. Thus, in this study, we present a bio-inspired approach to solve this task. Specifically, the approach combines neural mechanisms with plasticity, exteroceptive sensory feedback, and biomechanics. The neural mechanisms consist of adaptive neural sensory processing and modular neural locomotion control. The sensory processing is based on a small recurrent neural network consisting of two fully connected neurons. Online correlation-based learning with synaptic scaling is applied to adequately change the connections of the network. By doing so, we can effectively exploit neural dynamics (i.e., hysteresis effects and single attractors) in the network to generate different turning angles with short-term memory for a walking robot. The turning information is transmitted as descending steering signals to the neural locomotion control which translates the signals into motor actions. As a result, the robot can walk around and adapt its turning angle for avoiding obstacles in different situations. The adaptation also enables the robot to effectively escape from sharp corners or deadlocks. Using backbone joint control embedded in the the locomotion control allows the robot to climb over small obstacles

  8. Evidence for high-fidelity timing-dependent synaptic plasticity of human motor cortex.

    Science.gov (United States)

    Cash, R F H; Mastaglia, F L; Thickbroom, G W

    2013-01-01

    A single transcranial magnetic stimulation (TMS) pulse typically evokes a short series of spikes in corticospinal neurons [known as indirect (I)-waves] which are thought to arise from transynaptic input. Delivering a second pulse at inter-pulse intervals (IPIs) corresponding to the timing of these I-waves leads to a facilitation of the response, and if stimulus pairs are delivered repeatedly, a persistent LTP-like increase in excitability can occur. This has been demonstrated at an IPI of 1.5 ms, which corresponds to the first I-wave interval, in an intervention referred to as ITMS (I-wave TMS), and it has been argued that this may have similarities with timing-dependent plasticity models. Consequently, we hypothesized that if the second stimulus is delivered so as not to coincide with I-wave timing, it should lead to LTD. We performed a crossover study in 10 subjects in which TMS doublets were timed to coincide (1.5-ms IPI, ITMS(1.5)) or not coincide (2-ms IPI, ITMS(2)) with I-wave firing. Single pulse motor-evoked potential (MEP) amplitude, resting motor threshold (RMT), and short-interval cortical inhibition (SICI) were measured from the first dorsal interosseous (FDI) muscle. After ITMS(1.5) corticomotor excitability was increased by ~60% for 15 min (P < 0.05) and returned to baseline by 20 min. Increasing the IPI by just 500 μs to 2 ms reversed the aftereffect, and MEP amplitude was significantly reduced (~35%, P < 0.05) for 15 min before returning to baseline. This reduction was not associated with an increase in SICI, suggesting a reduction in excitatory transmission rather than an increase in inhibitory efficacy. RMT also remained unchanged, suggesting that these changes were not due to changes in membrane excitability. Amplitude-matching ITMS(2) did not modulate excitability. The results are consistent with timing-dependent synaptic LTP/D-like effects and suggest that there are plasticity mechanisms operating in the human motor cortex with a temporal

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Role of mental retardation-associated dystrophin-gene product Dp71 in excitatory synapse organization, synaptic plasticity and behavioral functions.

    Directory of Open Access Journals (Sweden)

    Fatma Daoud

    Full Text Available BACKGROUND: Duchenne muscular dystrophy (DMD is caused by deficient expression of the cytoskeletal protein, dystrophin. One third of DMD patients also have mental retardation (MR, likely due to mutations preventing expression of dystrophin and other brain products of the DMD gene expressed from distinct internal promoters. Loss of Dp71, the major DMD-gene product in brain, is thought to contribute to the severity of MR; however, the specific function of Dp71 is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Complementary approaches were used to explore the role of Dp71 in neuronal function and identify mechanisms by which Dp71 loss may impair neuronal and cognitive functions. Besides the normal expression of Dp71 in a subpopulation of astrocytes, we found that a pool of Dp71 colocalizes with synaptic proteins in cultured neurons and is expressed in synaptic subcellular fractions in adult brains. We report that Dp71-associated protein complexes interact with specialized modular scaffolds of proteins that cluster glutamate receptors and organize signaling in postsynaptic densities. We then undertook the first functional examination of the brain and cognitive alterations in the Dp71-null mice. We found that these mice display abnormal synapse organization and maturation in vitro, altered synapse density in the adult brain, enhanced glutamatergic transmission and reduced synaptic plasticity in CA1 hippocampus. Dp71-null mice show selective behavioral disturbances characterized by reduced exploratory and novelty-seeking behavior, mild retention deficits in inhibitory avoidance, and impairments in spatial learning and memory. CONCLUSIONS/SIGNIFICANCE: Results suggest that Dp71 expression in neurons play a regulatory role in glutamatergic synapse organization and function, which provides a new mechanism by which inactivation of Dp71 in association with that of other DMD-gene products may lead to increased severity of MR.

  11. Effects of amitriptyline and fluoxetine on synaptic plasticity in the dentate gyrus of hippocampal formation in rats

    Directory of Open Access Journals (Sweden)

    Ghasem Zarei

    2014-01-01

    Full Text Available Background: Several studies have been shown that antidepressant drugs have contradictory effects on cognitive processes. Therefore, the aim of this study was to investigate the effects of amitriptyline and fluoxetine on synaptic plasticity in the dentate gyrus (DG of the hippocampal formation in rat. Materials and Methods: Experimental groups were the control, the fluoxetine, and amitriptyline. The rats were treated for 21 days and then, paired pulse facilitation/inhibition (PPF/I and long-term potentiation (LTP in perforant path-DG synapses were assessed (by 400 Hz tetanization. Field excitatory post-synaptic potential (fEPSP slope and population spike (PS amplitude were measured. Results: The results of PPF/I showed that PS amplitude ratios were increased in 10-70 ms inter-stimulus intervals in the amitriptyline group compared to the control group. In the fluoxetine group, EPSP slope ratios were decreased in intervals 30, 40, and 50 ms inter-stimulus intervals compared to the control group. The PS-LTP was significantly lower in the fluoxetine and the amitriptyline groups with respect to the control group. Conclusion: The results showed that fluoxetine and amitriptyline affect synaptic plasticity in the hippocampus and these effects is probably due to the impact on the number of active neurons.

  12. Effects of the kainate receptor agonist ATPA on glutamatergic synaptic transmission and plasticity during early postnatal development.

    Science.gov (United States)

    Sallert, Marko; Malkki, Hemi; Segerstråle, Mikael; Taira, Tomi; Lauri, Sari E

    2007-05-01

    Kainate type of glutamate receptors (KARs) modulate synaptic transmission in a developmentally regulated manner at several synapses in the brain. Previous studies have shown that KARs depress glutamatergic transmission at CA3-CA1 synapses in the hippocampus and these receptors are tonically active during early postnatal development. Here we use the GluR5 subunit specific agonist ATPA to further characterize the role of KARs in the modulation of synaptic transmission and plasticity in area CA1 during the first two weeks of life. We find that the depressant effect of ATPA on evoked fEPSPs/EPSCs is smaller in the neonate (P3-P6) than in the juvenile (P14-P18) rat CA1, due to endogenous activity of KAR in the neonate. Further, in the neonate but not juvenile CA1, ATPA downregulates action-potential independent transmission (mEPSCs) and its effects are dependent on protein kinase C activity. ATPA-induced depression of fEPSPs in the neonate occludes the presynaptic component of long-term depression (LTD). In contrast, at P14-P18, ATPA prevents LTD indirectly via GABAergic mechanisms. These data show that GluR5 signaling mechanisms are developmentally regulated and suggest distinct functional role for KARs in the modulation of synaptic transmission and plasticity at different stages of development.

  13. Persistent deficits in hippocampal synaptic plasticity accompany losses of hippocampus-dependent memory in a rodent model of psychosis

    Directory of Open Access Journals (Sweden)

    Valentina eWiescholleck

    2013-03-01

    Full Text Available Irreversible N-methyl-D-aspartate receptor (NMDAR antagonism is known to provoke symptoms of psychosis and schizophrenia in healthy humans. NMDAR hypofunction is believed to play a central role in the pathophysiology of both disorders and in an animal model of psychosis, that is based on irreversible antagonism of NMDARs, pronounced deficits in hippocampal synaptic plasticity have been reported shortly after antagonist treatment. Here, we examined the long-term consequences for long-term potentiation (LTP of a single acute treatment with an irreversible antagonist and investigated whether deficits are associated with memory impairments.The ability to express long-term potentiation (LTP at the perforant pathway – dentate gyrus synapse, as well as object recognition memory was assessed 1, 2, 3 and 4 weeks after a single -treatment of the antagonist, MK801. Here, LTP in freely behaving rats was significantly impaired at all time-points compared to control LTP before treatment. Object recognition memory was also significantly poorer in MK801-treated compared to vehicle-treated animals for several weeks after treatment. Histological analysis revealed no changes in brain tissue.Taken together, these data support that acute treatment with an irreversible NMDAR antagonist persistently impairs hippocampal functioning on behavioral, as well as synaptic levels. The long-term deficits in synaptic plasticity may underlie the cognitive impairments that are associated with schizophrenia-spectrum disorders.

  14. Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.

    Science.gov (United States)

    Jaramillo, Thomas C; Speed, Haley E; Xuan, Zhong; Reimers, Jeremy M; Liu, Shunan; Powell, Craig M

    2016-03-01

    Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼ 0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3(e4-9) KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3(e4-9) heterozygous (HET) and Shank3(e4-9) KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3(e4-9) KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3(e4-9) KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3(e4-9) HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3(e4-9) KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3(e4-9) mutant mouse model of autism.

  15. Age-related deficits in synaptic plasticity rescued by activating PKA or PKC in sensory neurons of Aplysia californica

    Directory of Open Access Journals (Sweden)

    Andrew T Kempsell

    2015-09-01

    Full Text Available Brain aging is associated with declines in synaptic function that contribute to memory loss, including reduced postsynaptic response to neurotransmitters and decreased neuronal excitability. To understand how aging affects memory in a simple neural circuit, we studied neuronal proxies of memory for sensitization in mature versus advanced age Aplysia. Glutamate- (L-Glu- evoked excitatory currents were facilitated by the neuromodulator serotonin (5-HT in sensory neurons (SN isolated from mature but not aged animals. Activation of PKA and PKC signaling rescued facilitation of L-Glu currents in aged SN. Similarly, PKA and PKC activators restored increased excitability in aged tail SN. These results suggest that altered synaptic plasticity during aging involves defects in second messenger systems

  16. Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1β, BDNF and synaptic plasticity.

    Science.gov (United States)

    Patterson, Susan L

    2015-09-01

    Older individuals often experience declines in cognitive function after events (e.g. infection, or injury) that trigger activation of the immune system. This occurs at least in part because aging sensitizes the response of microglia (the brain's resident immune cells) to signals triggered by an immune challenge. In the aging brain, microglia respond to these signals by producing more pro-inflammatory cytokines (e.g. interleukin-1beta or IL-1β) and producing them for longer than microglia in younger brains. This exaggerated inflammatory response can compromise processes critical for optimal cognitive functioning. Interleukin-1β is central to the inflammatory response and is a key mediator and modulator of an array of associated biological functions; thus its production and release is usually very tightly regulated. This review will focus on the impact of dysregulated production of IL-1β on hippocampus dependent-memory systems and associated synaptic plasticity processes. The neurotrophin brain-derived neurotrophic factor (BNDF) helps to protect neurons from damage caused by infection or injury, and it plays a critical role in many of the same memory and hippocampal plasticity processes compromised by dysregulated production of IL-1β. This suggests that an exaggerated brain inflammatory response, arising from aging and a secondary immune challenge, may erode the capacity to provide the BDNF needed for memory-related plasticity processes at hippocampal synapses. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.

  17. Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice.

    Science.gov (United States)

    Clark, Jason K; Furgerson, Matthew; Crystal, Jonathon D; Fechheimer, Marcus; Furukawa, Ruth; Wagner, John J

    2015-11-01

    Alzheimer's disease is a neurodegenerative condition believed to be initiated by production of amyloid-beta peptide, which leads to synaptic dysfunction and progressive memory loss. Using a mouse model of Alzheimer's disease (3xTg-AD), an 8-arm radial maze was employed to assess spatial working memory. Unexpectedly, the younger (3month old) 3xTg-AD mice were as impaired in the spatial working memory task as the older (8month old) 3xTg-AD mice when compared with age-matched NonTg control animals. Field potential recordings from the CA1 region of slices prepared from the ventral hippocampus were obtained to assess synaptic transmission and capability for synaptic plasticity. At 3months of age, the NMDA receptor-dependent component of LTP was reduced in 3xTg-AD mice. However, the magnitude of the non-NMDA receptor-dependent component of LTP was concomitantly increased, resulting in a similar amount of total LTP in 3xTg-AD and NonTg mice. At 8months of age, the NMDA receptor-dependent LTP was again reduced in 3xTg-AD mice, but now the non-NMDA receptor-dependent component was decreased as well, resulting in a significantly reduced total amount of LTP in 3xTg-AD compared with NonTg mice. Both 3 and 8month old 3xTg-AD mice exhibited reductions in paired-pulse facilitation and NMDA receptor-dependent LTP that coincided with the deficit in spatial working memory. The early presence of this cognitive impairment and the associated alterations in synaptic plasticity demonstrate that the onset of some behavioral and neurophysiological consequences can occur before the detectable presence of plaques and tangles in the 3xTg-AD mouse model of Alzheimer's disease.

  18. Excitatory synaptic activity is associated with a rapid structural plasticity of inhibitory synapses on hippocampal CA1 pyramidal cells.

    Science.gov (United States)

    Lushnikova, Irina; Skibo, Galina; Muller, Dominique; Nikonenko, Irina

    2011-04-01

    Synaptic activity, such as long-term potentiation (LTP), has been shown to induce morphological plasticity of excitatory synapses on dendritic spines through the spine head and postsynaptic density (PSD) enlargement and reorganization. Much less, however, is known about activity-induced morphological modifications of inhibitory synapses. Using an in vitro model of rat organotypic hippocampal slice cultures and electron microscopy, we studied activity-related morphological changes of somatic inhibitory inputs triggered by a brief oxygen-glucose deprivation (OGD) episode, a condition associated with a synaptic enhancement referred to as anoxic LTP and a structural remodeling of excitatory synapses. Three-dimensional reconstruction of inhibitory axo-somatic synapses at different times before and after brief OGD revealed important morphological changes. The PSD area significantly and markedly increased at synapses with large and complex PSDs, but not at synapses with simple, macular PSDs. Activity-related changes of PSD size and presynaptic bouton volume developed in a strongly correlated manner. Analyses of single and serial sections further showed that the density of inhibitory synaptic contacts on the cell soma did not change within 1 h after OGD. In contrast, the proportion of the cell surface covered with inhibitory PSDs, as well as the complexity of these PSDs significantly increased, with less macular PSDs and more complex, segmented shapes. Together, these data reveal a rapid activity-related restructuring of somatic inhibitory synapses characterized by an enlargement and increased complexity of inhibitory PSDs, providing a new mechanism for a quick adjustment of the excitatory-inhibitory balance. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'.

  19. Levetiracetam attenuates hippocampal expression of synaptic plasticity-related immediate early and late response genes in amygdala-kindled rats

    Science.gov (United States)

    2010-01-01

    Background The amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity. Hippocampal RNA isolated from amygdala-kindled rats at different kindling stages was analyzed to identify kindling-induced genes. Furthermore, effects of the anti-epileptic drug levetiracetam on kindling-induced gene expression were examined. Results Cyclooxygenase-2 (Cox-2), Protocadherin-8 (Pcdh8) and TGF-beta-inducible early response gene-1 (TIEG1) were identified and verified as differentially expressed transcripts in the hippocampus of kindled rats by in situ hybridization and quantitative RT-PCR. In addition, we identified a panel of 16 additional transcripts which included Arc, Egr3/Pilot, Homer1a, Ania-3, MMP9, Narp, c-fos, NGF, BDNF, NT-3, Synaptopodin, Pim1 kinase, TNF-α, RGS2, Egr2/krox-20 and β-A activin that were differentially expressed in the hippocampus of amygdala-kindled rats. The list consists of many synaptic plasticity-related immediate early genes (IEGs) as well as some late response genes encoding transcription factors, neurotrophic factors and proteins that are known to regulate synaptic remodelling. In the hippocampus, induction of IEG expression was dependent on the afterdischarge (AD) duration. Levetiracetam, 40 mg/kg, suppressed the development of kindling measured as severity of seizures and AD duration. In addition, single animal profiling also showed that levetiracetam attenuated the observed kindling-induced IEG expression; an effect that paralleled the anti-epileptic effect of the drug on AD duration. Conclusions The present study provides mRNA expression data that suggest that levetiracetam attenuates expression of genes known to regulate synaptic remodelling. In the kindled rat, levetiracetam does so by shortening the AD duration thereby reducing the seizure-induced changes in mRNA expression in the hippocampus. PMID:20105316

  20. Levetiracetam attenuates hippocampal expression of synaptic plasticity-related immediate early and late response genes in amygdala-kindled rats

    Directory of Open Access Journals (Sweden)

    Watson William P

    2010-01-01

    Full Text Available Abstract Background The amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity. Hippocampal RNA isolated from amygdala-kindled rats at different kindling stages was analyzed to identify kindling-induced genes. Furthermore, effects of the anti-epileptic drug levetiracetam on kindling-induced gene expression were examined. Results Cyclooxygenase-2 (Cox-2, Protocadherin-8 (Pcdh8 and TGF-beta-inducible early response gene-1 (TIEG1 were identified and verified as differentially expressed transcripts in the hippocampus of kindled rats by in situ hybridization and quantitative RT-PCR. In addition, we identified a panel of 16 additional transcripts which included Arc, Egr3/Pilot, Homer1a, Ania-3, MMP9, Narp, c-fos, NGF, BDNF, NT-3, Synaptopodin, Pim1 kinase, TNF-α, RGS2, Egr2/krox-20 and β-A activin that were differentially expressed in the hippocampus of amygdala-kindled rats. The list consists of many synaptic plasticity-related immediate early genes (IEGs as well as some late response genes encoding transcription factors, neurotrophic factors and proteins that are known to regulate synaptic remodelling. In the hippocampus, induction of IEG expression was dependent on the afterdischarge (AD duration. Levetiracetam, 40 mg/kg, suppressed the development of kindling measured as severity of seizures and AD duration. In addition, single animal profiling also showed that levetiracetam attenuated the observed kindling-induced IEG expression; an effect that paralleled the anti-epileptic effect of the drug on AD duration. Conclusions The present study provides mRNA expression data that suggest that levetiracetam attenuates expression of genes known to regulate synaptic remodelling. In the kindled rat, levetiracetam does so by shortening the AD duration thereby reducing the seizure-induced changes in mRNA expression in the hippocampus.

  1. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons.

    Science.gov (United States)

    Magee, J C; Johnston, D

    1997-01-10

    The role of back-propagating dendritic action potentials in the induction of long-term potentiation (LTP) was investigated in CA1 neurons by means of dendritic patch recordings and simultaneous calcium imaging. Pairing of subthreshold excitatory postsynaptic potentials (EPSPs) with back-propagating action potentials resulted in an amplification of dendritic action potentials and evoked calcium influx near the site of synaptic input. This pairing also induced a robust LTP, which was reduced when EPSPs were paired with non-back-propagating action potentials or when stimuli were unpaired. Action potentials thus provide a synaptically controlled, associative signal to the dendrites for Hebbian modifications of synaptic strength.

  2. Learning Discloses Abnormal Structural and Functional Plasticity at Hippocampal Synapses in the APP23 Mouse Model of Alzheimer's Disease

    Science.gov (United States)

    Middei, Silvia; Roberto, Anna; Berretta, Nicola; Panico, Maria Beatrice; Lista, Simone; Bernardi, Giorgio; Mercuri, Nicola B.; Ammassari-Teule, Martine; Nistico, Robert

    2010-01-01

    B6-Tg/Thy1APP23Sdz (APP23) mutant mice exhibit neurohistological hallmarks of Alzheimer's disease but show intact basal hippocampal neurotransmission and synaptic plasticity. Here, we examine whether spatial learning differently modifies the structural and electrophysiological properties of hippocampal synapses in APP23 and wild-type mice. While…

  3. G-protein-coupled estrogen receptor 1 is anatomically positioned to modulate synaptic plasticity in the mouse hippocampus.

    Science.gov (United States)

    Waters, Elizabeth M; Thompson, Louisa I; Patel, Parth; Gonzales, Andreina D; Ye, Hector Zhiyu; Filardo, Edward J; Clegg, Deborah J; Gorecka, Jolanta; Akama, Keith T; McEwen, Bruce S; Milner, Teresa A

    2015-02-11

    Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors α and β, and synaptic levels in the rodent dorsal hippocampus. Here, we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and interspersed interneurons, especially those in the hilus of the dentate gyrus. Diffuse GPER1-IR was found in all lamina but was most dense in stratum lucidum of CA3. Ultrastructural analysis revealed discrete extranuclear GPER1-IR affiliated with the plasma membrane and endoplasmic reticulum of neuronal perikarya and dendritic shafts, synaptic specializations in dendritic spines, and clusters of vesicles in axon terminals. Moreover, GPER1-IR was found in unmyelinated axons and glial profiles. Overall, the types and amounts of GPER1-labeled profiles were similar between males and females; however, in females elevated estrogen levels generally increased axonal labeling. Some estradiol-induced changes observed in previous studies were replicated by the GPER agonist G1: G1 increased PSD95-IR in strata oriens, lucidum, and radiatum of CA3 in ovariectomized mice 6 h after administration. In contrast, estradiol but not G1 increased Akt phosphorylation levels. Instead, GPER1 actions in the synapse may be due to interactions with synaptic scaffolding proteins, such as SAP97. These results suggest that although estrogen's actions via GPER1 may converge on the same synaptic elements, different pathways are used to achieve these actions.

  4. Decrease of synaptic plasticity associated with alteration of information flow in a rat model of vascular dementia.

    Science.gov (United States)

    Xu, X; Li, Z; Yang, Z; Zhang, T

    2012-03-29

    This investigation examined whether the directional index of neural information flow (NIF) could be employed to characterize the synaptic plasticity in the CA3-CA1 pathway of the hippocampus and assessed which oscillatory rhythm was associated with cognitive impairments induced by vascular dementia (VD). Rats were randomly divided into control and VD groups. The animal model of VD used the two-vessel occlusion (2VO) method. Behavior was measured using the Morris water maze (MWM). Local field potentials (LFPs) from CA3 and CA1 were recorded after behavioral tests, followed by recording long-term potentiation (LTP) of the same CA3-CA1 pathway. General partial directed coherence (gPDC) approach was utilized to determine the directionality of NIF between CA3 and CA1 over five frequency bands, which were delta, theta, alpha, beta, and gamma. The results showed that the escape latencies were significantly prolonged in the VD group, whereas the swimming speeds of these two groups remained constant throughout testing. Moreover, the phase synchronization values between CA3 and CA1 regions were reduced in theta, alpha, beta, and gamma bands in the VD state compared to that in the normal state. The coupling directional index was considerably decreased in the previously given four frequency bands in VD rats, whereas the strength of CA3 driving CA1 was significantly reduced in the same frequency bands. Interestingly, LTP was significantly decreased in the VD group, which was consistent with the LFPs findings. The data suggest that the directionality index of NIF in these physiological oscillatory rhythms could be used as a measure of synaptic plasticity in the hippocampal CA3-CA1 pathway in VD states. The potential mechanism of the relationship between NIF direction and synaptic plasticity in VD state was discussed.

  5. Abnormal tau induces cognitive impairment through two different mechanisms: synaptic dysfunction and neuronal loss.

    Science.gov (United States)

    Di, J; Cohen, L S; Corbo, C P; Phillips, G R; El Idrissi, A; Alonso, A D

    2016-02-18

    The hyperphosphorylated microtubule-associated protein tau is present in several neurodegenerative diseases, although the causal relationship remains elusive. Few mouse models used to study Alzheimer-like dementia target tau phosphorylation. We created an inducible pseudophosphorylated tau (Pathological Human Tau, PH-Tau) mouse model to study the effect of conformationally modified tau in vivo. Leaky expression resulted in two levels of PH-Tau: low basal level and higher upon induction (4% and 14% of the endogenous tau, respectively). Unexpectedly, low PH-Tau resulted in significant cognitive deficits, decrease in the number of synapses (seen by EM in the CA1 region), reduction of synaptic proteins, and localization to the nucleus. Induction of PH-Tau triggered neuronal death (60% in CA3), astrocytosis, and loss of the processes in CA1. These findings suggest, that phosphorylated tau is sufficient to induce neurodegeneration and that two different mechanisms can induce cognitive impairment depending on the levels of PH-Tau expression.

  6. 突触可塑性分子机制的相关研究%Molecular Mechanisms of Synaptic Plasticity Related Research

    Institute of Scientific and Technical Information of China (English)

    张永杰

    2012-01-01

    In recent years,researchers have paid close attention to the role of synaptic plasticity in learning and memory. Synaptic is a key part of neural information transmission, and synaptic plasticity is considered as synaptic changes, the new synaptic formation and the establishment of transmission performance. Synaptic plasticity is the molecular basis of learning and memory, which mediates the transmission of nerve excitability, and has a major influence on synaptic plasticity of neurons establishment, therefore is closely related to learning and memory. Here is to make a review on the molecular mechanisms of synaptic plasticity in learning and memory.%近年来,突触可塑性在学习记忆中所产生的作用一直是人们关注的焦点.突触是神经信息传递的关键部位,突触可塑性被认为是突触形态的改变、新的突触的形成及传递性能的建立,突触可塑性是学习与记忆的细胞分子学基础,其介导了神经兴奋性的传导,对神经元突触可塑性和神经构筑产生了重要影响,因而与学习记忆关系密切.现就突触可塑性分子机制对学习记忆的影响进行综述.

  7. 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...

  8. Role of motor cortex NMDA receptors in learning-dependent synaptic plasticity of behaving mice

    OpenAIRE

    Mazahir T Hasan; Hernández-González, Samuel; Dogbevia, Godwin; Treviño, Mario; Bertocchi, Ilaria; Gruart, Agnès; Delgado-García, José M.

    2013-01-01

    The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, her...

  9. Dynamic control of synaptic vesicle replenishment and short-term plasticity by Ca(2+)-calmodulin-Munc13-1 signaling.

    Science.gov (United States)

    Lipstein, Noa; Sakaba, Takeshi; Cooper, Benjamin H; Lin, Kun-Han; Strenzke, Nicola; Ashery, Uri; Rhee, Jeong-Seop; Taschenberger, Holger; Neher, Erwin; Brose, Nils

    2013-07-10

    Short-term synaptic plasticity, the dynamic alteration of synaptic strength during high-frequency activity, is a fundamental characteristic of all synapses. At the calyx of Held, repetitive activity eventually results in short-term synaptic depression, which is in part due to the gradual exhaustion of releasable synaptic vesicles. This is counterbalanced by Ca(2+)-dependent vesicle replenishment, but the molecular mechanisms of this replenishment are largely unknown. We studied calyces of Held in knockin mice that express a Ca(2+)-Calmodulin insensitive Munc13-1(W464R) variant of the synaptic vesicle priming protein Munc13-1. Calyces of these mice exhibit a slower rate of synaptic vesicle replenishment, aberrant short-term depression and reduced recovery from synaptic depression after high-frequency stimulation. Our data establish Munc13-1 as a major presynaptic target of Ca(2+)-Calmodulin signaling and show that the Ca(2+)-Calmodulin-Munc13-1 complex is a pivotal component of the molecular machinery that determines short-term synaptic plasticity characteristics.

  10. Age-Dependent Glutamate Induction of Synaptic Plasticity in Cultured Hippocampal Neurons

    Science.gov (United States)

    Ivenshitz, Miriam; Segal, Menahem; Sapoznik, Stav

    2006-01-01

    A common denominator for the induction of morphological and functional plasticity in cultured hippocampal neurons involves the activation of excitatory synapses. We now demonstrate massive morphological plasticity in mature cultured hippocampal neurons caused by a brief exposure to glutamate. This plasticity involves a slow, 70%-80% increase in…

  11. Sleep deprivation during a specific 3-hour time window post-training impairs hippocampal synaptic plasticity and memory.

    Science.gov (United States)

    Prince, Toni-Moi; Wimmer, Mathieu; Choi, Jennifer; Havekes, Robbert; Aton, Sara; Abel, Ted

    2014-03-01

    Sleep deprivation disrupts hippocampal function and plasticity. In particular, long-term memory consolidation is impaired by sleep deprivation, suggesting that a specific critical period exists following learning during which sleep is necessary. To elucidate the impact of sleep deprivation on long-term memory consolidation and synaptic plasticity, long-term memory was assessed when mice were sleep deprived following training in the hippocampus-dependent object place recognition task. We found that 3h of sleep deprivation significantly impaired memory when deprivation began 1h after training. In contrast, 3 h of deprivation beginning immediately post-training did not impair spatial memory. Furthermore, a 3-h sleep deprivation beginning 1h after training impaired hippocampal long-term potentiation (LTP), whereas sleep deprivation immediately after training did not affect LTP. Together, our findings define a specific 3-h critical period, extending from 1 to 4h after training, during which sleep deprivation impairs hippocampal function.

  12. The role of additive neurogenesis and synaptic plasticity in a hippocampal memory model with grid-cell like input.

    Directory of Open Access Journals (Sweden)

    Peter A Appleby

    Full Text Available Recently, we presented a study of adult neurogenesis in a simplified hippocampal memory model. The network was required to encode and decode memory patterns despite changing input statistics. We showed that additive neurogenesis was a more effective adaptation strategy compared to neuronal turnover and conventional synaptic plasticity as it allowed the network to respond to changes in the input statistics while preserving representations of earlier environments. Here we extend our model to include realistic, spatially driven input firing patterns in the form of grid cells in the entorhinal cortex. We compare network performance across a sequence of spatial environments using three distinct adaptation strategies: conventional synaptic plasticity, where the network is of fixed size but the connectivity is plastic; neuronal turnover, where the network is of fixed size but units in the network may die and be replaced; and additive neurogenesis, where the network starts out with fewer initial units but grows over time. We confirm that additive neurogenesis is a superior adaptation strategy when using realistic, spatially structured input patterns. We then show that a more biologically plausible neurogenesis rule that incorporates cell death and enhanced plasticity of new granule cells has an overall performance significantly better than any one of the three individual strategies operating alone. This adaptation rule can be tailored to maximise performance of the network when operating as either a short- or long-term memory store. We also examine the time course of adult neurogenesis over the lifetime of an animal raised under different hypothetical rearing conditions. These growth profiles have several distinct features that form a theoretical prediction that could be tested experimentally. Finally, we show that place cells can emerge and refine in a realistic manner in our model as a direct result of the sparsification performed by the dentate gyrus

  13. Is a 4-bit synaptic weight resolution enough? - constraints on enabling spike-timing dependent plasticity in neuromorphic hardware.

    Science.gov (United States)

    Pfeil, Thomas; Potjans, Tobias C; Schrader, Sven; Potjans, Wiebke; Schemmel, Johannes; Diesmann, Markus; Meier, Karlheinz

    2012-01-01

    Large-scale neuromorphic hardware systems typically bear the trade-off between detail level and required chip resources. Especially when implementing spike-timing dependent plasticity, reduction in resources leads to limitations as compared to floating point precision. By design, a natural modification that saves resources would be reducing synaptic weight resolution. In this study, we give an estimate for the impact of synaptic weight discretization on different levels, ranging from random walks of individual weights to computer simulations of spiking neural networks. The FACETS wafer-scale hardware system offers a 4-bit resolution of synaptic weights, which is shown to be sufficient within the scope of our network benchmark. Our findings indicate that increasing the resolution may not even be useful in light of further restrictions of customized mixed-signal synapses. In addition, variations due to production imperfections are investigated and shown to be uncritical in the context of the presented study. Our results represent a general framework for setting up and configuring hardware-constrained synapses. We suggest how weight discretization could be considered for other backends dedicated to large-scale simulations. Thus, our proposition of a good hardware verification practice may rise synergy effects between hardware developers and neuroscientists.

  14. Spatiotemporal discrimination in neural networks with short-term synaptic plasticity

    Science.gov (United States)

    Shlaer, Benjamin; Miller, Paul

    2015-03-01

    Cells in recurrently connected neural networks exhibit bistability, which allows for stimulus information to persist in a circuit even after stimulus offset, i.e. short-term memory. However, such a system does not have enough hysteresis to encode temporal information about the stimuli. The biophysically described phenomenon of synaptic depression decreases synaptic transmission strengths due to increased presynaptic activity. This short-term reduction in synaptic strengths can destabilize attractor states in excitatory recurrent neural networks, causing the network to move along stimulus dependent dynamical trajectories. Such a network can successfully separate amplitudes and durations of stimuli from the number of successive stimuli. Stimulus number, duration and intensity encoding in randomly connected attractor networks with synaptic depression. Front. Comput. Neurosci. 7:59., and so provides a strong candidate network for the encoding of spatiotemporal information. Here we explicitly demonstrate the capability of a recurrent neural network with short-term synaptic depression to discriminate between the temporal sequences in which spatial stimuli are presented.

  15. Long-term plasticity determines the postsynaptic response to correlated afferents with multivesicular short-term synaptic depression

    Directory of Open Access Journals (Sweden)

    Alexander David Bird

    2014-01-01

    Full Text Available Synchrony in a presynaptic population leads to correlations in vesicle occupancy at the active sites for neurotransmitter release. The number of independent release sites per presynaptic neuron, a synaptic parameter recently shown to be modifed during long-term plasticity, will modulate these correlations and therefore have a significant effect on the firing rate of the postsynaptic neuron. To understand how correlations from synaptic dynamics and from presynaptic synchrony shape the postsynaptic response, we study a model of multiple release site short-term plasticity and derive exact results for the crosscorrelation function of vesicle occupancy and neurotransmitter release, as well as the postsynaptic voltage variance. Using approximate forms for the postsynaptic firing rate in the limits of low and high correlations, we demonstrate that short-term depression leads to a maximum response for an intermediate number of presynaptic release sites, and that this leads to a tuning-curve response peaked at an optimal presynaptic synchrony setby the number of neurotransmitter release sites per presynaptic neuron. These effects arise because, above a certain level of correlation, activity in the presynaptic population is overly strong resulting in wastage of the pool of releasable neurotransmitter. As the nervous system operates under constraints of efficient metabolism it is likely that this phenomenon provides an activity-dependent constraint on network architecture.

  16. A novel form of synaptic plasticity in field CA3 of hippocampus requires GPER1 activation and BDNF release.

    Science.gov (United States)

    Briz, Victor; Liu, Yan; Zhu, Guoqi; Bi, Xiaoning; Baudry, Michel

    2015-09-28

    Estrogen is an important modulator of hippocampal synaptic plasticity and memory consolidation through its rapid action on membrane-associated receptors. Here, we found that both estradiol and the G-protein-coupled estrogen receptor 1 (GPER1) specific agonist G1 rapidly induce brain-derived neurotrophic factor (BDNF) release, leading to transient stimulation of activity-regulated cytoskeleton-associated (Arc) protein translation and GluA1-containing AMPA receptor internalization in field CA3 of hippocampus. We also show that type-I metabotropic glutamate receptor (mGluR) activation does not induce Arc translation nor long-term depression (LTD) at the mossy fiber pathway, as opposed to its effects in CA1, and it only triggers LTD after GPER1 stimulation. Furthermore, this form of mGluR-dependent LTD is associated with ubiquitination and proteasome-mediated degradation of GluA1, and is prevented by proteasome inhibition. Overall, our study identifies a novel mechanism by which estrogen and BDNF regulate hippocampal synaptic plasticity in the adult brain.

  17. Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning.

    Directory of Open Access Journals (Sweden)

    David Ng

    2009-02-01

    Full Text Available The N-methyl-D-aspartate receptor (NMDAR, a major excitatory ligand-gated ion channel in the central nervous system (CNS, is a principal mediator of synaptic plasticity. Here we report that neuropilin tolloid-like 1 (Neto1, a complement C1r/C1s, Uegf, Bmp1 (CUB domain-containing transmembrane protein, is a novel component of the NMDAR complex critical for maintaining the abundance of NR2A-containing NMDARs in the postsynaptic density. Neto1-null mice have depressed long-term potentiation (LTP at Schaffer collateral-CA1 synapses, with the subunit dependency of LTP induction switching from the normal predominance of NR2A- to NR2B-NMDARs. NMDAR-dependent spatial learning and memory is depressed in Neto1-null mice, indicating that Neto1 regulates NMDA receptor-dependent synaptic plasticity and cognition. Remarkably, we also found that the deficits in LTP, learning, and memory in Neto1-null mice were rescued by the ampakine CX546 at doses without effect in wild-type. Together, our results establish the principle that auxiliary proteins are required for the normal abundance of NMDAR subunits at synapses, and demonstrate that an inherited learning defect can be rescued pharmacologically, a finding with therapeutic implications for humans.

  18. Inactivation of BRD7 results in impaired cognitive behavior and reduced synaptic plasticity of the medial prefrontal cortex.

    Science.gov (United States)

    Xu, Yang; Cao, Wenyu; Zhou, Ming; Li, Changqi; Luo, Yanwei; Wang, Heran; Zhao, Ran; Jiang, Shihe; Yang, Jing; Liu, Yukun; Wang, Xinye; Li, Xiayu; Xiong, Wei; Ma, Jian; Peng, Shuping; Zeng, Zhaoyang; Li, Xiaoling; Tan, Ming; Li, Guiyuan

    2015-06-01

    BRD7 is a bromodomain-containing protein (BCP), and recent evidence implicates the role of BCPs in the initiation and development of neurodevelopmental disorders. However, few studies have investigated the biological functions of BRD7 in the central nervous system. In our study, BRD7 was found to be widely expressed in various regions of the mouse brain, including the medial prefrontal cortex (mPFC), caudate putamen (CPu), hippocampus (Hip), midbrain (Mb), cerebellum (Cb), and mainly co-localized with neuron but not with glia. Using a BRD7 knockout mouse model and a battery of behavioral tests, we report that disruption of BRD7 results in impaired cognitive behavior leaving the emotional behavior unaffected. Moreover, a series of proteins involved in synaptic plasticity were decreased in the medial prefrontal cortex and there was a concomitant decrease in neuronal spine density and dendritic branching in the medial prefrontal cortex. However, no significant difference was found in the hippocampus compared to the wild-type mice. Thus, BRD7 might play a critical role in the regulation of synaptic plasticity and affect cognitive behavior.

  19. Enriched environment, nitric oxide production and synaptic plasticity prevent the aging-dependent impairment of spatial cognition.

    Science.gov (United States)

    Arnaiz, Silvia Lores; D'Amico, Gabriela; Paglia, Nora; Arismendi, Mariana; Basso, Nidia; del Rosario Lores Arnaiz, María

    2004-01-01

    In rodents, neuronal plasticity decreases and spatial learning and working memory deficits increase upon aging. Several authors have shown that rats reared in enriched environments have better cognitive performance in association with increased neuronal plasticity than animals reared in standard environments. We hypothesized that enriched environment could preserve animals from the age-associated neurological impairments, mainly through NO-dependent mechanisms of induction of neuronal plasticity. We present evidence that 27 months old rats from an enriched environment show a better performance in spatial working memory than standard reared rats of the same age. Both mtNOS and cytosolic nNOS activities were found significantly increased (73% and 155%, respectively) in female rats from enriched environment as compared with control animals kept in a standard environment. The enzymatic activity of complex I was 80% increased in rats from enriched environment as compared with control rats. We conclude that an extensively enriched environment prevents old rats from the aging-associated impairment of spatial cognition, synaptic plasticity and nitric oxide production.

  20. Schisandra N-butanol extract improves synaptic morphology and plasticity in ovarectomized mice

    Institute of Scientific and Technical Information of China (English)

    Meiyan Yang; Zhaolin Cai; Peng Xiao; Chuhua Li

    2012-01-01

    Preliminary work by our research team revealed that Schisandra, a renowned traditional Chinese medicine, causes learning and memory improvements in ovariectomized mice. This activity was attributed to active ingredients extracted with N-butyl alcohol, named Schisandra N-butanol extract. In this study, ovariectomized mice were pretreated with Schisandra N-butanol extract given by intragastric administration. This treatment led to the enhancement of learning, and an increase in hippocampal CA1 synaptic, surface and postsynaptic density. A decrease in the average size of the synaptic active zone was also observed. These experimental findings showing that Schisandra N-butanol extract improved synaptic morphology indicate an underlying mechanism by which the ability of learning is enhanced in ovariectomized mice.

  1. Exercise, Alzheimer's Disease and Synaptic Plasticity (review)%运动、阿尔茨海默病与突触可塑性

    Institute of Scientific and Technical Information of China (English)

    刘慧莉; 赵刚

    2012-01-01

    Exercise can improve cognitive performance in Alzheimer's disease (AD), which may involve in synaptic plasticity. This paper reviewed the benefit of exercise on AD, the synaptic plasticity in AD, and the effects of exercise on synaptic plasticity.%运动能够减缓阿尔茨海默病(AD)的发病和进展,突触可塑性可能是AD学习和记忆功能障碍的神经生物学基础,也是运动防治AD的细胞机制.本文就运动对AD的防治作用、AD突触可塑性的改变及运动对突触可塑性的影响进行综述.

  2. Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats.

    Science.gov (United States)

    Matheus, Filipe C; Rial, Daniel; Real, Joana I; Lemos, Cristina; Ben, Juliana; Guaita, Gisele O; Pita, Inês R; Sequeira, Ana C; Pereira, Frederico C; Walz, Roger; Takahashi, Reinaldo N; Bertoglio, Leandro J; Da Cunha, Cláudio; Cunha, Rodrigo A; Prediger, Rui D

    2016-03-15

    Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity.

  3. Effect of Chronic Morphine Consumption on Synaptic Plasticity of Rat’s Hippocampus: A Transmission Electron Microscopy Study

    Directory of Open Access Journals (Sweden)

    Mohammad Hassan Heidari

    2013-01-01

    Full Text Available It is well known that the synapses undergo some changes in the brain during the course of normal life and under certain pathological or experimental circumstances. One of the main goals of numerous researchers has been to find the reasons for these structural changes. In the present study, we investigated the effects of chronic morphine consumption on synaptic plasticity, postsynaptic density thickness, and synaptic curvatures of hippocampus CA1 area of rats. So for reaching these goals, 24 N-Mary male rats were randomly divided into three groups, morphine (n=8, placebo (n=8, and control (n=8 groups. In the morphine group, complex of morphine (0.1, 0.2, 0.3, and 0.4 mg/mL and in the placebo (sucrose group complex of sucrose (% 0.3 were used for 21 days. After the end of drug treatment the animals were scarified and perfused intracardinally and finally the CA1 hippocampal samples were taken for ultrastructural studies, and then the obtained data were analyzed by SPSS and one-way analysis of variance. Our data indicated that synaptic numbers per nm3 change significantly in morphine group compared to the other two groups (placebo and control (P<0.001 and also statistical analysis revealed a significant difference between groups in terms of thickness of postsynaptic density (P<0.001 and synaptic curvature (P<0.007. It seems that morphine dependence in rats plays a main role in the ultrastructural changes of hippocampus.

  4. Regional-specific effects of ovarian hormone loss on synaptic plasticity in adult human APOE targeted replacement mice.

    Directory of Open Access Journals (Sweden)

    Rebecca C Klein

    Full Text Available The human apolipoprotein ε4 allele (APOE4 has been implicated as one of the strongest genetic risk factors associated with Alzheimer's disease (AD and in influencing normal cognitive functioning. Previous studies have demonstrated that mice expressing human apoE4 display deficits in behavioral and neurophysiological outcomes compared to those with apoE3. Ovarian hormones have also been shown to be important in modulating synaptic processes underlying cognitive function, yet little is known about how their effects are influenced by apoE. In the current study, female adult human APOE targeted replacement (TR mice were utilized to examine the effects of human APOE genotype and long-term ovarian hormone loss on synaptic plasticity in limbic regions by measuring dendritic spine density and electrophysiological function. No significant genotype differences were observed on any outcomes within intact mice. However, there was a significant main effect of genotype on total spine density in apical dendrites in the hippocampus, with post-hoc t-tests revealing a significant reduction in spine density in apoE3 ovariectomized (OVX mice compared to sham operated mice. There was also a significant main effect of OVX on the magnitude of LTP, with post-hoc t-tests revealing a decrease in apoE3 OVX mice relative to sham. In contrast, apoE4 OVX mice showed increased synaptic activity relative to sham. In the lateral amygdala, there was a significant increase in total spine density in apoE4 OVX mice relative to sham. This increase in spine density was consistent with a significant increase in spontaneous excitatory activity in apoE4 OVX mice. These findings suggest that ovarian hormones differentially modulate synaptic integrity in an apoE-dependent manner within brain regions that are susceptible to neurophysiological dysfunction associated with AD.

  5. Cognition and Synaptic-Plasticity Related Changes in Aged Rats Supplemented with 8- and 10-Carbon Medium Chain Triglycerides

    Science.gov (United States)

    Wang, Dongmei; Mitchell, Ellen S.

    2016-01-01

    Brain glucose hypometabolism is a common feature of Alzheimer’s disease (AD). Previous studies have shown that cognition is improved by providing AD patients with an alternate energy source: ketones derived from either ketogenic diet or supplementation with medium chain triglycerides (MCT). Recently, data on the neuroprotective capacity of MCT-derived medium chain fatty acids (MCFA) suggest 8-carbon and 10-carbon MCFA may have cognition-enhancing properties which are not related to ketone production. We investigated the effect of 8 week treatment with MCT8, MCT10 or sunflower oil supplementation (5% by weight of chow diet) in 21 month old Wistar rats. Both MCT diets increased ketones plasma similarly compared to control diet, but MCT diets did not increase ketones in the brain. Treatment with MCT10, but not MCT8, significantly improved novel object recognition memory compared to control diet, while social recognition increased in both MCT groups. MCT8 and MCT10 diets decreased weight compared to control diet, where MCFA plasma levels were higher in MCT10 groups than in MCT8 groups. Both MCT diets increased IRS-1 (612) phosphorylation and decreased S6K phosphorylation (240/244) but only MCT10 increased Akt phosphorylation (473). MCT8 supplementation increased synaptophysin, but not PSD-95, in contrast MCT10 had no effect on either synaptic marker. Expression of Ube3a, which controls synaptic stability, was increased by both MCT diets. Cortex transcription via qPCR showed that immediate early genes related to synaptic plasticity (arc, plk3, junb, egr2, nr4a1) were downregulated by both MCT diets while MCT8 additionally down-regulated fosb and egr1 but upregulated grin1 and gba2. These results demonstrate that treatment of 8- and 10-carbon length MCTs in aged rats have slight differential effects on synaptic stability, protein synthesis and behavior that may be independent of brain ketone levels. PMID:27517611

  6. Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Sancheti, Harsh; Akopian, Garnik; Yin, Fei; Brinton, Roberta D; Walsh, John P; Cadenas, Enrique

    2013-01-01

    Alzheimer's disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity have been shown to be affected in the early stages of Alzheimer's disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer's disease (3xTg-AD) that shows progression of pathology as a function of age; two age groups: 6 months (young) and 12 months (old) were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O) and long term potentiation (LTP) (measured by electrophysiology). Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice.

  7. Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Harsh Sancheti

    Full Text Available Alzheimer's disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits and synaptic plasticity have been shown to be affected in the early stages of Alzheimer's disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer's disease (3xTg-AD that shows progression of pathology as a function of age; two age groups: 6 months (young and 12 months (old were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O and long term potentiation (LTP (measured by electrophysiology. Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice.

  8. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Calkins, Marcus J; Manczak, Maria; Mao, Peizhong; Shirendeb, Ulziibat; Reddy, P Hemachandra

    2011-12-01

    Increasing evidence suggests that the accumulation of amyloid beta (Aβ) in synapses and synaptic mitochondria causes synaptic mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of Aβ in mitochondrial activity and synaptic alterations in neurons from a mouse model of AD. Using primary neurons from a well-characterized Aβ precursor protein transgenic (AβPP) mouse model (Tg2576 mouse line), for the first time, we studied mitochondrial activity, including axonal transport of mitochondria, mitochondrial dynamics, morphology and function. Further, we also studied the nature of Aβ-induced synaptic alterations, and cell death in primary neurons from Tg2576 mice, and we sought to determine whether the mitochondria-targeted antioxidant SS31 could mitigate the effects of oligomeric Aβ. We found significantly decreased anterograde mitochondrial movement, increased mitochondrial fission and decreased fusion, abnormal mitochondrial and synaptic proteins and defective mitochondrial function in primary neurons from AβPP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed a large number of small mitochondria and structurally damaged mitochondria, with broken cristae in AβPP primary neurons. We also found an increased accumulation of oligomeric Aβ and increased apoptotic neuronal death in the primary neurons from the AβPP mice relative to the WT neurons. Our results revealed an accumulation of intraneuronal oligomeric Aβ, leading to mitochondrial and synaptic deficiencies, and ultimately causing neurodegeneration in AβPP cultures. However, we found that the mitochondria-targeted antioxidant SS31 restored mitochondrial transport and synaptic viability, and decreased the percentage of defective mitochondria, indicating that SS31 protects mitochondria and synapses from Aβ toxicity.

  9. Closed-loop Robots Driven by Short-Term Synaptic Plasticity: Emergent Explorative vs. Limit-Cycle Locomotion

    Science.gov (United States)

    Martin, Laura; Sándor, Bulcsú; Gros, Claudius

    2016-01-01

    We examine the hypothesis, that short-term synaptic plasticity (STSP) may generate self-organized motor patterns. We simulated sphere-shaped autonomous robots, within the LPZRobots simulation package, containing three weights moving along orthogonal internal rods. The position of a weight is controlled by a single neuron receiving excitatory input from the sensor, measuring its actual position, and inhibitory inputs from the other two neurons. The inhibitory connections are transiently plastic, following physiologically inspired STSP-rules. We find that a wide palette of motion patterns are generated through the interaction of STSP, robot, and environment (closed-loop configuration), including various forward meandering and circular motions, together with chaotic trajectories. The observed locomotion is robust with respect to additional interactions with obstacles. In the chaotic phase the robot is seemingly engaged in actively exploring its environment. We believe that our results constitute a concept of proof that transient synaptic plasticity, as described by STSP, may potentially be important for the generation of motor commands and for the emergence of complex locomotion patterns, adapting seamlessly also to unexpected environmental feedback. We observe spontaneous and collision induced mode switchings, finding in addition, that locomotion may follow transiently limit cycles which are otherwise unstable. Regular locomotion corresponds to stable limit cycles in the sensorimotor loop, which may be characterized in turn by arbitrary angles of propagation. This degeneracy is, in our analysis, one of the drivings for the chaotic wandering observed for selected parameter settings, which is induced by the smooth diffusion of the angle of propagation. PMID:27803661

  10. In Vitro Studies of Neuronal Networks and Synaptic Plasticity in Invertebrates and in Mammals Using Multielectrode Arrays

    Directory of Open Access Journals (Sweden)

    Paolo Massobrio

    2015-01-01

    Full Text Available Brain functions are strictly dependent on neural connections formed during development and modified during life. The cellular and molecular mechanisms underlying synaptogenesis and plastic changes involved in learning and memory have been analyzed in detail in simple animals such as invertebrates and in circuits of mammalian brains mainly by intracellular recordings of neuronal activity. In the last decades, the evolution of techniques such as microelectrode arrays (MEAs that allow simultaneous, long-lasting, noninvasive, extracellular recordings from a large number of neurons has proven very useful to study long-term processes in neuronal networks in vivo and in vitro. In this work, we start off by briefly reviewing the microelectrode array technology and the optimization of the coupling between neurons and microtransducers to detect subthreshold synaptic signals. Then, we report MEA studies of circuit formation and activity in invertebrate models such as Lymnaea, Aplysia, and Helix. In the following sections, we analyze plasticity and connectivity in cultures of mammalian dissociated neurons, focusing on spontaneous activity and electrical stimulation. We conclude by discussing plasticity in closed-loop experiments.

  11. In Vitro Studies of Neuronal Networks and Synaptic Plasticity in Invertebrates and in Mammals Using Multielectrode Arrays

    Science.gov (United States)

    Tessadori, Jacopo; Ghirardi, Mirella

    2015-01-01

    Brain functions are strictly dependent on neural connections formed during development and modified during life. The cellular and molecular mechanisms underlying synaptogenesis and plastic changes involved in learning and memory have been analyzed in detail in simple animals such as invertebrates and in circuits of mammalian brains mainly by intracellular recordings of neuronal activity. In the last decades, the evolution of techniques such as microelectrode arrays (MEAs) that allow simultaneous, long-lasting, noninvasive, extracellular recordings from a large number of neurons has proven very useful to study long-term processes in neuronal networks in vivo and in vitro. In this work, we start off by briefly reviewing the microelectrode array technology and the optimization of the coupling between neurons and microtransducers to detect subthreshold synaptic signals. Then, we report MEA studies of circuit formation and activity in invertebrate models such as Lymnaea, Aplysia, and Helix. In the following sections, we analyze plasticity and connectivity in cultures of mammalian dissociated neurons, focusing on spontaneous activity and electrical stimulation. We conclude by discussing plasticity in closed-loop experiments. PMID:25866681

  12. Increased Expression of the PI3K Enhancer PIKE Mediates Deficits in Synaptic Plasticity and Behavior in Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Christina Gross

    2015-05-01

    Full Text Available The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5 and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability fragile X syndrome (FXS. Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and -independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects, and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects in FXS.

  13. Free D-aspartate regulates neuronal dendritic morphology, synaptic plasticity, gray matter volume and brain activity in mammals.

    Science.gov (United States)

    Errico, F; Nisticò, R; Di Giorgio, A; Squillace, M; Vitucci, D; Galbusera, A; Piccinin, S; Mango, D; Fazio, L; Middei, S; Trizio, S; Mercuri, N B; Teule, M A; Centonze, D; Gozzi, A; Blasi, G; Bertolino, A; Usiello, A

    2014-01-01

    D-aspartate (D-Asp) is an atypical amino acid, which is especially abundant in the developing mammalian brain, and can bind to and activate N-methyl-D-Aspartate receptors (NMDARs). In line with its pharmacological features, we find that mice chronically treated with D-Asp show enhanced NMDAR-mediated miniature excitatory postsynaptic currents and basal cerebral blood volume in fronto-hippocampal areas. In addition, we show that both chronic administration of D-Asp and deletion of the gene coding for the catabolic enzyme D-aspartate oxidase (DDO) trigger plastic modifications of neuronal cytoarchitecture in the prefrontal cortex and CA1 subfield of the hippocampus and promote a cytochalasin D-sensitive form of synaptic plasticity in adult mouse brains. To translate these findings in humans and consistent with the experiments using Ddo gene targeting in animals, we performed a hierarchical stepwise translational genetic approach. Specifically, we investigated the association of variation in the gene coding for DDO with complex human prefrontal phenotypes. We demonstrate that genetic variation predicting reduced expression of DDO in postmortem human prefrontal cortex is mapped on greater prefrontal gray matter and activity during working memory as measured with MRI. In conclusion our results identify novel NMDAR-dependent effects of D-Asp on plasticity and physiology in rodents, which also map to prefrontal phenotypes in humans.

  14. Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome.

    Science.gov (United States)

    Gross, Christina; Chang, Chia-Wei; Kelly, Seth M; Bhattacharya, Aditi; McBride, Sean M J; Danielson, Scott W; Jiang, Michael Q; Chan, Chi Bun; Ye, Keqiang; Gibson, Jay R; Klann, Eric; Jongens, Thomas A; Moberg, Kenneth H; Huber, Kimberly M; Bassell, Gary J

    2015-05-05

    The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability fragile X syndrome (FXS). Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and -independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects, and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects in FXS.

  15. In vitro studies of neuronal networks and synaptic plasticity in invertebrates and in mammals using multielectrode arrays.

    Science.gov (United States)

    Massobrio, Paolo; Tessadori, Jacopo; Chiappalone, Michela; Ghirardi, Mirella

    2015-01-01

    Brain functions are strictly dependent on neural connections formed during development and modified during life. The cellular and molecular mechanisms underlying synaptogenesis and plastic changes involved in learning and memory have been analyzed in detail in simple animals such as invertebrates and in circuits of mammalian brains mainly by intracellular recordings of neuronal activity. In the last decades, the evolution of techniques such as microelectrode arrays (MEAs) that allow simultaneous, long-lasting, noninvasive, extracellular recordings from a large number of neurons has proven very useful to study long-term processes in neuronal networks in vivo and in vitro. In this work, we start off by briefly reviewing the microelectrode array technology and the optimization of the coupling between neurons and microtransducers to detect subthreshold synaptic signals. Then, we report MEA studies of circuit formation and activity in invertebrate models such as Lymnaea, Aplysia, and Helix. In the following sections, we analyze plasticity and connectivity in cultures of mammalian dissociated neurons, focusing on spontaneous activity and electrical stimulation. We conclude by discussing plasticity in closed-loop experiments.

  16. Interaction of inhibition and triplets of excitatory spikes modulates the NMDA-R-mediated synaptic plasticity in a computational model of spike timing-dependent plasticity.

    Science.gov (United States)

    Cutsuridis, Vassilis

    2013-01-01

    Spike timing-dependent plasticity (STDP) experiments have shown that a synapse is strengthened when a presynaptic spike precedes a postsynaptic one and depressed vice versa. The canonical form of STDP has been shown to have an asymmetric shape with the peak long-term potentiation at +6 ms and the peak long-term depression at -5 ms. Experiments in hippocampal cultures with more complex stimuli such as triplets (one presynaptic spike combined with two postsynaptic spikes or one postsynaptic spike with two presynaptic spikes) have shown that pre-post-pre spike triplets result in no change in synaptic strength, whereas post-pre-post spike triplets lead to significant potentiation. The sign and magnitude of STDP have also been experimentally hypothesized to be modulated by inhibition. Recently, a computational study showed that the asymmetrical form of STDP in the CA1 pyramidal cell dendrite when two spikes interact switches to a symmetrical one in the presence of inhibition under certain conditions. In the present study, I investigate computationally how inhibition modulates STDP in the CA1 pyramidal neuron dendrite when it is driven by triplets. The model uses calcium as the postsynaptic signaling agent for STDP and is shown to be consistent with the experimental triplet observations in the absence of inhibition: simulated pre-post-pre spike triplets result in no change in synaptic strength, whereas simulated post-pre-post spike triplets lead to significant potentiation. When inhibition is bounded by the onset and offset of the triplet stimulation, then the strength of the synapse is decreased as the strength of inhibition increases. When inhibition arrives either few milliseconds before or at the onset of the last spike in the pre-post-pre triplet stimulation, then the synapse is potentiated. Variability in the frequency of inhibition (50 vs. 100 Hz) produces no change in synaptic strength. Finally, a 5% variation in model's calcium parameters (calcium thresholds

  17. The NO-cGMP-PKG Signaling Pathway Regulates Synaptic Plasticity and Fear Memory Consolidation in the Lateral Amygdala via Activation of ERK/MAP Kinase

    Science.gov (United States)

    Ota, Kristie T.; Pierre, Vicki J.; Ploski, Jonathan E.; Queen, Kaila; Schafe, Glenn E.

    2008-01-01

    Recent studies have shown that nitric oxide (NO) signaling plays a crucial role in memory consolidation of Pavlovian fear conditioning and in synaptic plasticity in the lateral amygdala (LA). In the present experiments, we examined the role of the cGMP-dependent protein kinase (PKG), a downstream effector of NO, in fear memory consolidation and…

  18. Enhanced group II mGluR-mediated inhibition of pain-related synaptic plasticity in the amygdala

    Directory of Open Access Journals (Sweden)

    Bird Gary C

    2006-05-01

    Full Text Available Abstract Background The latero-capsular part of the central nucleus of the amygdala (CeLC is the target of the spino-parabrachio-amygdaloid pain pathway. Our previous studies showed that CeLC neurons develop synaptic plasticity and increased neuronal excitability in the kaolin/carrageenan model of arthritic pain. These pain-related changes involve presynaptic group I metabotropic glutamate receptors (mGluRs and postsynaptic NMDA and calcitonin gene-related peptide (CGRP1 receptors. Here we address the role of group II mGluRs. Results Whole-cell current- and voltage-clamp recordings were made from CeLC neurons in brain slices from control rats and arthritic rats (>6 h postinjection of kaolin/carrageenan into the knee. Monosynaptic excitatory postsynaptic currents (EPSCs were evoked by electrical stimulation of afferents from the pontine parabrachial (PB area. A selective group II mGluR agonist (LY354740 decreased the amplitude of EPSCs more potently in CeLC neurons from arthritic rats (IC50 = 0.59 nM than in control animals (IC50 = 15.0 nM. The inhibitory effect of LY354740 was reversed by a group II mGluR antagonist (EGLU but not a GABAA receptor antagonist (bicuculline. LY354740 decreased frequency, but not amplitude, of miniature EPSCs in the presence of TTX. No significant changes of neuronal excitability measures (membrane slope conductance and action potential firing rate were detected. Conclusion Our data suggest that group II mGluRs act presynaptically to modulate synaptic plasticity in the amygdala in a model of arthritic pain.

  19. EFFECT OF ELECTROACUPUNCTURE ON SYNAPTIC PLASTICITY OF HPPOCAMPAL NEURONS IN CEREBRAL ISCHEMIA RATS

    Institute of Scientific and Technical Information of China (English)

    杨卓欣; 于海波; 王玲; 张家维

    2004-01-01

    Objective:To observe the effect of electroacupuncture (EA) on synaptic structure of hippocampal nerve felts and synaptophysin(SYN)expression in rats with cerebral ischemic injury. Methods: Sixty Wistar rats were randomized into sham-operation group, cerebral ischemia (CI) group and EA group, each of which was further divided into 1week (W) and 5W subgroups. CI injury model was established by occlusion of the bilateral common carotid arteries. "Baihui"(百会 GV 20), "Dazhui" (大椎 GV 14), "Renzhong"(人中 GV 26) and "Guanyuan"(关元 CV 4) were punctured and stimulated electrically. The brain tissue sections containing hippocampus region were stained with immunohistochemical technique and observed under light microscope and transmission electronic microscope. Results: After CI, the ischemic injury as degeneration of the presynapse compositions, decrease of the synaptic numeral density, and low expression of SYN were observed in hippocampal CA1 area. By the 5th week after CI, the neonatal synapses of CI and EA groups appeared, and SYN expression was upregulated. In EA group, the recovery of the numeral density of synapses was especially noticeable, being 93.8% of that of sham-operation group and significantly higher than that in CI group (P<0.01). Compared with sham-operation group, the calibrated optical density (COD) values of SYN increased to 70% in CI group, and 93.3% in EA group, and COD value in EA group was significantly higher than that in CI group (P<0.01). Conclusion: EA can function in promoting synaptic regeneration and enhancing and perfecting the actions of the reconstructed synapses in hippocampal CA1 area in CI rats.

  20. Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation

    OpenAIRE

    Lopez, AJ; Kramar, E; Matheos, DP; White, AO; Kwapis, J; Vogel-Ciernia, A; Sakata, K.; Espinoza, M; Wood, MA

    2016-01-01

    Designer receptors exclusively activated by designer drug (DREADDs) are a novel tool with the potential to bidirectionally drive cellular, circuit, and ultimately, behavioral changes. We used DREADDs to evaluate memory formation in a hippocampus-dependent task in mice and effects on synaptic physiology in the dorsal hippocampus. We expressed neuron-specific (hSyn promoter) DREADDs that were either excitatory (HM3D) or inhibitory (HM4D) in the dorsal hippocampus. As predicted, hSyn–HM3D was ab...

  1. Genetic deletion of melanin-concentrating hormone neurons impairs hippocampal short-term synaptic plasticity and hippocampal-dependent forms of short-term memory.

    Science.gov (United States)

    Le Barillier, Léa; Léger, Lucienne; Luppi, Pierre-Hervé; Fort, Patrice; Malleret, Gaël; Salin, Paul-Antoine

    2015-11-01

    The cognitive role of melanin-concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero-lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long-term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal-dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long-term potentiation and depression in the CA1 area of the hippocampus. Post-tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre-synaptic forms of short-term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short-term memory T-maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short-term memory by impairing short-term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short-term synaptic plasticity in the hippocampus.

  2. Synaptic determinants of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Elena M B Boggio

    2010-08-01

    Full Text Available There is mounting evidence showing that the structural and molecular organization of synaptic connections are affected both in human patients and in animal models of neurological and psychiatric diseases. As a consequence of these experimental observations, it has been introduced the concept of synapsopathies, a notion describing brain disorders of synaptic function and plasticity. A close correlation between neurological diseases and synaptic abnormalities is especially relevant for those syndromes including also mental retardation in their symptomatology, such as Rett Syndrome (RS. RS (MIM312750 is an X-linked dominant neurological disorder that is caused, in the majority of cases by mutations in methyl-CpG-binding protein 2 (MeCP2. This review will focus on the current knowledge of the synaptic alterations produced by mutations of the gene MeCP2 in mouse models of RS and will highlight prospects experimental therapies currently in use. Different experimental approaches have revealed that RS could be the consequence of an impairment in the homeostasis of synaptic transmission in specific brain regions. Indeed, several forms of experience-induced neuronal plasticity are impaired in the absence of MeCP2. Based on the results presented in this review, it is reasonable to propose that understanding how the brain is affected by diseases such as RS is at reach. This effort will bring us closer to identify the neurobiological bases of human cognition.

  3. ATM protein is located on presynaptic vesicles and its deficit leads to failures in synaptic plasticity.

    Science.gov (United States)

    Vail, Graham; Cheng, Aifang; Han, Yu Ray; Zhao, Teng; Du, Shengwang; Loy, Michael M T; Herrup, Karl; Plummer, Mark R

    2016-07-01

    Ataxia telangiectasia is a multisystemic disorder that includes a devastating neurodegeneration phenotype. The ATM (ataxia-telangiectasia mutated) protein is well-known for its role in the DNA damage response, yet ATM is also found in association with cytoplasmic vesicular structures: endosomes and lysosomes, as well as neuronal synaptic vesicles. In keeping with this latter association, electrical stimulation of the Schaffer collateral pathway in hippocampal slices from ATM-deficient mice does not elicit normal long-term potentiation (LTP). The current study was undertaken to assess the nature of this deficit. Theta burst-induced LTP was reduced in Atm(-/-) animals, with the reduction most pronounced at burst stimuli that included 6 or greater trains. To assess whether the deficit was associated with a pre- or postsynaptic failure, we analyzed paired-pulse facilitation and found that it too was significantly reduced in Atm(-/-) mice. This indicates a deficit in presynaptic function. As further evidence that these synaptic effects of ATM deficiency were presynaptic, we used stochastic optical reconstruction microscopy. Three-dimensional reconstruction revealed that ATM is significantly more closely associated with Piccolo (a presynaptic marker) than with Homer1 (a postsynaptic marker). These results underline how, in addition to its nuclear functions, ATM plays an important functional role in the neuronal synapse where it participates in the regulation of presynaptic vesicle physiology.

  4. Diversity in Long-Term Synaptic Plasticity at Inhibitory Synapses of Striatal Spiny Neurons

    Science.gov (United States)

    Rueda-Orozco, Pavel E.; Mendoza, Ernesto; Hernandez, Ricardo; Aceves, Jose J.; Ibanez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, Jose

    2009-01-01

    Procedural memories and habits are posited to be stored in the basal ganglia, whose intrinsic circuitries possess important inhibitory connections arising from striatal spiny neurons. However, no information about long-term plasticity at these synapses is available. Therefore, this work describes a novel postsynaptically dependent long-term…

  5. Stimulation of the Hippocampal POMC/MC4R Circuit Alleviates Synaptic Plasticity Impairment in an Alzheimer’s Disease Model

    Directory of Open Access Journals (Sweden)

    Yang Shen

    2016-11-01

    Full Text Available Hippocampal synaptic plasticity is modulated by neuropeptides, the disruption of which might contribute to cognitive deficits observed in Alzheimer’s disease (AD. Although pro-opiomelanocortin (POMC-derived neuropeptides and melanocortin 4 receptor (MC4R are implicated in hippocampus-dependent synaptic plasticity, how the POMC/MC4R system functions in the hippocampus and its role in synaptic dysfunction in AD are largely unknown. Here, we mapped a functional POMC circuit in the mouse hippocampus, wherein POMC neurons in the cornu ammonis 3 (CA3 activate MC4R in the CA1. Suppression of hippocampal MC4R activity in the APP/PS1 transgenic mouse model of AD exacerbates long-term potentiation impairment, which is alleviated by the replenishment of hippocampal POMC/MC4R activity or activation of hippocampal MC4R-coupled Gs signaling. Importantly, MC4R activation rescues amyloid-β-induced synaptic dysfunction via a Gs/cyclic AMP (cAMP/PKA/cAMP-response element binding protein (CREB-dependent mechanism. Hence, disruption of this hippocampal POMC/MC4R circuit might contribute to synaptic dysfunction observed in AD, revealing a potential therapeutic target for the disease.

  6. Short-term versus long-term water maze training effects on hippocampal neuronal synaptic plasticity in a rat model of senile dementia

    Institute of Scientific and Technical Information of China (English)

    Guogui Li

    2008-01-01

    BACKGROUND: Changes in synaptic plasticity might underlie senile dementia, and might be the neurobiological basis for learning and memory dysfunctions in patients with Alzheimer's Disease. OBJECTIVE: To investigate the effects of water maze training on hippocampal neuronal synaptic plasticity in rats with senile dementia, and to compare changes in synaptic plasticity between short- and long-term water maze training sessions.DESIGN, TIME AND SETTING: A randomized, controlled, neuromorphological observation with animal models of senile dementia was performed at the laboratory of College of Pharmacy, Chongqing Medical University between November 2006 and April 2007.MATERIALS: Fifty male, Sprague Dawley rats were randomized into five groups, with 10 rats per group: model, control, sham-operated, short-term water maze training, and long-term water maze training. METHODS: In the model group, senile dementia was induced by fimbria-fornix lesion method. The control rats remained untreated. In the sham-operated group, water maze training was performed without fimbria-fornix lesion induction. Rats from the short-term water maze training group underwent 20-day water maze training from day 26 after fimbria-fornix lesion induction. The long-term water maze training group underwent 40-day water maze training beginning at day 6 following fimbria-fornix lesion induction. Beginning at day 41, each group underwent 5-day spatial learning and memory training. MAIN OUTCOME MEASURES: Following experimentation, the morphological parameters of synapses, including synaptic numerical density, synaptic surface density, and the average synapse size were stereologically measured. Through the use of an electron microscope, synaptic morphological changes in the hippocampai CA3 region were observed.RESULTS: Compared with the control group, synaptic numerical and surface densities were significantly decreased in the model group (P < 0.01). Synaptic numerical and surface densities significantly

  7. The effect of synaptic plasticity on orientation selectivity in a balanced model of primary visual cortex

    Directory of Open Access Journals (Sweden)

    Soledad eGonzalo Cogno

    2015-08-01

    Full Text Available Orientation selectivity is ubiquitous in the primary visual cortex (V1 of mammals. In cats and monkeys, V1 displays spatially ordered maps of orientation preference. Instead, in mice, squirrels and rats, orientation selective neurons in V1 are not spatially organized, giving rise to a seemingly random pattern usually referred to as a salt-and-pepper layout. The fact that such different organizations can sharpen orientation tuning leads to question the structural role of the intracortical connections; specifically the influence of plasticity and the generation of functional connectivity. In this work, we analyze the effect of plasticity processes on orientation selectivity for both scenarios. We study a computational model of layer 2/3 and a reduced one-dimensional model of orientation selective neurons, both in the balanced state. We analyze two plasticity mechanisms. The first one involves spike-timing dependent plasticity (STDP, while the second one considers the reconnection of the interactions according to the preferred orientations of the neurons. We find that under certain conditions STDP can indeed improve selectivity but it works in a somehow unexpected way, that is, effectively decreasing the modulated part of the intracortical connectivity as compared to the non-modulated part of it. For the reconnection mechanism we find that increasing functional connectivity leads, in fact, to a decrease in orientation selectivity if the network is in a stable balanced state. Both counterintuitive results are a consequence of the dynamics of the balanced state. We also find that selectivity can increase due to a reconnection process if the resulting connections give rise to an unstable balanced state. We compare these findings with recent experimental results.

  8. Emergence of cortical inhibition by coordinated sensory–driven plasticity at distinct synaptic loci

    OpenAIRE

    Chittajallu, Ramesh; Isaac, John T. R.

    2010-01-01

    Feed–forward GABAergic inhibition sets dendritic integration window thereby controlling timing and output in cortical circuits. However, it is unclear how feed–forward inhibitory circuits emerge, even though this is a critical step for neocortical development and function. Here we show that sensory–experience drives plasticity of the feed–forward inhibitory circuit in mouse layer 4 somatosensory “barrel” cortex in the second postnatal week by two distinct mechanisms. Firstly, sensory–experien...

  9. Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats

    Directory of Open Access Journals (Sweden)

    Gleb eBarmashenko

    2014-12-01

    Full Text Available The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B and its ligand C-type natriuretic peptide (CNP, one of several cGMP producing signalling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP. We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BdeltaKC lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BdeltaKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1-100 Hz was assessed in transgenic rats the threshold for LTP induction was raised, but LTD induction was facilitated. In parallel, NPR-BdeltaKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signalling has a modulatory role for synaptic information storage and learning.

  10. Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats

    Science.gov (United States)

    Barmashenko, Gleb; Buttgereit, Jens; Herring, Neil; Bader, Michael; Özcelik, Cemil; Manahan-Vaughan, Denise; Braunewell, Karl H.

    2014-01-01

    The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B) and its ligand C-type natriuretic peptide (CNP), one of several cGMP producing signaling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD) in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP). We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BΔKC) lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BΔKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1–100 Hz was assessed in transgenic rats, the threshold for both, LTP and LTD induction, was shifted to lower frequencies. In parallel, NPR-BΔKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signaling has a modulatory role for synaptic information storage and learning. PMID:25520616

  11. Regional differences in GABAergic modulation for TEA-induced synaptic plasticity in rat hippocampal CA1, CA3 and dentate gyrus.

    Science.gov (United States)

    Suzuki, Etsuko; Okada, Takashi

    2007-10-01

    Tetraethylammonium (TEA), a K(+)-channel blocker, reportedly induces long-term potentiation (LTP) of hippocampal CA1 synaptic responses, but at CA3 and the dentate gyrus (DG), the characteristics of TEA-induced plasticity and modulation by inhibitory interneurons remain unclear. This study recorded field EPSPs from CA1, CA3 and DG to examine the involvement of GABAergic modulation in TEA-induced synaptic plasticity for each region. In Schaffer collateral-CA1 synapses and associational fiber (AF)-CA3 synapses, bath application of TEA-induced LTP in the presence and absence of picrotoxin (PTX), a GABA(A) receptor blocker, whereas TEA-induced LTP at mossy fiber (MF)-CA3 synapses was detected only in the absence of GABA(A) receptor blockers. MF-CA3 LTP showed sensitivity to Ni(2+), but not to nifedipine. In DG, synaptic plasticity was modulated by GABAergic inputs, but characteristics differed between the afferent lateral perforant path (LPP) and medial perforant path (MPP). LPP-DG synapses showed TEA-induced LTP during PTX application, whereas at MPP-DG synapses, TEA-induced long-term depression (LTD) was seen in the absence of PTX. This series of results demonstrates that TEA-induced DG and CA3 plasticity displays afferent specificity and is exposed to GABAergic modulation in an opposite manner.

  12. The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition.

    Science.gov (United States)

    Wu, Aiguo; Ying, Zhe; Gomez-Pinilla, Fernando

    2004-04-01

    A diet high in saturated fat (HF) decreases levels of brain-derived neurotrophic factor (BDNF), to the extent that compromises neuroplasticity and cognitive function, and aggravates the outcome of brain insult. By using the antioxidant power of vitamin E, we performed studies to determine the role of oxidative stress as a mediator for the effects of BDNF on synaptic plasticity and cognition caused by consumption of the HF diet. Male adult rats were maintained on a HF diet for 2 months with or without 500 IU/kg of vitamin E. Supplementation of the HF diet with vitamin E dramatically reduced oxidative damage, normalized levels of BDNF, synapsin I and cyclic AMP-response element-binding protein (CREB), caused by the consumption of the HF diet. In addition, vitamin E supplementation preserved the process of activation of synapsin I and CREB, and reversed the HF-impaired cognitive function. It is known that BDNF facilitates the synapse by modulating synapsin I and CREB, which have been implicated in synaptic plasticity associated to learning and memory. These results show that oxidative stress can interact with the BDNF system to modulate synaptic plasticity and cognitive function. Therefore, studies appear to reveal a mechanism by which events classically related to the maintenance of energy balance of the cell, such as oxidative stress, can interact with molecular events that modulate neuronal and behavioural plasticity.

  13. Large and Small Dendritic Spines Serve Different Interacting Functions in Hippocampal Synaptic Plasticity and Homeostasis

    Directory of Open Access Journals (Sweden)

    Joshua J. W. Paulin

    2016-01-01

    Full Text Available The laying down of memory requires strong stimulation resulting in specific changes in synaptic strength and corresponding changes in size of dendritic spines. Strong stimuli can also be pathological, causing a homeostatic response, depressing and shrinking the synapse to prevent damage from too much Ca2+ influx. But do all types of dendritic spines serve both of these apparently opposite functions? Using confocal microscopy in organotypic slices from mice expressing green fluorescent protein in hippocampal neurones, the size of individual spines along sections of dendrite has been tracked in response to application of tetraethylammonium. This strong stimulus would be expected to cause both a protective homeostatic response and long-term potentiation. We report separation of these functions, with spines of different sizes reacting differently to the same strong stimulus. The immediate shrinkage of large spines suggests a homeostatic protective response during the period of potential danger. In CA1, long-lasting growth of small spines subsequently occurs consolidating long-term potentiation but only after the large spines return to their original size. In contrast, small spines do not change in dentate gyrus where potentiation does not occur. The separation in time of these changes allows clear functional differentiation of spines of different sizes.

  14. The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity.

    Science.gov (United States)

    Yin, Fei; Yao, Jia; Sancheti, Harsh; Feng, Tao; Melcangi, Roberto C; Morgan, Todd E; Finch, Caleb E; Pike, Christian J; Mack, Wendy J; Cadenas, Enrique; Brinton, Roberta D

    2015-07-01

    The perimenopause is an aging transition unique to the female that leads to reproductive senescence which can be characterized by multiple neurological symptoms. To better understand potential underlying mechanisms of neurological symptoms of perimenopause, the present study determined genomic, biochemical, brain metabolic, and electrophysiological transformations that occur during this transition using a rat model recapitulating fundamental characteristics of the human perimenopause. Gene expression analyses indicated two distinct aging programs: chronological and endocrine. A critical period emerged during the endocrine transition from regular to irregular cycling characterized by decline in bioenergetic gene expression, confirmed by deficits in fluorodeoxyglucose-positron emission tomography (FDG-PET) brain metabolism, mitochondrial function, and long-term potentiation. Bioinformatic analysis predicted insulin/insulin-like growth factor 1 and adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK/PGC1α) signaling pathways as upstream regulators. Onset of acyclicity was accompanied by a rise in genes required for fatty acid metabolism, inflammation, and mitochondrial function. Subsequent chronological aging resulted in decline of genes required for mitochondrial function and β-amyloid degradation. Emergence of glucose hypometabolism and impaired synaptic function in brain provide plausible mechanisms of neurological symptoms of perimenopause and may be predictive of later-life vulnerability to hypometabolic conditions such as Alzheimer's.

  15. Compensating Inhomogeneities of Neuromorphic VLSI Devices Via Short-Term Synaptic Plasticity.

    Science.gov (United States)

    Bill, Johannes; Schuch, Klaus; Brüderle, Daniel; Schemmel, Johannes; Maass, Wolfgang; Meier, Karlheinz

    2010-01-01

    Recent developments in neuromorphic hardware engineering make mixed-signal VLSI neural network models promising candidates for neuroscientific research tools and massively parallel computing devices, especially for tasks which exhaust the computing power of software simulations. Still, like all analog hardware systems, neuromorphic models suffer from a constricted configurability and production-related fluctuations of device characteristics. Since also future systems, involving ever-smaller structures, will inevitably exhibit such inhomogeneities on the unit level, self-regulation properties become a crucial requirement for their successful operation. By applying a cortically inspired self-adjusting network architecture, we show that the activity of generic spiking neural networks emulated on a neuromorphic hardware system can be kept within a biologically realistic firing regime and gain a remarkable robustness against transistor-level variations. As a first approach of this kind in engineering practice, the short-term synaptic depression and facilitation mechanisms implemented within an analog VLSI model of I&F neurons are functionally utilized for the purpose of network level stabilization. We present experimental data acquired both from the hardware model and from comparative software simulations which prove the applicability of the employed paradigm to neuromorphic VLSI devices.

  16. The adult abdominal neuromuscular junction of Drosophila: a model for synaptic plasticity.

    Science.gov (United States)

    Hebbar, Sarita; Hall, Rachel E; Demski, Sarah A; Subramanian, Aswati; Fernandes, Joyce J

    2006-09-01

    During its life cycle, Drosophila makes two sets of neuromuscular junctions (NMJs), embryonic/larval and adult, which serve distinct stage-specific functions. During metamorphosis, the larval NMJs are restructured to give rise to their adult counterparts, a process that is integrated into the overall remodeling of the nervous system. The NMJs of the prothoracic muscles and the mesothoracic dorsal longitudinal (flight) muscles have been previously described. Given the diversity and complexity of adult muscle groups, we set out to examine the less complex abdominal muscles. The large bouton sizes of these NMJs are particularly advantageous for easy visualization. Specifically, we have characterized morphological attributes of the ventral abdominal NMJ and show that an embryonic motor neuron identity gene, dHb9, is expressed at these adult junctions. We quantified bouton numbers and size and examined the localization of synaptic markers. We have also examined the formation of boutons during metamorphosis and examined the localization of presynaptic markers at these stages. To test the usefulness of the ventral abdominal NMJs as a model system, we characterized the effects of altering electrical activity and the levels of the cell adhesion molecule, FasciclinII (FasII). We show that both manipulations affect NMJ formation and that the effects are specific as they can be rescued genetically. Our results indicate that both activity and FasII affect development at the adult abdominal NMJ in ways that are distinct from their larval and adult thoracic counterparts

  17. Neonatal sensory nerve injury-induced synaptic plasticity in the trigeminal principal sensory nucleus.

    Science.gov (United States)

    Lo, Fu-Sun; Erzurumlu, Reha S

    2016-01-01

    Sensory deprivation studies in neonatal mammals, such as monocular eye closure, whisker trimming, and chemical blockade of the olfactory epithelium have revealed the importance of sensory inputs in brain wiring during distinct critical periods. But very few studies have paid attention to the effects of neonatal peripheral sensory nerve damage on synaptic wiring of the central nervous system (CNS) circuits. Peripheral somatosensory nerves differ from other special sensory afferents in that they are more prone to crush or severance because of their locations in the body. Unlike the visual and auditory afferents, these nerves show regenerative capabilities after damage. Uniquely, damage to a somatosensory peripheral nerve does not only block activity incoming from the sensory receptors but also mediates injury-induced neuro- and glial chemical signals to the brain through the uninjured central axons of the primary sensory neurons. These chemical signals can have both far more and longer lasting effects than sensory blockade alone. Here we review studies which focus on the consequences of neonatal peripheral sensory nerve damage in the principal sensory nucleus of the brainstem trigeminal complex.

  18. Synaptic plasticity in a cerebellum-like structure depends on temporal order

    Science.gov (United States)

    Bell, Curtis C.; Han, Victor Z.; Sugawara, Yoshiko; Grant, Kirsty

    1997-05-01

    Cerebellum-like structures in fish appear to act as adaptive sensory processors, in which learned predictions about sensory input are generated and subtracted from actual sensory input, allowing unpredicted inputs to stand out1-3. Pairing sensory input with centrally originating predictive signals, such as corollary discharge signals linked to motor commands, results in neural responses to the predictive signals alone that are Negative images' of the previously paired sensory responses. Adding these 'negative images' to actual sensory inputs minimizes the neural response to predictable sensory features. At the cellular level, sensory input is relayed to the basal region of Purkinje-like cells, whereas predictive signals are relayed by parallel fibres to the apical dendrites of the same cells4. The generation of negative images could be explained by plasticity at parallel fibre synapses5-7. We show here that such plasticity exists in the electrosensory lobe of mormyrid electric fish and that it has the necessary properties for such a model: it is reversible, anti-hebbian (excitatory postsynaptic potentials (EPSPs) are depressed after pairing with a postsynaptic spike) and tightly dependent on the sequence of pre- and postsynaptic events, with depression occurring only if the postsynaptic spike follows EPSP onset within 60 ms.

  19. Synaptic plasticity and neuronal refractory time cause scaling behaviour of neuronal avalanches.

    Science.gov (United States)

    Michiels van Kessenich, L; de Arcangelis, L; Herrmann, H J

    2016-08-18

    Neuronal avalanches measured in vitro and in vivo in different cortical networks consistently exhibit power law behaviour for the size and duration distributions with exponents typical for a mean field self-organized branching process. These exponents are also recovered in neuronal network simulations implementing various neuronal dynamics on different network topologies. They can therefore be considered a very robust feature of spontaneous neuronal activity. Interestingly, this scaling behaviour is also observed on regular lattices in finite dimensions, which raises the question about the origin of the mean field behavior observed experimentally. In this study we provide an answer to this open question by investigating the effect of activity dependent plasticity in combination with the neuronal refractory time in a neuronal network. Results show that the refractory time hinders backward avalanches forcing a directed propagation. Hebbian plastic adaptation plays the role of sculpting these directed avalanche patterns into the topology of the network slowly changing it into a branched structure where loops are marginal.

  20. Synaptic plasticity and neuronal refractory time cause scaling behaviour of neuronal avalanches

    Science.gov (United States)

    Michiels van Kessenich, L.; de Arcangelis, L.; Herrmann, H. J.

    2016-08-01

    Neuronal avalanches measured in vitro and in vivo in different cortical networks consistently exhibit power law behaviour for the size and duration distributions with exponents typical for a mean field self-organized branching process. These exponents are also recovered in neuronal network simulations implementing various neuronal dynamics on different network topologies. They can therefore be considered a very robust feature of spontaneous neuronal activity. Interestingly, this scaling behaviour is also observed on regular lattices in finite dimensions, which raises the question about the origin of the mean field behavior observed experimentally. In this study we provide an answer to this open question by investigating the effect of activity dependent plasticity in combination with the neuronal refractory time in a neuronal network. Results show that the refractory time hinders backward avalanches forcing a directed propagation. Hebbian plastic adaptation plays the role of sculpting these directed avalanche patterns into the topology of the network slowly changing it into a branched structure where loops are marginal.

  1. MeCP2 post-translational modifications: a mechanism to control its involvement in synaptic plasticity and homeostasis?

    Directory of Open Access Journals (Sweden)

    Elisa eBellini

    2014-08-01

    Full Text Available Although Rett syndrome (RTT represents one of the most frequent forms of severe intellectual disability in females worldwide, we still have an inadequate knowledge of the many roles played by MeCP2 (whose mutations are responsible for most cases of RTT and their relevance for RTT pathobiology. Several studies support a role of MeCP2 in the regulation of synaptic plasticity and homeostasis. At the molecular level, MeCP2 is described as a repressor capable of inhibiting gene transcription through chromatin compaction. Indeed, it interacts with several chromatin remodeling factors, such as HDAC-containing complexes and ATRX. Other studies have inferred that MeCP2 functions also as an activator; a role in regulating mRNA splicing and in modulating protein synthesis has also been proposed. Further, MeCP2 avidly binds both 5-methyl- and 5-hydroxymethyl-cytosine. Recent evidence suggests that it is the highly disorganized structure of MeCP2, together with its post-translational modifications (PTMs that generate and regulate this functional versatility. Indeed, several reports have demonstrated that differential phosphorylation of MeCP2 is a key mechanism by which the methyl binding protein modulates its affinity for its partners, gene expression and cellular adaptations to stimuli and neuronal plasticity. As logic consequence, generation of phospho-defective Mecp2 knock-in mice has permitted associating alterations in neuronal morphology, circuit formation, and mouse behavioral phenotypes with specific phosphorylation events. MeCP2 undergoes various other PTMs, including acetylation, ubiquitination and sumoylation, whose functional roles remain largely unexplored. These results, together with the genome-wide distribution of MeCP2 and its capability to substitute histone H1, recall the complex regulation of histones and suggest the relevance of quickly gaining a deeper comprehension of MeCP2 PTMs, the respective writers and readers and the consequent

  2. The contribution of synaptic plasticity in the basal ganglia to the processing of visual information.

    Science.gov (United States)

    Sil'kis, I G

    2007-10-01

    A mechanism for the involvement of the basal ganglia in the processing of visual information, based on dopamine-dependent modulation of the efficiency of synaptic transmission in interconnected parallel associative and limbic cortex-basal ganglia-thalamus-cortex circuits, is proposed. Each circuit consists of a visual or prefrontal area of the cortex connected with the thalamic nucleus and the corresponding areas in different nuclei of the basal ganglia. The circulation of activity in these circuits is supported by the recurrent arrival of information in the thalamus and cortex. Dopamine released in response to a visual stimulus modulates the efficiencies of "strong" and "weak" corticostriatal inputs in different directions, and the subsequent reorganization of activity in the circuit leads to disinhibition (inhibition) of the activity of those cortical neurons which are "strongly" ("weakly") excited by the visual stimulus simultaneously with dopaminergic cells. The pattern in each cortical area is the neuronal reflection of the properties of the visual stimulus processed by this area. Excitation of dopaminergic cells by the visual stimulus via the superior colliculi requires parallel activation of the disinhibitory input to the superior colliculi via the thalamus and the "direct" pathway" in the basal ganglia. The prefrontal cortex, excited by the visual stimulus via the mediodorsal nucleus of the thalamus, mediates the descending influence on the activity of dopaminergic cells, simultaneously controlling dopamine release in different areas of the striatum and thus facilitating the mutual selection of neural reflections of the individual properties of the visual stimulus and their binding into an integral image.

  3. Resveratrol Improves Cognitive Impairment by Regulating Apoptosis and Synaptic Plasticity in Streptozotocin-Induced Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Zhiyan Tian

    2016-12-01

    Full Text Available Aims: To investigate the effects of resveratrol on cognitive impairment in streptozotocin (STZ-induced diabetic rats and to explore the mechanisms of that phenomenon. Methods: Sixty healthy male Sprague Dawley rats were randomly divided into four groups: normal control group (Con group, n = 15, Res group (normal Sprague Dawley rats treated with resveratrol, n = 15, diabetes mellitus group (DM group, n = 15 and DM + Res group (diabetic rats treat with resveratrol, n = 15. Streptozotocin (STZ was injected intraperitoneally to establish the diabetic model. One week after diabetic model induction, the animals in the Res group and the DM + Res group received resveratrol intraperitoneally once a day for consecutive 4 weeks. The Morris water maze test was applied to assess the effect of resveratrol on learning and memory. To explore the mechanisms of resveratrol on cognition, we detected the protein expression levels of Caspase-3, Bcl-2, Bax, NMDAR1 (N-Methyl-d-Aspartate receptor and BDNF (Brain Derived Neurotrophic Factor via western blotting analysis. Results: Resveratrol has no obvious effect on normal SD rats. Compared to Con group, cognitive ability was significantly impaired with increased expression of Caspase-3, Bax and down-regulation of Bcl-2, NMDAR1 and BDNF in diabetic rats. By contrast, resveratrol treatment improved the cognitive decline. Evidently, resveratrol treatment reversed diabetes-induced changes of protein expression. Conclusions: Resveratrol significantly ameliorates cognitive decline in STZ-induced diabetic model rats. The potential mechanism underlying the protective effect could be attributed to the inhibition of hippocampal apoptosis through the Bcl-2, Bax and Caspase-3 signaling pathways and improvement of synaptic dysfunction. BDNF may also play an indispensable role in this mechanism.

  4. Acute Modulation of Synaptic Plasticity of Pyramidal Neurons by Activin in Adult Hippocampus

    Directory of Open Access Journals (Sweden)

    Yoshitaka eHasegawa

    2014-06-01

    Full Text Available Activin A is known as a neuroprotective factor produced upon acute excitotoxic injury of the hippocampus (in pathological states. We attempt to reveal the role of activin as a neuromodulator in the adult male hippocampus under physiological conditions (in healthy states, which remains largely unknown. We showed endogenous/basal expression of activin in the hippocampal neurons. Localization of activin receptors in dendritic spines (= postsynapses was demonstrated by immunoelectron microscopy. The incubation of hippocampal acute slices with activin A (10 ng/mL, 0.4 nM for 2 h altered the density and morphology of spines in CA1 pyramidal neurons. The total spine density increased by 1.2-fold upon activin treatments. Activin selectively increased the density of large-head spines, without affecting middle-head and small-head spines. Blocking of Erk/MAPK, PKA or PKC prevented the activin-induced spinogenesis by reducing the density of large-head spines, independent of Smad-induced gene transcription which usually takes more than several hours. Incubation of acute slices with activin for 2 h induced the moderate early long-term potentiation (moderate LTP upon weak theta burst stimuli. This moderate LTP induction was blocked by follistatin, MAPK inhibitor (PD98059 and inhibitor of NR2B subunit of NMDA receptors (Ro25-6981. It should be noted that the weak theta burst stimuli alone cannot induce moderate LTP. These results suggest that MAPK-induced phosphorylation of NMDA receptors (including NR2B may play an important role for activin-induced moderate LTP. Taken together, the current results reveal interesting physiological roles of endogenous activin as a synaptic modulator in the adult hippocampus.

  5. Nicotine exposure during adolescence alters the rules for prefrontal cortical synaptic plasticity during adulthood

    Directory of Open Access Journals (Sweden)

    Huib eMansvelder

    2012-08-01

    Full Text Available The majority of adolescents report to have smoked a cigarette at least once. Adolescence is a critical period of brain development during which maturation of areas involved in cognitive functioning, such as the medial prefrontal cortex (mPFC, is still ongoing. Tobacco smoking during this age may compromise the normal course of prefrontal development and lead to cognitive impairments in later life. In addition, adolescent smokers suffer from attention deficits, which progress with the years of smoking. Recent studies in rodents reveal the molecular changes induced by adolescent nicotine exposure that alter the functioning of synapses in the PFC and underlie the lasting effects on cognitive function. In particular, the expression and function of metabotropic glutamate receptors (mGluRs are changed and this has an impact on short- and long-term plasticity of glutamatergic synapses in the PFC and ultimately on the attention performance. Here, we review and discuss these recent findings.

  6. Effect of developmental lead exposure on synaptic plasticity and N—methyl—D—aspartate receptor subunit in rat hippocampus

    Institute of Scientific and Technical Information of China (English)

    RuanDY; SuiL

    2002-01-01

    Chronic lead(Pb) exposure is known to be associated with learning and memory,and cognitive dysfunction in children.Previous studies have demonstrated that Pb exposure may impair neuronal process underlying synaptic plasticity via a direct interaction with N-methyl-D-aspartate (NMDA) receptors(NMDARs).The studies described here were carried out to investigate effect of developmental Pb exposure on long-term potentiation(LTP),long-tern depression(LTD) and NMDAs subunits in rat hippocampus.The results are listed as follows:(1)low-level Pb exposture can impair the induction and maintenance of LTP in vivo and in vitro;(2)the Pb-induced impairment of LTD magnitude was an age-related decline in area CA1 of rat hippocampus;(3)chronic Pb exposure affected two components,voltage-gated calcium channel-dependent LTD and NMDARs-dependent LTD,of LTD induction in area CA1 of rat hippocampus;(4)different effects of developmental Pb exposure on NMDA receptor NR1,NR2A,NR2B,NR2C,NR2D and NR3A subunits in area CA1,CA2,CA3 and CA4 of rat hippocampus were observed;(5)the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors enriched in area CA1,CA3 and dentate gyrus and kainite receptors enriched in area CA1 and dentate gyrus of rat hippocampus were impaired by Pb exposure.

  7. ZD7288, a selective hyperpolarization-activated cyclic nucleotide-gated channel blocker, inhibits hippocampal synaptic plasticity

    Institute of Scientific and Technical Information of China (English)

    Xiao-xue Zhang; Xiao-chun Min; Xu-lin Xu; Min Zheng; Lian-jun Guo

    2016-01-01

    The selective hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker 4-(N-ethyl-N-phenylamino)-1,2-dimeth-yl-6-(methylamino) pyrimidinium chloride (ZD7288) blocks the induction of long-term potentiation in the perforant path–CA3 region in rat hippocampusin vivo. To explore the mechanisms underlying the action of ZD7288, we recorded excitatory postsynaptic potentials in perforant path–CA3 synapses in male Sprague-Dawley rats. We measured glutamate content in the hippocampus and in cultured hip-pocampal neurons using high performance liquid chromatography, and determined intracellular Ca2+ concentration ([Ca2+]i) using Fura-2. ZD7288 inhibited the induction and maintenance of long-term potentiation, and these effects were mirrored by the nonspeciifc HCN channel blocker cesium. ZD7288 also decreased glutamate release in hippocampal tissue and in cultured hippocampal neurons. Further-more, ZD7288 attenuated glutamate-induced rises in [Ca2+]i in a concentration-dependent manner and reversed 8-Br-cAMP-mediated facilitation of these glutamate-induced [Ca2+]i rises. Our results suggest that ZD7288 inhibits hippocampal synaptic plasticity both gluta-mate release and resultant [Ca2+]i increases in rat hippocampal neurons.

  8. Use of multi-electrode array recordings in studies of network synaptic plasticity in both time and space

    Institute of Scientific and Technical Information of China (English)

    Ming-Gang Liu; Xue-Feng Chen; Ting He; Zhen Li; Jun Chen

    2012-01-01

    Simultaneous multisite recording using multi-electrode arrays (MEAs) in cultured and acutely-dissociated brain slices and other tissues is an emerging technique in the field of network electrophysiology.Over the past 40 years,great efforts have been made by both scientists and commercial concerns,to advance this technique.The MEA technique has been widely applied to many regions of the brain,retina,heart and smooth muscle in various studies at the network level.The present review starts from the development of MEA techniques and their uses in brain preparations,and then specifically concentrates on the use of MEA recordings in studies of synaptic plasticity at the network level in both the temporal and spatial domains.Because the MEA technique helps bridge the gap between single-cell recordings and behavioral assays,its wide application will undoubtedly shed light on the mechanisms underlying brain functions and dysfunctions at the network level that remained largely unknown due to the technical difficulties before it matured.

  9. St. John's wort may relieve negative effects of stress on spatial working memory by changing synaptic plasticity.

    Science.gov (United States)

    Trofimiuk, Emil; Holownia, Adam; Braszko, Jan J

    2011-04-01

    Beneficial effects of St. John's wort (Hypericum perforatum) in the treatment of stress-evoked memory impairment were recently described. In this study, we tested a hypothesis that St. John's wort alleviates stress- and corticosterone-related memory impairments by restoring levels of synaptic plasticity proteins: neuromoduline (GAP-43) and synaptophysin (SYP) in hippocampus and prefrontal cortex. Stressed and corticosterone-treated rats displayed a decline in the acquisition of spatial working memory (p < 0.001) in the Barnes maze (BM). Chronic administration of H. perforatum (350 mg kg(-1) for 21 days), potently and significantly improved processing of spatial information in the stressed and corticosterone-injected rats (p < 0.001). Also, St Johns' wort statistically significantly (p < 0.05) increased levels of GAP-43 and SYP, respectively in the hippocampi and prefrontal cortex as measured by western immunoblotting. We found that H. perforatum prevented the deleterious effects of both chronic restraint stress and prolonged corticosterone administration on working memory measured in the BM test. The herb significantly (p < 0.01) improved hippocampus-dependent spatial working memory in comparison with control and alleviated some other negative effects of stress on cognitive functions. These findings increase our understanding of the reaction of the hippocampus and prefrontal cortex to stressful assaults and provide new insight into the possible actions of H. perforatum in the treatment of patients with impaired adaptation to environmental stressors and simultaneously suffering from cognitive impairment.

  10. Osthole improves synaptic plasticity in the hippocampus and cognitive function of Alzheimer's disease rats via regulating glutamate

    Institute of Scientific and Technical Information of China (English)

    Xiaohua Dong; Danshen Zhang; Li Zhang; Wei Li; Xianyong Meng

    2012-01-01

    Osthole,an effective monomer in Chinese medicinal herbs,can cross the blood-brain barrier and protect against brain injury,with few toxic effects.In this study,a rat model of Alzheimer's disease was established after intracerebroventricular injection of β-amyloid peptide (25-35).Subsequently,the rats were intraperitoneally treated with osthole (12.5 or 25.0 mg/kg) for 14 successive days.Results showed that osthole treatment significantly improved cognitive impairment and protected hippocampal neurons of Alzheimer's disease rats.Also,osthole treatment alleviated suppressed long-term potentiation in the hippocampus of Alzheimer's disease rats.In these osthole-treated Alzheimer's disease rats,the level of glutamate decreased,but there was no significant change in Y-amino-butyric acid.These experimental findings suggest that osthole can improve learning and memory impairment,and increase synaptic plasticity in Alzheimer's disease rats.These effects of osthole may be because of its regulation of central glutamate and Y-amino-butyric acid levels.

  11. Novelty-Induced Phase-Locked Firing to Slow Gamma Oscillations in the Hippocampus: Requirement of Synaptic Plasticity.

    Science.gov (United States)

    Kitanishi, Takuma; Ujita, Sakiko; Fallahnezhad, Mehdi; Kitanishi, Naomi; Ikegaya, Yuji; Tashiro, Ayumu

    2015-06-03

    Temporally precise neuronal firing phase-locked to gamma oscillations is thought to mediate the dynamic interaction of neuronal populations, which is essential for information processing underlying higher-order functions such as learning and memory. However, the cellular mechanisms determining phase locking remain unclear. By devising a virus-mediated approach to perform multi-tetrode recording from genetically manipulated neurons, we demonstrated that synaptic plasticity dependent on the GluR1 subunit of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor mediates two dynamic changes in neuronal firing in the hippocampal CA1 area during novel experiences: the establishment of phase-locked firing to slow gamma oscillations and the rapid formation of the spatial firing pattern of place cells. The results suggest a series of events potentially underlying the acquisition of new spatial information: slow gamma oscillations, originating from the CA3 area, induce the two GluR1-dependent changes of CA1 neuronal firing, which in turn determine information flow in the hippocampal-entorhinal system.

  12. Extracellular matrix molecules and synaptic plasticity: immunomapping of intracellular and secreted Reelin in the adult rat brain.

    Science.gov (United States)

    Ramos-Moreno, Tania; Galazo, Maria J; Porrero, Cesar; Martínez-Cerdeño, Verónica; Clascá, Francisco

    2006-01-01

    Reelin, a large extracellular matrix glycoprotein, is secreted by several neuron populations in the developing and adult rodent brain. Secreted Reelin triggers a complex signaling pathway by binding lipoprotein and integrin membrane receptors in target cells. Reelin signaling regulates migration and dendritic growth in developing neurons, while it can modulate synaptic plasticity in adult neurons. To identify which adult neural circuits can be modulated by Reelin-mediated signaling, we systematically mapped the distribution of Reelin in adult rat brain using sensitive immunolabeling techniques. Results show that the distribution of intracellular and secreted Reelin is both very widespread and specific. Some interneuron and projection neuron populations in the cerebral cortex contain Reelin. Numerous striatal neurons are weakly immunoreactive for Reelin and these cells are preferentially located in striosomes. Some thalamic nuclei contain Reelin-immunoreactive cells. Double-immunolabeling for GABA and Reelin reveals that the Reelin-immunoreactive cells in the visual thalamus are the intrinsic thalamic interneurons. High local concentrations of extracellular Reelin selectively outline several dendrite spine-rich neuropils. Together with previous mRNA data, our observations suggest abundant axoplasmic transport and secretion in pathways such as the retino-collicular tract, the entorhino-hippocampal ('perforant') path, the lateral olfactory tract or the parallel fiber system of the cerebellum. A preferential secretion of Reelin in these neuropils is consistent with reports of rapid, activity-induced structural changes in adult brain circuits.

  13. Hydrogen Sulfide Prevents Synaptic Plasticity from VD-Induced Damage via Akt/GSK-3β Pathway and Notch Signaling Pathway in Rats.

    Science.gov (United States)

    Liu, Chunhua; Xu, Xiaxia; Gao, Jing; Zhang, Tao; Yang, Zhuo

    2016-08-01

    Our previous study has demonstrated that hydrogen sulfide (H2S) attenuates neuronal injury induced by vascular dementia (VD) in rats, but the mechanism is still poorly understood. In this study, we aimed to investigate whether the neuroprotection of H2S was associated with synaptic plasticity and try to interpret the potential underlying mechanisms. Adult male Wistar rats were suffered the ligation of bilateral common carotid arteries. At 24 h after surgery, rats were administered intraperitoneally with sodium hydrosulfide (NaHS, 5.6 mg·kg(-1)·day(-1)), a H2S donor, for 3 weeks in the VD+NaHS group and treated intraperitoneally with saline in the VD group respectively. Our results demonstrated that NaHS significantly decreased the level of glutamate. It obviously ameliorated cognitive flexibility as well as the spatial learning and memory abilities by Morris water maze. Moreover, NaHS significantly improved the long-term depression (LTD), and was able to elevate the expression of N-methyl-D-aspartate receptor subunit 2A, which plays a pivotal role in synaptic plasticity. Interestingly, NaHS decreased the phosphorylation of Akt, and it could maintain the activity of glycogen synthase kinase-3β (GSK-3β). Surprisingly, NaHS triggered the canonical Notch pathway by increasing expressions of Jagged-1 and Hes-1. These findings suggest that NaHS prevents synaptic plasticity from VD-induced damage partly via Akt/GSK-3β pathway and Notch signaling pathway.Hydrogen sulfide modulated the ratio of NMDAR 2A/2B and improved the synaptic plasticity via Akt/GSK-3β pathway and Notch signaling pathway in VD rats.

  14. Extracellular signal-regulated kinase (ERK) signaling in the ventral tegmental area mediates cocaine-induced synaptic plasticity and rewarding effects

    OpenAIRE

    Pan, Bin; Zhong, Peng; Sun, Dalong; Liu, Qing-song

    2011-01-01

    Drugs of abuse such as cocaine induce long-term synaptic plasticity in the reward circuitry, which underlies the formation of drug-associated memories and addictive behavior. We reported previously that repeated cocaine exposure in vivo facilitates long-term potentiation in dopamine neurons of the ventral tegmental area (VTA) by reducing the strength of GABAergic inhibition and that endocannabinoid (eCB)-dependent long-term depression at inhibitory synapses (I-LTD) constitutes a mechanism for...

  15. The wiring of developing sensory circuits - from patterned spontaneous activity to mechanisms of synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Alexandra Helen Leighton

    2016-09-01

    Full Text Available In order to accurately process incoming sensory stimuli, neurons must be organized into functional networks, with both genetic and environmental factors influencing the precise arrangement of connections between cells. Teasing apart the relative contributions of molecular guidance cues, spontaneous activity and visual experience during this maturation is on-going. During development of the sensory system, the first, rough organization of connections is created by molecular factors. These connections are then modulated by the intrinsically generated activity of neurons, even before the senses have become operational. Spontaneous waves of depolarisations sweep across the nervous system, placing them in a prime position to strengthen correct connections and weaken others, shaping synapses into a useful network. A large body of work now supports the idea that, rather than being a mere side-effect of the system, spontaneous activity actually contains information which readies the nervous system so that, as soon as the senses become active, sensory information can be utilized by the animal. An example is the neonatal mouse. As soon as the eyelids first open, neurons in the cortex respond to visual information without the animal having previously encountered structured sensory input (Cang et al., 2005a; Ko et al., 2013; Rochefort et al., 2011; Zhang et al., 2012. In vivo imaging techniques have advanced considerably, allowing observation of the natural activity in the brain of living animals down to the level of the individual synapse. New (optogenetic methods make it possible to subtly modulate the spatio-temporal properties of activity, aiding our understanding of how these characteristics relate to the function of spontaneous activity. Such experiments have had a huge impact on our knowledge by permitting direct testing of ideas about the plasticity mechanisms at play in the intact system, opening up a provocative range of fresh questions. Here, we

  16. Early pre- and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer’s disease mice

    Science.gov (United States)

    Chakroborty, Shreaya; Kim, Joyce; Schneider, Corinne; Jacobson, Christopher; Molgó, Jordi; Stutzmann, Grace E.

    2012-01-01

    Alzheimer’s disease (AD)-linked presenilin mutations result in pronounced endoplasmic reticulum (ER) calcium disruptions that occur prior to detectable histopathology and cognitive deficits. More subtly, these early AD-linked calcium alterations also reset neurophysiological homeostasis, such that calcium-dependent pre- and postsynaptic signaling appear functionally normal yet are actually operating under aberrant calcium signaling systems. In these 3xTg-AD mouse brains, upregulated RyR activity is associated with a shift towards synaptic depression, likely through a reduction in presynaptic vesicle stores and increased postsynaptic outward currents through SK2 channels. The deviant RyR-calcium involvement in the 3xTg-AD mice also compensates for an intrinsic predisposition for hippocampal LTD and reduced LTP. In this study we detail the impact of disrupted ryanodine receptor (RyR)-mediated calcium stores on synaptic transmission properties, long term depression (LTD) and calcium-activated membrane channels of hippocampal CA1 pyramidal neurons in presymptomatic 3xTg-AD mice. Using electrophysiological recordings in young 3xTg-AD and NonTg hippocampal slices, we show that increased RyR-evoked calcium release in 3xTg-AD mice ‘normalizes’ an altered synaptic transmission system operating under a shifted homeostatic state that is not present in NonTg mice. In the process, we uncover compensatory signaling mechanisms recruited early in the disease process which counterbalance the disrupted RyR-calcium dynamics, namely increases in presynaptic spontaneous vesicle release, altered probability of vesicle release, and upregulated postsynaptic SK channel activity. As AD is increasingly recognized as a ‘synaptic disease’, calcium-mediated signaling alterations may serve as a proximal trigger for the synaptic degradation driving the cognitive loss in AD. PMID:22699914

  17. Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats.

    Science.gov (United States)

    Shaffery, James P; Lopez, Jorge; Bissette, Garth; Roffwarg, Howard P

    2006-01-01

    The critical period for observing a developmentally regulated form of synaptic plasticity in the visual cortex of young rats normally ends at about postnatal day 30. This developmentally regulated form of in vitro long-term potentiation (LTP) can be reliably induced in layers II-III by aiming high frequency, theta burst stimulation (TBS) at the white matter situated directly below visual cortex (LTPWM-III). Previous work has demonstrated that suppression of sensory activation of visual cortex, achieved by rearing young rats in total darkness from birth, delays termination of the critical period for inducing LTPWM-III. Subsequent data also demonstrated that when rapid eye movement sleep (REMS) is suppressed, thereby reducing REMS cortical activation, just prior to the end of the critical period, termination of this developmental phase is delayed, and LTPWM-III can still be reliably produced in the usual post-critical period. Here, we report that for approximately 3 weeks immediately following the usual end of the critical period, suppression of REMS disrupts the maturational processes that close the critical period, and LTPWM-III is readily induced in brain slices taken from these somewhat older animals. Insofar as in vitro LTP is a model for the cellular and molecular changes that underlie developmental synaptic plasticity, these results suggest that mechanisms of synaptic plasticity, which participate in brain development and perhaps also in learning and memory processes, remain susceptible to the effects of REMS deprivation during the general period of adolescence in the rat.

  18. Tinnitus: pathology of synaptic plasticity at the cellular and system levels

    Directory of Open Access Journals (Sweden)

    Matthieu J Guitton

    2012-03-01

    Full Text Available Despite being more and more common, and having a high impact on the quality of life of sufferers, tinnitus does not yet have a cure. This has been mostly the result of limited knowledge of the biological mechanisms underlying this adverse pathology. However, the last decade has witnessed tremendous progress in our understanding on the pathophysiology of tinnitus. Animal models have demonstrated that tinnitus is a pathology of neural plasticity, and has two main components: a molecular, peripheral component related to the initiation phase of tinnitus; and a system-level, central component related to the long-term maintenance of tinnitus. Using the most recent experimental data and the molecular/system dichotomy as a framework, we describe here the biological basis of tinnitus. We then discuss these mechanisms from an evolutionary perspective, highlighting similarities with memory. Finally, we consider how these discoveries can translate into therapies, and we suggest operative strategies to design new and effective combined therapeutic solutions using both pharmacological (local and systemic and behavioral tools (e.g., using tele-medicine and virtual reality settings.

  19. Modulatory role of androgenic and estrogenic neurosteroids in determining the direction of synaptic plasticity in the CA1 hippocampal region of male rats.

    Science.gov (United States)

    Pettorossi, Vito Enrico; Di Mauro, Michela; Scarduzio, Mariangela; Panichi, Roberto; Tozzi, Alessandro; Calabresi, Paolo; Grassi, Silvarosa

    2013-12-01

    Estrogenic and androgenic neurosteroids can rapidly modulate synaptic plasticity in the brain through interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used electrophysiological recordings in slices of young and adolescent male rats to explore the influence of sex neurosteroids on synaptic plasticity in the CA1 hippocampal region, by blocking ARs or ERs during induction of long-term depression (LTD) and depotentiation (DP) by low-frequency stimulation (LFS) and long-term potentiation (LTP) by high-frequency stimulation (HFS). We found that LTD and DP depend on ARs, while LTP on ERs in both age groups. Accordingly, the AR blocker flutamide affected induction of LTD reverting it into LTP, and prevented DP, while having no effect on HFS-dependent LTP. Conversely, ER blockade with ICI 182,780 (ICI) markedly reduced LTP, but did not influence LTD and DP. However, the receptor blockade did not affect the maintenance of either LTD or LTP. Moreover, we found that similar to LTP and LTD induced in control condition, the LTP unveiled by flutamide during LFS and residual LTP induced by HFS under ICI depended on N-methyl-d aspartate receptor (NMDAR) activation. Furthermore, as the synaptic paired-pulse facilitation (PPF) was not affected by either AR or ER blockade, we suggest that sex neurosteroids act primarily at a postsynaptic level. This study demonstrates for the first time the crucial role of estrogenic and androgenic neurosteroids in determining the sign of hippocampal synaptic plasticity in male rat and the activity-dependent recruitment of androgenic and estrogenic pathways leading to LTD and LTP, respectively.

  20. Synaptic Plasticity and Learning Behaviors Mimicked in Single Inorganic Synapses of Pt/HfOx/ZnOx/TiN Memristive System

    Science.gov (United States)

    Wang, Lai-Guo; Zhang, Wei; Chen, Yan; Cao, Yan-Qiang; Li, Ai-Dong; Wu, Di

    2017-01-01

    In this work, a kind of new memristor with the simple structure of Pt/HfOx/ZnOx/TiN was fabricated completely via combination of thermal-atomic layer deposition (TALD) and plasma-enhanced ALD (PEALD). The synaptic plasticity and learning behaviors of Pt/HfOx/ZnOx/TiN memristive system have been investigated deeply. Multilevel resistance states are obtained by varying the programming voltage amplitudes during the pulse cycling. The device conductance can be continuously increased or decreased from cycle to cycle with better endurance characteristics up to about 3 × 103 cycles. Several essential synaptic functions are simultaneously achieved in such a single double-layer of HfOx/ZnOx device, including nonlinear transmission properties, such as long-term plasticity (LTP), short-term plasticity (STP), and spike-timing-dependent plasticity. The transformation from STP to LTP induced by repetitive pulse stimulation is confirmed in Pt/HfOx/ZnOx/TiN memristive device. Above all, simple structure of Pt/HfOx/ZnOx/TiN by ALD technique is a kind of promising memristor device for applications in artificial neural network.

  1. Effects of nanoparticle zinc oxide on spatial cognition and synaptic plasticity in mice with depressive-like behaviors

    Directory of Open Access Journals (Sweden)

    Xie Yongling

    2012-02-01

    Full Text Available Abstract Background Nanomaterials, as a new kind of materials, have been greatly applied in different fields due to their special properties. With the industrialization of nanostructured materials and increasing public exposure, the biosafety and potential influences on central nervous system (CNS have received more attention. Nanosized zinc oxide (nanoZnO was suggested to up-regulate neuronal excitability and to induce glutamate release in vitro. Therefore, we hypothesized nanoparticles of nanoZnO may lead to changes in balance of neurotransmitter or neuronal excitability of CNS. This study was to investigate if there were effects of nanoZnO on animal model of depression. Methods Male Swiss mice were given lipopolysaccharides (LPS, 100 μg/kg, 100 μg/ml, every other day, 8 times, i.p. from weaning to induce depressive-like behaviors. NanoZnO (5.6 mg/kg, 5.6 mg/ml, every other day, 8 times, i.p. was given as the interaction. The mouse model was characterized using the methods of open field test, tail suspension test and forced swim test. Furthermore, the spatial memory was evaluated using Morris water maze (MWM and the synaptic plasticity was assessed by measuring the long-term potentiation (LTP in the perforant pathway (PP to dentate gyrus (DG in vivo. Results Results indicated that model mice showed disrupted spatial memory and LTP after LPS injections and the behavioral and electrophysiological improvements after nanoZnO treatment. Conclusion Data suggested that nanoZnO may play some roles in CNS of mental disorders, which could provide some useful direction on the new drug exploring and clinical researches.

  2. Vitamins C and E reverse melamine-induced deficits in spatial cognition and hippocampal synaptic plasticity in rats.

    Science.gov (United States)

    An, Lei; Zhang, Tao

    2014-09-01

    Albeit the pathogenesis of cognitive impairment after exposure to melamine has not been fully elucidated, factors such as oxidative stress is thought to play potential roles. In the present study, we investigated the effect of treatment with vitamin C (150mg/kg) and vitamin E (200mg/kg) on the impairment induced by melamine. Three-week-old male Wistar rats were submitted to oral gavage with 300mg/kg melamine in 1% carboxymethylcellulose (CMC) for 28 days (MEL-SAL group). After treatment with melamine, animals received administration of a combination of vitamin C and vitamin E once a day for 7 days (MEL-VIT group). Both control (CT-SAL) group and pair-fed (CT-VIT) group received the same dosage of CMC and vitamin complex, respectively. Melamine-treated rats presented a marked decrease in learning and memory in the Morris water maze (MWM) as well as a reduced efficiency to find the platform in the reversal learning task. The rats treated with vitamins E and C had part of the above effects rescued in MWM tests, with mitigating the melamine-induced deficit in the learning and memory but slightly improving the reversal learning ability. The vitamins C plus E regimen mitigated melamine-induced impairment of hippocampal synaptic plasticity. It showed that the modulation of oxidative stress with vitamins E and C reduced melamine-induced damage. The data suggested that there was a novel therapeutic strategy to the cognitive dysfunction observed in melamine-induced neuropathy.

  3. A realistic neural mass model of the cortex with laminar-specific connections and synaptic plasticity - evaluation with auditory habituation.

    Directory of Open Access Journals (Sweden)

    Peng Wang

    Full Text Available In this work we propose a biologically realistic local cortical circuit model (LCCM, based on neural masses, that incorporates important aspects of the functional organization of the brain that have not been covered by previous models: (1 activity dependent plasticity of excitatory synaptic couplings via depleting and recycling of neurotransmitters and (2 realistic inter-laminar dynamics via laminar-specific distribution of and connections between neural populations. The potential of the LCCM was demonstrated by accounting for the process of auditory habituation. The model parameters were specified using Bayesian inference. It was found that: (1 besides the major serial excitatory information pathway (layer 4 to layer 2/3 to layer 5/6, there exists a parallel "short-cut" pathway (layer 4 to layer 5/6, (2 the excitatory signal flow from the pyramidal cells to the inhibitory interneurons seems to be more intra-laminar while, in contrast, the inhibitory signal flow from inhibitory interneurons to the pyramidal cells seems to be both intra- and inter-laminar, and (3 the habituation rates of the connections are unsymmetrical: forward connections (from layer 4 to layer 2/3 are more strongly habituated than backward connections (from Layer 5/6 to layer 4. Our evaluation demonstrates that the novel features of the LCCM are of crucial importance for mechanistic explanations of brain function. The incorporation of these features into a mass model makes them applicable to modeling based on macroscopic data (like EEG or MEG, which are usually available in human experiments. Our LCCM is therefore a valuable building block for future realistic models of human cognitive function.

  4. Intracellular accumulation of amyloid-β (Aβ) protein plays a major role in Aβ-induced alterations of glutamatergic synaptic transmission and plasticity.

    Science.gov (United States)

    Ripoli, Cristian; Cocco, Sara; Li Puma, Domenica D; Piacentini, Roberto; Mastrodonato, Alessia; Scala, Federico; Puzzo, Daniela; D'Ascenzo, Marcello; Grassi, Claudio

    2014-09-17

    Intracellular accumulation of amyloid-β (Aβ) protein has been proposed as an early event in AD pathogenesis. In patients with mild cognitive impairment, intraneuronal Aβ immunoreactivity was found especially in brain regions critically involved in the cognitive deficits of AD. Although a large body of evidence demonstrates that Aβ42 accumulates intraneuronally ((in)Aβ), the action and the role of Aβ42 buildup on synaptic function have been poorly investigated. Here, we demonstrate that basal synaptic transmission and LTP were markedly depressed following Aβ42 injection into the neuron through the patch pipette. Control experiments performed with the reverse peptide (Aβ42-1) allowed us to exclude that the effects of (in)Aβ depended on changes in oncotic pressure. To further investigate (in)Aβ synaptotoxicity we used an Aβ variant harboring oxidized methionine in position 35 that does not cross the neuronal plasma membrane and is not uploaded from the extracellular space. This Aβ42 variant had no effects on synaptic transmission and plasticity when applied extracellularly, but induced synaptic depression and LTP inhibition after patch-pipette dialysis. Finally, the injection of an antibody raised against human Aβ42 (6E10) in CA1 pyramidal neurons of mouse hippocampal brain slices and autaptic microcultures did not, per se, significantly affect LTP and basal synaptic transmission, but it protected against the toxic effects of extracellular Aβ42. Collectively, these findings suggest that Aβ42-induced impairment of glutamatergic synaptic function depends on its internalization and intracellular accumulation thus paving the way to a systemic proteomic analysis of intracellular targets/partners of Aβ42.

  5. Effect of chronic intracerebroventricular insulin administration in rats on the peripheral glucose metabolism and synaptic plasticity of CA1 hippocampal neurons.

    Science.gov (United States)

    Kamal, Amer; Ramakers, Geert M J; Gispen, Willem Hendrik; Biessels, Geert Jan

    2012-01-30

    In this study we examined the effects of sustained intracerebroventricular insulin infusion on hippocampal synaptic plasticity in rats. Insulin was infused intracerebroventricularly in male Wistar rats (n=12) for 3 months using osmotic minipumps. A control group (n=12) received a sham operation. Insulin infusion led to an initial reduction in food intake and body weight gain, but these differences attenuated over 12 weeks. Insulin infusion did not affect fasting or non-fasting blood glucose levels. Field synaptic potentials recording from the hippocampus demonstrated a defect in the expression of long-term potentiation. Sharp electrode current-clamp recording showed that CA1 pyramidal cells fire action potentials in response to prolonged depolarizing current injection and those action potentials showed progressive broadening. The action potential broadening in the insulin-perfused animals were significantly longer than the control. The amplitude of slow after hyperpolarization (sAHP) was measured after manually "clamping" the cells at -65 mV and injecting currents to evoke a train of four APs. The sAHP amplitude was significantly longer than in the control animals. We conclude that local insulin infusion into the brain of rats had significant effects on synaptic plasticity in the absence of marked effects on systemic glucose levels. These results indicate that long-term elevation of insulin levels can have adverse effects directly on the brain.

  6. Microwave Exposure Impairs Synaptic Plasticity in the Rat Hippocampus and PC12 Cells through Over-activation of the NMDA Receptor Signaling Pathway

    Institute of Scientific and Technical Information of China (English)

    XIONG Lu; DONG Ji; YAO Bin Wei; ZHAO Li; PENG Rui Yun; SUN Cheng Feng; ZHANG Jing; GAO Ya Bing; WANG Li Feng; ZUO Hong Yan; WANG Shui Ming; ZHOU Hong Mei; XU Xin Ping

    2015-01-01

    Objective The aim of this study is to investigate whether microwave exposure would affect the N-methyl-D-aspartate receptor (NMDAR) signaling pathway to establish whether this plays a role in synaptic plasticity impairment. Methods 48 male Wistar rats were exposed to 30 mW/cm² microwave for 10 min every other day for three times. Hippocampal structure was observed through H&E staining and transmission electron microscope. PC12 cells were exposed to 30 mW/cm² microwave for 5 min and the synapse morphology was visualized with scanning electron microscope and atomic force microscope. The release of amino acid neurotransmitters and calcium influx were detected. The expressions of several key NMDAR signaling molecules were evaluated. Results Microwave exposure caused injury in rat hippocampal structure and PC12 cells, especially the structure and quantity of synapses. The ratio of glutamic acid and gamma-aminobutyric acid neurotransmitters was increased and the intracellular calcium level was elevated in PC12 cells. A significant change in NMDAR subunits (NR1, NR2A, and NR2B) and related signaling molecules (Ca2+/calmodulin-dependent kinase II gamma and phosphorylated cAMP-response element binding protein) were examined. Conclusion 30 mW/cm² microwave exposure resulted in alterations of synaptic structure, amino acid neurotransmitter release and calcium influx. NMDAR signaling molecules were closely associated with impaired synaptic plasticity.

  7. Prenatal melamine exposure impairs spatial cognition and hippocampal synaptic plasticity by presynaptic and postsynaptic inhibition of glutamatergic transmission in adolescent offspring.

    Science.gov (United States)

    An, Lei; Sun, Wei

    2017-03-05

    Our previous studies showed that prenatal melamine exposure (PME) could impair spatial cognition and hippocampal long-term potentiation (LTP). More importantly, the synaptic dysfunction induced by PME was associated with the probability of presynaptic glutamate release. Considering the crucial role of the other form of synaptic plasticity, long-term depression (LTD), in some types of learning and memory process, the aim of present study was to investigate if the hippocampal LTD and cognitive flexibility were affected. And then we attempted to explore the underlying mechanism. The animal model was produced by melamine exposure throughout gestational period with 400mg/kg bodyweight, the male offspring rats were used in the study. Morris water maze (MWM) test was performed, and then LTD was recorded from Schaffer collaterals to CA1 region in the hippocampus. Behavioral test showed that learning, reference memory and re-acquisition learning abilities were impaired significantly by PME. The field excitatory postsynaptic potentials (fEPSPs) slopes of LTD were significantly higher after PME. Furthermore, the data of whole-cell patch-clamp experiments showed that PME markedly diminished the frequencies of spontaneous EPSCs (sEPSCs) and simultaneously reduced the amplitude of sEPSCs. In conclusion, PME inhibited glutamate transmission presynaptically and postsynaptically which could contribute importantly to the depressed hippocampal synaptic plasticity and further induced cognitive deficits in MWM tests.

  8. miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity.

    Directory of Open Access Journals (Sweden)

    Judit Remenyi

    Full Text Available miR-132 and miR-212 are two closely related miRNAs encoded in the same intron of a small non-coding gene, which have been suggested to play roles in both immune and neuronal function. We describe here the generation and initial characterisation of a miR-132/212 double knockout mouse. These mice were viable and fertile with no overt adverse phenotype. Analysis of innate immune responses, including TLR-induced cytokine production and IFNβ induction in response to viral infection of primary fibroblasts did not reveal any phenotype in the knockouts. In contrast, the loss of miR-132 and miR-212, while not overtly affecting neuronal morphology, did affect synaptic function. In both hippocampal and neocortical slices miR-132/212 knockout reduced basal synaptic transmission, without affecting paired-pulse facilitation. Hippocampal long-term potentiation (LTP induced by tetanic stimulation was not affected by miR-132/212 deletion, whilst theta burst LTP was enhanced. In contrast, neocortical theta burst-induced LTP was inhibited by loss of miR-132/212. Together these results indicate that miR-132 and/or miR-212 play a significant role in synaptic function, possibly by regulating the number of postsynaptic AMPA receptors under basal conditions and during activity-dependent synaptic plasticity.

  9. Propylthiouracil (PTU)-induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus.

    Science.gov (United States)

    Gilbert, M E; Paczkowski, C

    2003-10-10

    Reductions in thyroid hormone during critical periods of brain development can have devastating effects on neurological function that are permanent. Neurochemical, molecular and structural alterations in a variety of brain regions have been well documented, but little information is available on the consequences of developmental hypothyroidism on synaptic function. Developing rats were exposed to the thyrotoxicant, propylthiouracil (PTU: 0 or 15 ppm), through the drinking water of pregnant dams beginning on GD18 and extending throughout the lactational period. Male offspring were allowed to mature after termination of PTU exposure at weaning on PND21 and electrophyiological assessments of field potentials in the dentate gyrus were conducted under urethane anesthesia between 2 and 5 months of age. PTU dramatically reduced thyroid hormones on PND21 and produced deficits in body weight that persisted to adulthood. Synaptic transmission was impaired as evidenced by reductions in excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitudes at a range of stimulus intensities. Long-term potentiation of the EPSP slope was impaired at both modest and strong intensity trains, whereas a paradoxical increase in PS amplitude was observed in PTU-treated animals in response to high intensity trains. These data are the first to describe functional impairments in synaptic transmission and plasticity in situ as a result of PTU treatment and suggest that perturbations in synaptic function may contribute to learning deficits associated with developmental hypothyroidism.

  10. Apolipoprotein E4 impairs in vivo hippocampal long-term synaptic plasticity by reducing the phosphorylation of CaMKIIα and CREB.

    Science.gov (United States)

    Qiao, Feng; Gao, Xiu-Ping; Yuan, Li; Cai, Hong-Yan; Qi, Jin-Shun

    2014-01-01

    Inheritance of the apolipoprotein E genotype ε4 (APOE4) is a powerful risk factor for most cases of late-onset Alzheimer's disease (AD). However, the effects of ApoE4 on the long-term synaptic plasticity and its underlying mechanism have not clearly investigated. In the present study, we examined the effects of ApoE4 on the hippocampal late-phase long-term potentiation (L-LTP) and investigated its probable molecular mechanisms by using in vivo field potential recording, immunohistochemistry, and western blotting. The results showed that: (1) intra-hippocampal injection of 0.2 μg ApoE4, but not ApoE2, before high frequency stimulations (HFSs) attenuated the induction of hippocampal L-LTP in the CA1 region, while injection of the same concentration of ApoE4 after HFSs, even at a higher concentration (2 μg), did not affect the long term synaptic plasticity; (2) ApoE4 injection did not affect the paired pulse facilitation in the hippocampal CA1 region; (3) ApoE4 injection before, not after, HFSs significantly decreased the levels of phosphorylated Ca2+/calmodulin-dependent protein kinase IIα (p-CaMKIIα) and phosphorylated cAMP response element-binding protein (p-CREB) in the hippocampus. These results demonstrated for the first time that ApoE4 could impair hippocampal L-LTP by reducing p-CaMKIIα and p-CREB, suggesting that the ApoE4-induced suppression of hippocampal long-term synaptic plasticity may contribute to the cognitive impairments in genetic AD; and both CaMKIIα and CREB are important intracellular targets of the neurotoxic ApoE4.

  11. Nicotine-induced enhancement of synaptic plasticity at CA3-CA1 synapses requires GABAergic interneurons in adult anti-NGF mice.

    Science.gov (United States)

    Rosato-Siri, Marcelo; Cattaneo, Antonino; Cherubini, Enrico

    2006-10-15

    The hippocampus, a key structure for learning and memory processes, receives an important cholinergic innervation and is densely packed with a variety of nicotinic acetylcholine receptors (nAChRs) localized on principal cells and interneurons. Activation of these receptors by nicotine or endogenously released acetylcholine enhances activity-dependent synaptic plasticity processes. Deficits in the cholinergic system produce impairment of cognitive functions that are particularly relevant during senescence and in age-related neurodegenerative pathologies. In particular, Alzheimer's disease (AD) is characterized by a selective loss of cholinergic neurons in the basal forebrain and nAChRs in particular regions controlling memory processes such as the cortex and the hippocampus. Field excitatory postsynaptic potentials were recorded in order to examine whether nicotine was able to regulate induction of long-term potentiation at CA3-CA1 synapses in hippocampal slices from adult anti-NGF transgenic mice (AD 11), a comprehensive animal model of AD, in which cholinergic deficits due to nerve growth factor depletion are accompanied by progressive Alzheimer-like neurodegeneration. Both AD 11 and wild-type (WT) mice exhibited short- and long-lasting synaptic plasticity processes that were boosted by nicotine. The effects of nicotine on WT and AD 11 mice were mediated by both alpha7- and beta2-containing nAChRs. In the presence of GABA(A) receptor antagonists, nicotine failed to boost synaptic plasticity in AD 11 but not in WT mice, indicating that in anti-NGF transgenic mice GABAergic interneurons are able to compensate for the deficit in cholinergic modulation of glutamatergic transmission. This compensation may occur at different levels and may involve the reorganization of the GABAergic circuit. However, patch-clamp whole-cell recordings from principal cells failed to reveal any change in spontaneous release of GABA following pressure application of nicotine to nearby

  12. Congenital visual pathway abnormalities : A window onto cortical stability and plasticity

    NARCIS (Netherlands)

    Hoffmann, Michael B.; Dumoulin, Serge O.

    2015-01-01

    Sensory systems project information in a highly organized manner to the brain, where it is preserved in maps of the sensory structures. These sensory projections are altered in congenital abnormalities, such as anophthalmia, albinism, achiasma, and hemihydranencephaly. Consequently, these abnormalit

  13. Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning

    Science.gov (United States)

    Hagena, Hardy; Manahan-Vaughan, Denise

    2016-01-01

    Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an

  14. Dopamine D1/D5, but not D2/D3, receptor dependency of synaptic plasticity at hippocampal mossy fiber synapses that is enabled by patterned afferent stimulation, or spatial learning

    Directory of Open Access Journals (Sweden)

    Hardy Hagena

    2016-09-01

    Full Text Available Although the mossy fiber (MF synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24h synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH-CA1 and perforant path (PP-dentate gyrus (DG synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP and long-term depression (LTD. These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about spatial experience effectively occurs and the neuromodulator dopamine plays a key role in motivation-based learning. Prior research on the regulation by dopamine receptors of long-term synaptic plasticity in CA1 and dentate gyrus synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of these receptors in persistent (>24h forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data

  15. dFMRP and Caprin, translational regulators of synaptic plasticity, control the cell cycle at the Drosophila mid-blastula transition.

    Science.gov (United States)

    Papoulas, Ophelia; Monzo, Kathryn F; Cantin, Greg T; Ruse, Cristian; Yates, John R; Ryu, Young Hee; Sisson, John C

    2010-12-01

    The molecular mechanisms driving the conserved metazoan developmental shift referred to as the mid-blastula transition (MBT) remain mysterious. Typically, cleavage divisions give way to longer asynchronous cell cycles with the acquisition of a gap phase. In Drosophila, rapid synchronous nuclear divisions must pause at the MBT to allow the formation of a cellular blastoderm through a special form of cytokinesis termed cellularization. Drosophila Fragile X mental retardation protein (dFMRP; FMR1), a transcript-specific translational regulator, is required for cellularization. The role of FMRP has been most extensively studied in the nervous system because the loss of FMRP activity in neurons causes the misexpression of specific mRNAs required for synaptic plasticity, resulting in mental retardation and autism in humans. Here, we show that in the early embryo dFMRP associates specifically with Caprin, another transcript-specific translational regulator implicated in synaptic plasticity, and with eIF4G, a key regulator of translational initiation. dFMRP and Caprin collaborate to control the cell cycle at the MBT by directly mediating the normal repression of maternal Cyclin B mRNA and the activation of zygotic frühstart mRNA. These findings identify two new targets of dFMRP regulation and implicate conserved translational regulatory mechanisms in processes as diverse as learning, memory and early embryonic development.

  16. Dynamic range of GSK3α not GSK3β is essential for bidirectional synaptic plasticity at hippocampal CA3-CA1 synapses

    Science.gov (United States)

    Shahab, Lion; Plattner, Florian; Irvine, Elaine E; Cummings, Damian M; Edwards, Frances A

    2014-01-01

    Glycogen synthase kinase-3 (GSK3), particularly the isoform GSK3β, has been implicated in a wide range of physiological systems and neurological disorders including Alzheimer's Disease. However, the functional importance of GSK3α has been largely untested. The multifunctionality of GSK3 limits its potential as a drug target because of inevitable side effects. Due to its greater expression in the CNS, GSK3β rather than GSK3α has also been assumed to be of primary importance in synaptic plasticity. Here, we investigate bidirectional long-term synaptic plasticity in knockin mice with a point mutation in GSK3α or GSK3β that prevents their inhibitory regulation. We report that only the mutation in GSK3α affects long-term potentiation (LTP) and depression (LTD). This stresses the importance of investigating isoform specificity for GSK3 in all systems and suggests that GSK3α should be investigated as a drug target in cognitive disorders including Alzheimer's Disease. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc. PMID:25208523

  17. Drebrin depletion alters neurotransmitter receptor levels in protein complexes, dendritic spine morphogenesis and memory-related synaptic plasticity in the mouse hippocampus.

    Science.gov (United States)

    Jung, Gangsoo; Kim, Eun-Jung; Cicvaric, Ana; Sase, Sunetra; Gröger, Marion; Höger, Harald; Sialana, Fernando Jayson; Berger, Johannes; Monje, Francisco J; Lubec, Gert

    2015-07-01

    Drebrin an actin-bundling key regulator of dendritic spine genesis and morphology, has been recently proposed as a regulator of hippocampal glutamatergic activity which is critical for memory formation and maintenance. Here, we examined the effects of genetic deletion of drebrin on dendritic spine and on the level of complexes containing major brain receptors. To this end, homozygous and heterozygous drebrin knockout mice generated in our laboratory and related wild-type control animals were studied. Level of protein complexes containing dopamine receptor D1/dopamine receptor D2, 5-hydroxytryptamine receptor 1A (5-HT1(A)R), and 5-hydroxytryptamine receptor 7 (5-HT7R) were significantly reduced in hippocampus of drebrin knockout mice whereas no significant changes were detected for GluR1, 2, and 3 and NR1 as examined by native gel-based immunoblotting. Drebrin depletion also altered dendritic spine formation, morphology, and reduced levels of dopamine receptor D1 in dendritic spines as evaluated using immunohistochemistry/confocal microscopy. Electrophysiological studies further showed significant reduction in memory-related hippocampal synaptic plasticity upon drebrin depletion. These findings provide unprecedented experimental support for a role of drebrin in the regulation of memory-related synaptic plasticity and neurotransmitter receptor signaling, offer relevant information regarding the interpretation of previous studies and help in the design of future studies on dendritic spines.

  18. Metabolic demand stimulates CREB signaling in the limbic cortex: implication for the induction of hippocampal synaptic plasticity by intrinsic stimulus for survival

    Directory of Open Access Journals (Sweden)

    Nelly M Estrada

    2009-06-01

    Full Text Available Caloric restriction by fasting has been implicated to facilitate synaptic plasticity and promote contextual learning. However, cellular and molecular mechanisms underlying the effect of fasting on memory consolidation are not completely understood. We hypothesized that fasting-induced enhancement of synaptic plasticity was mediated by the increased signaling mediated by CREB (c-AMP response element binding protein, an important nuclear protein and the transcription factor that is involved in the consolidation of memories in the hippocampus. In the in vivo rat model of 18 h fasting, the expression of phosphorylated CREB (pCREB was examined using anti-phospho-CREB (Ser133 in cardially-perfused and cryo-sectioned rat brain specimens. When compared with control animals, the hippocampus exhibited up to a two-fold of increase in pCREB expression in fasted animals. The piriform cortex, the entorhinal cortex, and the cortico-amygdala transitional zone also significantly increased immunoreactivities to pCREB. In contrast, the amygdala did not show any change in the magnitude of pCREB expression in response to fasting. The arcuate nucleus in the medial hypothalamus, which was previously reported to up-regulate CREB phosphorylation during fasting of up to 48 h, was also strongly immunoreactive and provided a positive control in the present study. Our findings demonstrate a metabolic demand not only stimulates cAMP-dependent signaling cascades in the hypothalamus, but also signals to various limbic brain regions including the hippocampus by activating the CREB signaling mechanism. The hippocampus is a primary brain structure for learning and memory. It receives hypothalamic and arcuate projections directly from the fornix. The hippocampus is also situated centrally for functional interactions with other limbic cortexes by establishing reciprocal synaptic connections. We suggest that hippocampal neurons and those in the surrounding limbic cortexes are

  19. Synaptic plasticity and NO-cGMP-PKG signaling regulate pre- and postsynaptic alterations at rat lateral amygdala synapses following fear conditioning.

    Directory of Open Access Journals (Sweden)

    Kristie T Ota

    Full Text Available In vertebrate models of synaptic plasticity, signaling via the putative "retrograde messenger" nitric oxide (NO has been hypothesized to serve as a critical link between functional and structural alterations at pre- and postsynaptic sites. In the present study, we show that auditory Pavlovian fear conditioning is associated with significant and long-lasting increases in the expression of the postsynaptically-localized protein GluR1 and the presynaptically-localized proteins synaptophysin and synapsin in the lateral amygdala (LA within 24 hrs following training. Further, we show that rats given intra-LA infusion of either the NR2B-selective antagonist Ifenprodil, the NOS inhibitor 7-Ni, or the PKG inhibitor Rp-8-Br-PET-cGMPS exhibit significant decreases in training-induced expression of GluR1, synaptophysin, and synapsin immunoreactivity in the LA, while those rats infused with the PKG activator 8-Br-cGMP exhibit a significant increase in these proteins in the LA. In contrast, rats given intra-LA infusion of the NO scavenger c-PTIO exhibit a significant decrease in synapsin and synaptophysin expression in the LA, but no significant impairment in the expression of GluR1. Finally, we show that intra-LA infusions of the ROCK inhibitor Y-27632 or the CaMKII inhibitor KN-93 impair training-induced expression of GluR1, synapsin, and synaptophysin in the LA. These findings suggest that the NO-cGMP-PKG, Rho/ROCK, and CaMKII signaling pathways regulate fear memory consolidation, in part, by promoting both pre- and post-synaptic alterations at LA synapses. They further suggest that synaptic plasticity in the LA during auditory fear conditioning promotes alterations at presynaptic sites via NO-driven "retrograde signaling".

  20. Orchestrated regulation of Nogo receptors, LOTUS, AMPA receptors and BDNF in an ECT model suggests opening and closure of a window of synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Max Nordgren

    Full Text Available Electroconvulsive therapy (ECT is an efficient and relatively fast acting treatment for depression. However, one severe side effect of the treatment is retrograde amnesia, which in certain cases can be long-term. The mechanisms behind the antidepressant effect and the amnesia are not well understood. We hypothesized that ECT causes transient downregulation of key molecules needed to stabilize synaptic structure and to prevent Ca2+ influx, and a simultaneous increase in neurotrophic factors, thus providing a short time window of increased structural synaptic plasticity. Here we followed regulation of NgR1, NgR3, LOTUS, BDNF, and AMPA subunits GluR1 and GluR2 flip and flop mRNA levels in hippocampus at 2, 4, 12, 24, and 72 hours after a single episode of induced electroconvulsive seizures (ECS in rats. NgR1 and LOTUS mRNA levels were transiently downregulated in the dentate gyrus 2, 4, 12 and 4, 12, 24 h after ECS treatment, respectively. GluR2 flip, flop and GluR1 flop were downregulated at 4 h. GluR2 flip remained downregulated at 12 h. In contrast, BDNF, NgR3 and GluR1 flip mRNA levels were upregulated. Thus, ECS treatment induces a transient regulation of factors important for neuronal plasticity. Our data provide correlations between ECS treatment and molecular events compatible with the hypothesis that both effects and side effects of ECT may be caused by structural synaptic rearrangements.

  1. Role of mast cell- and non-mast cell-derived inflammatory mediators in immunologic induction of synaptic plasticity

    Directory of Open Access Journals (Sweden)

    A.A.C. Albuquerque

    1997-07-01

    Full Text Available We have previously discovered a long-lasting enhancement of synaptic transmission in mammal autonomic ganglia caused by immunological activation of ganglionic mast cells. Subsequent to mast cell activation, lipid and peptide mediators are released which may modulate synaptic function. In this study we determined whether some mast cell-derived mediators, prostaglandin D2 (PGD2; 1.0 µM, platelet aggregating factor (PAF; 0.3 µM and U44619 (a thromboxane analogue; 1.0 µM, and also endothelin-1 (ET-1; 0.5 µM induce synaptic potentiation in the guinea pig superior cervical ganglion (SCG, and compared their effects on synaptic transmission with those induced by a sensitizing antigen, ovalbumin (OVA; 10 µg/ml. The experiments were carried out on SCGs isolated from adult male guinea pigs (200-250 g actively sensitized to OVA, maintained in oxygenated Locke solution at 37oC. Synaptic potentiation was measured through alterations of the integral of the post-ganglionic compound action potential (CAP. All agents tested caused long-term (LTP; duration ³30 min or short-term (STP; <30 min potentiation of synaptic efficacy, as measured by the increase in the integral of the post-ganglionic CAP. The magnitude of mediator-induced potentiation was never the same as the antigen-induced long-term potentiation (A-LTP. The agent that best mimicked the antigen was PGD2, which induced a 75% increase in CAP integral for LTP (antigen: 94% and a 34% increase for STP (antigen: 91%. PAF-, U44619-, and ET-1-induced increases in CAP integral ranged for LTP from 34 to 47%, and for STP from 0 to 26%. These results suggest that the agents investigated may participate in the induction of A-LTP

  2. Gravin orchestrates protein kinase A and β2-adrenergic receptor signaling critical for synaptic plasticity and memory

    NARCIS (Netherlands)

    Havekes, Robbert; Canton, David A; Park, Alan J; Huang, Ted; Nie, Ting; Day, Jonathan P; Guercio, Leonardo A; Grimes, Quinn; Luczak, Vincent; Gelman, Irwin H; Baillie, George S; Scott, John D; Abel, Ted

    2012-01-01

    A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of protein kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plast

  3. Synaptic electronics: materials, devices and applications.

    Science.gov (United States)

    Kuzum, Duygu; Yu, Shimeng; Wong, H-S Philip

    2013-09-27

    In this paper, the recent progress of synaptic electronics is reviewed. The basics of biological synaptic plasticity and learning are described. The material properties and electrical switching characteristics of a variety of synaptic devices are discussed, with a focus on the use of synaptic devices for neuromorphic or brain-inspired computing. Performance metrics desirable for large-scale implementations of synaptic devices are illustrated. A review of recent work on targeted computing applications with synaptic devices is presented.

  4. Reversible Recruitment of a Homeostatic Reserve Pool of Synaptic Vesicles Underlies Rapid Homeostatic Plasticity of Quantal Content.

    Science.gov (United States)

    Wang, Xueyong; Pinter, Martin J; Rich, Mark M

    2016-01-20

    Homeostatic regulation is essential for the maintenance of synaptic strength within the physiological range. The current study is the first to demonstrate that both induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds of blocking or unblocking acetylcholine receptors at the mouse neuromuscular junction. Our data suggest that the homeostatic upregulation of release is due to Ca(2+)-dependent increase in the size of the readily releasable pool (RRP). Blocking vesicle refilling prevented upregulation of quantal content (QC), while leaving baseline release relatively unaffected. This suggested that the upregulation of QC was due to mobilization of a distinct pool of vesicles that were rapidly recycled and thus were dependent on continued vesicle refilling. We term this pool the "homeostatic reserve pool." A detailed analysis of the time course of vesicle release triggered by a presynaptic action potential suggests that the homeostatic reserve pool of vesicles is normally released more slowly than other vesicles, but the rate of their release becomes similar to that of the major pool during homeostatic upregulation of QC. Remarkably, instead of finding a generalized increase in the recruitment of vesicles into RRP, we identified a distinct homeostatic reserve pool of vesicles that appear to only participate in synchronized release following homeostatic upregulation of QC. Once this small pool of vesicles is depleted by the block of vesicle refilling, homeostatic upregulation of QC is no longer observed. This is the first identification of the population of vesicles responsible for the blockade-induced upregulation of release previously described. Significance statement: The current study is the first to demonstrate that both the induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds. Our data suggest that homeostatic upregulation of release is due to Ca(2+)-dependent

  5. Synaptic plasticity and the analysis of the field-EPSP as well as the population spike using separate recording electrodes in the dentate gyrus in freely moving rats.

    Science.gov (United States)

    Frey, Sabine; Frey, Julietta U

    2009-10-30

    Commonly, synaptic plasticity events such as long-term potentiation (LTP) are investigated by using a stimulation electrode and a single, monopolar field recording electrode in the dentate gyrus in intact, freely moving rats. The recording electrode is mostly positioned in the granular cell layer, or the hilar region of the dentate gyrus, i.e. far away from the place of generation of monosynaptic postsynaptic excitatory potentials (EPSP). Since LTP is a synaptic phenomenon and field recordings far away from the activated synapses do not guarantee a specific interpretation of the overlaid, mixture of complex potentials of several different electrical fields it is often difficult or even impossible to interpret the data obtained by such a single recording electrode. Therefore, at least a separate or two recording electrodes should be used to record the EPSP as well as the spike, respectively, ideally at their places of generation. Here, we describe a method by implanting a chronic bipolar recording electrode which fulfils the above requirements by recording the field-EPSP as well as the population spike at their places of generation and describe the time course of LTP measured using this "double-recording" electrode. We show that different tetanization protocols resulted in EPSP- or population spike-LTP but only if the potentials were recorded by electrodes positioned within adequate places of potential generation. Interestingly, the commonly used recording in the hilus of a distinct part of a potential, mistakenly analyzed as an "EPSP" did not reveal any LTP.

  6. Modification of hippocampal markers of synaptic plasticity by memantine in animal models of acute and repeated restraint stress: implications for memory and behavior.

    Science.gov (United States)

    Amin, Shaimaa Nasr; El-Aidi, Ahmed Amro; Ali, Mohamed Mostafa; Attia, Yasser Mahmoud; Rashed, Laila Ahmed

    2015-06-01

    Stress is any condition that impairs the balance of the organism physiologically or psychologically. The response to stress involves several neurohormonal consequences. Glutamate is the primary excitatory neurotransmitter in the central nervous system, and its release is increased by stress that predisposes to excitotoxicity in the brain. Memantine is an uncompetitive N-methyl D-aspartate glutamatergic receptors antagonist and has shown beneficial effect on cognitive function especially in Alzheimer's disease. The aim of the work was to investigate memantine effect on memory and behavior in animal models of acute and repeated restraint stress with the evaluation of serum markers of stress and the expression of hippocampal markers of synaptic plasticity. Forty-two male rats were divided into seven groups (six rats/group): control, acute restraint stress, acute restraint stress with Memantine, repeated restraint stress, repeated restraint stress with Memantine and Memantine groups (two subgroups as positive control). Spatial working memory and behavior were assessed by performance in Y-maze. We evaluated serum cortisol, tumor necrotic factor, interleukin-6 and hippocampal expression of brain-derived neurotrophic factor, synaptophysin and calcium-/calmodulin-dependent protein kinase II. Our results revealed that Memantine improved spatial working memory in repeated stress, decreased serum level of stress markers and modified the hippocampal synaptic plasticity markers in both patterns of stress exposure; in ARS, Memantine upregulated the expression of synaptophysin and brain-derived neurotrophic factor and downregulated the expression of calcium-/calmodulin-dependent protein kinase II, and in repeated restraint stress, it upregulated the expression of synaptophysin and downregulated calcium-/calmodulin-dependent protein kinase II expression.

  7. The free radical scavenger Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance in a mouse model of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Oliwia Alicja Janc

    2014-02-01

    Full Text Available Rett syndrome (RS causes severe cognitive impairment, loss of speech, epilepsy, and breathing disturbances with intermittent hypoxia. Also mitochondria are affected; a subunit of respiratory complex III is dysregulated, the inner mitochondrial membrane is leaking protons, and brain ATP levels seem reduced. Our recent assessment of mitochondrial function in MeCP2-deficient mouse (Mecp2-/y hippocampus, confirmed early metabolic alterations, an increased oxidative burden, and a more vulnerable cellular redox balance. As these changes may contribute to the manifestation of symptoms and disease progression, we now evaluated whether free radical scavengers are capable of improving neuronal and mitochondrial function in RS. Acute hippocampal slices of adult mice were incubated with the vitamin E derivative Trolox for 3-5 h. In Mecp2-/y slices this treatment dampened neuronal hyperexcitability, improved short-term plasticity, and fully restored synaptic long-term potentiation. Furthermore, Trolox specifically attenuated the increased hypoxia susceptibility of Mecp2-/y slices. Also, the anticonvulsive effects of Trolox were assessed, but the severity of 4-aminopyridine provoked seizure-like discharges was not significantly affected. Adverse side effects of Trolox on mitochondria can be excluded, but clear indications for an improvement of mitochondrial function were not found. Since several ion-channels and neurotransmitter receptors are redox modulated, the mitochondrial alterations and the associated oxidative burden may contribute to the neuronal dysfunction in RS. We confirmed in Mecp2-/y hippocampus that Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance. Therefore, radical scavengers are promising compounds for the treatment of neuronal dysfunction in RS and deserve further detailed evaluation.

  8. Abnormal plasticity of the sensorimotor cortex to slow repetitive transcranial magnetic stimulation in patients with writer's cramp.

    Science.gov (United States)

    Bäumer, Tobias; Demiralay, Cüneyt; Hidding, Ute; Bikmullina, Rosalia; Helmich, Rick C; Wunderlich, Silke; Rothwell, John; Liepert, Joachim; Siebner, Hartwig R; Münchau, Alexander

    2007-01-01

    Previous studies demonstrated functional abnormalities in the somatosensory system, including a distorted functional organization of the somatosensory cortex (S1) in patients with writer's cramp. We tested the hypothesis that these functional alterations render S1 of these patients more susceptible to the "inhibitory" effects of subthreshold 1 Hz repetitive transcranial magnetic stimulation (rTMS) given to S1. Seven patients with writer's cramp and eight healthy subjects were studied. Patients also received rTMS to the motor cortex hand area (M1). As an outcome measure, short-latency afferent inhibition (SAI) was tested. SAI was studied in the relaxed first dorsal interosseous muscle using conditioning electrical stimulation of the index finger and TMS pulses over the contralateral M1. Baseline SAI did not differ between groups. S1 but not M1 rTMS reduced SAI in patients. rTMS had no effects on SAI in healthy subjects. Because SAI is mediated predominantly at a cortical level in the sensorimotor cortex, we conclude that there is an abnormal responsiveness of this area to 1 Hz rTMS in writer's cramp, which may represent a trait toward maladaptive plasticity in the sensorimotor system in these patients.

  9. Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex.

    Science.gov (United States)

    Sakata, Kazuko; Woo, Newton H; Martinowich, Keri; Greene, Joshua S; Schloesser, Robert J; Shen, Liya; Lu, Bai

    2009-04-07

    Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression. BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven Bdnf transcription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from BDNF-KIV, but not wild-type littermates. These results demonstrate the importance of promoter IV-dependent Bdnf transcription in GABAergic function and reveal an unexpected regulation of STDP in the PFC by BDNF.

  10. Sleep deprivation during a specific 3-hour time window post-training impairs hippocampal synaptic plasticity and memory

    NARCIS (Netherlands)

    Prince, Toni-Moi; Wimmer, Mathieu; Choi, Jennifer; Havekes, Robbert; Aton, Sara; Abel, Ted

    2014-01-01

    Sleep deprivation disrupts hippocampal function and plasticity. In particular, long-term memory consolidation is impaired by sleep deprivation, suggesting that a specific critical period exists following learning during which sleep is necessary. To elucidate the impact of sleep deprivation on long-t

  11. Extensive enriched environments protect old rats from the aging dependent impairment of spatial cognition, synaptic plasticity and nitric oxide production.

    Science.gov (United States)

    Lores-Arnaiz, S; Bustamante, J; Arismendi, M; Vilas, S; Paglia, N; Basso, N; Capani, F; Coirini, H; Costa, J J López; Arnaiz, M R Lores

    2006-05-15

    In aged rodents, neuronal plasticity decreases while spatial learning and working memory (WM) deficits increase. As it is well known, rats reared in enriched environments (EE) show better cognitive performances and an increased neuronal plasticity than rats reared in standard environments (SE). We hypothesized that EE could preserve the aged animals from cognitive impairment through NO dependent mechanisms of neuronal plasticity. WM performance and plasticity were measured in 27-month-old rats from EE and SE. EE animals showed a better spatial WM performance (66% increase) than SE ones. Cytosolic NOS activity was 128 and 155% higher in EE male and female rats, respectively. Mitochondrial NOS activity and expression were also significantly higher in EE male and female rats. Mitochondrial NOS protein expression was higher in brain submitochondrial membranes from EE reared rats. Complex I activity was 70-80% increased in EE as compared to SE rats. A significant increase in the area of NADPH-d reactive neurons was observed in the parietotemporal cortex and CA1 hippocampal region of EE animals.

  12. Principle Discussion of Utilizing Synaptic Plasticity Characteristics in Applying Depressive Disorder Treatment of Electric Acupuncture%从神经突触可塑性探讨电针治疗抑郁症的机制

    Institute of Scientific and Technical Information of China (English)

    陈喆思; 郑重; 张虹; 邹可; 彭玉琳

    2013-01-01

    The number of depressive disorder patients is increasing yearly due to growing competitions in all forms in society.It has become the focal point of current clinical research which the key symptom is decaying capability in learning and memory.Clinical curative effect for the treatment of depression has been proven effective and without side-effect,its principle is closely related to the synaptic plasticity.The synaptic plasticity consists of synaptic morphological plasticity and synaptic functional plasticity.LTP (Longterm Potentation) and LTD (Long-term Depression),being two major representations of synaptic plasticity,take part in improving learning and memory.This article discussed the principle of electric acupuncture treatment of depression by researching through the electricity for the synaptic LTP,LTD induction and the morphological plasticity,and further elaborates the enhancing effect towards rTMS from the field of "The remodeling of synapfic plasticity".%由于社会竞争的日益加剧,抑郁症患者逐年攀升,目前已成为当代医学研究的热点,其核心症状为学习及记忆能力的减退.临床电针治疗抑郁症疗效确切,且无副作用,其机理与神经突触的可塑性有着密切联系.神经突触可塑性分为形态可塑及功能可塑,长时程增强(LTP)、长时程抑制(LTD)作为突触可塑性的主要表现形式,参与学习、记忆的改善.通过综述电针对神经突触LTP、LTD的诱导及对突触形态的可塑探讨了电针治疗抑郁症的机制,并从“突触再可塑”阐述了电针对重复经颅磁刺激(rTMS)的增效作用.

  13. Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents.

    Science.gov (United States)

    Qi, Yingjie; Klyubin, Igor; Harney, Sarah C; Hu, NengWei; Cullen, William K; Grant, Marianne K; Steffen, Julia; Wilson, Edward N; Do Carmo, Sonia; Remy, Stefan; Fuhrmann, Martin; Ashe, Karen H; Cuello, A Claudio; Rowan, Michael J

    2014-12-24

    Long before synaptic loss occurs in Alzheimer's disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Aß in a very complete model of Alzheimer's disease amyloidosis, the McGill-R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2-3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor-mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Aß antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the γ-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Aß selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer's disease amyloidosis.

  14. Differential regulation of BDNF, synaptic plasticity and sprouting in the hippocampal mossy fiber pathway of male and female rats

    OpenAIRE

    SCHARFMAN, HELEN E.; MacLusky, Neil J.

    2013-01-01

    Many studies have described potent effects of BDNF, 17β-estradiol or androgen on hippocampal synapses and their plasticity. Far less information is available about the interactions between 17β-estradiol and BDNF in hippocampus, or interactions between androgen and BDNF in hippocampus. Here we review the regulation of BDNF in the mossy fiber pathway, a critical part of hippocampal circuitry. We discuss the emerging view that 17β-estradiol upregulates mossy fiber BDNF synthesis in the adult fem...

  15. Impairment of cognitive function and synaptic plasticity associated with alteration of information flow in theta and gamma oscillations in melamine-treated rats.

    Directory of Open Access Journals (Sweden)

    Xiaxia Xu

    Full Text Available Changes of neural oscillations at a variety of physiological rhythms are effectively associated with cognitive performance. The present study investigated whether the directional indices of neural information flow (NIF could be used to symbolize the synaptic plasticity impairment in hippocampal CA3-CA1 network in a rat model of melamine. Male Wistar rats were employed while melamine was administered at a dose of 300 mg/kg/day for 4 weeks. Behavior was measured by the Morris water maze(MWMtest. Local field potentials (LFPs were recorded before long-term potentiation (LTP induction. Generalized partial directed coherence (gPDC and phase-amplitude coupling conditional mutual information (PAC_CMI were used to measure the unidirectional indices in both theta and low gamma oscillations (LG, ~ 30-50 Hz. Our results showed that melamine induced the cognition deficits consistent with the reduced LTP in CA1 area. Phase locking values (PLVs showed that the synchronization between CA3 and CA1 in both theta and LG rhythms was reduced by melamine. In both theta and LG rhythms, unidirectional indices were significantly decreased in melamine treated rats while a similar variation trend was observed in LTP reduction, implying that the effects of melamine on cognitive impairment were possibly mediated via profound alterations of NIF on CA3-CA1 pathway in hippocampus. The results suggested that LFPs activities at these rhythms were most likely involved in determining the alterations of information flow in the hippocampal CA3-CA1 network, which might be associated with the alteration of synaptic transmission to some extent.

  16. Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling

    NARCIS (Netherlands)

    Benevento, M; Iacono, G.; Selten, M.M; Ba, W; Oudakker, A.R; Frega, M; Keller, J.; Mancini, R.; Lewerissa, E.; Kleefstra, T; Stunnenberg, H.G.; Zhou, H.; Bokhoven, H; Nadif Kasri, N

    2016-01-01

    Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains po

  17. EDITORIAL: Synaptic electronics Synaptic electronics

    Science.gov (United States)

    Demming, Anna; Gimzewski, James K.; Vuillaume, Dominique

    2013-09-01

    neuromorphic circuit composed of a nanoscale 1-kbit resistive random-access memory (RRAM) cross-point array of synapses and complementary metal-oxide-semiconductor (CMOS) neuron circuits [13]; a WO3-x-based nanoionics device from Masakazu Aono's group with a wide scale of reprogrammable memorization functions [14]; a new spike-timing dependent plasticity scheme based on a MOS transistor as a selector and a RRAM as a variable resistance device [15]; a new hybrid memristor-CMOS neuromorphic circuit [16]; and a photo-assisted atomic switch [17]. Synaptic electronics evidently has many emerging facets, and Duygu Kuzum, Shimeng Yu, and H-S Philip Wong in the US provide a review of the field, including the materials, devices and applications [18]. In embracing the expertise acquired over thousands of years of evolution, biomimetics and bio-inspired design is a common, smart approach to technological innovation. Yet in successfully mimicking the physiological mechanisms of the human mind synaptic electronics research has a potential impact that is arguably unprecedented. That the quirks and eccentricities recently unearthed in the behaviour of nanomaterials should lend themselves so accommodatingly to emulating synaptic functions promises some very exciting developments in the field, as the articles in this special issue emphasize. References [1] von Neumann J (ed) 2012 The Computer and the Brain 3rd edn (Yale: Yale University Press) [2] Strukov D B, Snider G S, Stewart D R and Williams R S 2008 The missing memristor found Nature 453 80-3 [3] Chua L O 1971 Memristor—the missing circuit element IEEE Trans. Circuit Theory 18 507-19 [4] Chua L O 2013 Memristor, Hodgkin-Huxley, and Edge of Chaos Nanotechnology 24 383001 [5] Pickett M D and Williams R S 2013 Phase transitions enable computational universality in neuristor-based cellular automata Nanotechnology 24 384002 [6] Cruz-Albrecht J M, Derosier T and Srinivasa N 2013 Scalable neural chip with synaptic electronics using CMOS

  18. An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

    Science.gov (United States)

    Kempf, Stefan J.; Metaxas, Athanasios; Ibáñez-Vea, María; Darvesh, Sultan; Finsen, Bente; Larsen, Martin R.

    2016-01-01

    The aim of this study was to elucidate the molecular signature of Alzheimer's disease-associated amyloid pathology. We used the double APPswe/PS1ΔE9 mouse, a widely used model of cerebral amyloidosis, to compare changes in proteome, including global phosphorylation and sialylated N-linked glycosylation patterns, pathway-focused transcriptome and neurological disease-associated miRNAome with age-matched controls in neocortex, hippocampus, olfactory bulb and brainstem. We report that signalling pathways related to synaptic functions associated with dendritic spine morphology, neurite outgrowth, long-term potentiation, CREB signalling and cytoskeletal dynamics were altered in 12 month old APPswe/PS1ΔE9 mice, particularly in the neocortex and olfactory bulb. This was associated with cerebral amyloidosis as well as formation of argyrophilic tangle-like structures and microglial clustering in all brain regions, except for brainstem. These responses may be epigenetically modulated by the interaction with a number of miRNAs regulating spine restructuring, Aβ expression and neuroinflammation. We suggest that these changes could be associated with development of cognitive dysfunction in early disease states in patients with Alzheimer's disease. PMID:27144524

  19. Unlocking the secrets of the δ2 glutamate receptor: A gatekeeper for synaptic plasticity in the cerebellum.

    Science.gov (United States)

    Kohda, Kazuhisa; Kakegawa, Wataru; Yuzaki, Michisuke

    2013-11-01

    Long-term changes in synaptic transmission in the central nervous system, such as long-term potentiation and long-term depression (LTD), are believed to underlie learning and memory in vivo. Despite intensive research, the precise molecular mechanisms underlying these phenomena have remained unclear. LTD is most commonly caused by the endocytosis of postsynaptic AMPA-type glutamate receptors, triggered by activity-induced serine phosphorylation of the GluA2 subunit. Interestingly, cerebellar LTD, which occurs at synapses between parallel fibers (PFs; axons of granule cells) and Purkinje cells, is unique in requiring an additional type of glutamate receptor, the δ2 receptor (GluD2). Cbln1 was recently identified as a GluD2 ligand that regulates PF synapse formation and maintenance. However, how GluD2 induces downstream signaling in Purkinje cells to regulate LTD induction is unknown. We here present evidence that GluD2 reduces the tyrosine phosphorylation level of the GluA2 subunit via PTPMEG, a protein tyrosine phosphatase that binds to GluD2's C-terminus. We also found that the serine phosphorylation of GluA2, a crucial step for AMPA-receptor endocytosis, requires prior tyrosine dephosphorylation. Thus, GluD2 may serve as a gatekeeper for LTD induction by coordinating interactions between GluA2's 2 phosphorylation sites.

  20. VSNL1 Co-expression networks in aging include calcium signaling, synaptic plasticity, and Alzheimer’s disease pathways

    Directory of Open Access Journals (Sweden)

    C W Lin

    2015-03-01

    Full Text Available The Visinin-like 1 (VSNL1 gene encodes Visinin-like protein 1, a peripheral biomarker for Alzheimer disease (AD. Little is known, however, about normal VSNL1 expression in brain and the biologic networks in which it participates. Frontal cortex gray matter from 209 subjects without neurodegenerative or psychiatric illness, ranging in age from 16–91, were processed on Affymetrix GeneChip 1.1 ST and Human SNP Array 6.0. VSNL1 expression was unaffected by age and sex, and not significantly associated with SNPs in cis or trans. VSNL1 was significantly co-expressed with genes in pathways for Calcium Signaling, AD, Long Term Potentiation, Long Term Depression, and Trafficking of AMPA Receptors. The association with AD was driven, in part, by correlation with amyloid precursor protein (APP expression. These findings provide an unbiased link between VSNL1 and molecular mechanisms of AD, including pathways implicated in synaptic pathology in AD. Whether APP may drive increased VSNL1 expression, VSNL1 drives increased APP expression, or both are downstream of common pathogenic regulators will need to be evaluated in model systems.

  1. Sensory deprivation unmasks a PKA-dependent synaptic plasticity mechanism that operates in parallel with CaMKII.

    Science.gov (United States)

    Hardingham, Neil; Wright, Nick; Dachtler, James; Fox, Kevin

    2008-12-10

    Calcium/calmodulin kinase II (CaMKII) is required for LTP and experience-dependent potentiation in the barrel cortex. Here, we find that whisker deprivation increases LTP in the layer IV to II/III pathway and that PKA antagonists block the additional LTP. No LTP was seen in undeprived CaMKII-T286A mice, but whisker deprivation again unmasked PKA-sensitive LTP. Infusion of a PKA agonist potentiated EPSPs in deprived wild-types and deprived CaMKII-T286A point mutants but not in undeprived animals of either genotype. The PKA-dependent potentiation mechanism was not present in GluR1 knockouts. Infusion of a PKA antagonist caused depression of EPSPs in undeprived but not deprived cortex. LTD was occluded by whisker deprivation and blocked by PKA manipulation, but not blocked by cannabinoid antagonists. NMDA receptor currents were unaffected by sensory deprivation. These results suggest that sensory deprivation causes synaptic depression by reversing a PKA-dependent process that may act via GluR1.

  2. Endocannabinoids and synaptic function in the CNS.

    Science.gov (United States)

    Hashimotodani, Yuki; Ohno-Shosaku, Takako; Kano, Masanobu

    2007-04-01

    Marijuana affects neural functions through the binding of its active component (Delta(9)-THC) to cannabinoid receptors in the CNS. Recent studies have elucidated that endogenous ligands for cannabinoid receptors, endocannabinoids, serve as retrograde messengers at central synapses. Endocannabinoids are produced on demand in activity-dependent manners and released from postsynaptic neurons. The released endocannabinoids travel backward across the synapse, activate presynaptic CB1 cannabinoid receptors, and modulate presynaptic functions. Retrograde endocannabinoid signaling is crucial for certain forms of short-term and long-term synaptic plasticity at excitatory or inhibitory synapses in many brain regions, and thereby contributes to various aspects of brain function including learning and memory. Molecular identities of the CB1 receptor and enzymes involved in production and degradation of endocannabinoids have been elucidated. Anatomical studies have demonstrated unique distributions of these molecules around synapses, which provide morphological bases for the roles of endocannabinoids as retrograde messengers. CB1-knockout mice exhibit various behavioral abnormalities and multiple defects in synaptic plasticity, supporting the notion that endocannabinoid signaling is involved in various aspects of neural function. In this review article, the authors describe molecular mechanisms of the endocannabinoid-mediated synaptic modulation and its possible physiological significance.

  3. Dopaminergic modulation of short-term synaptic plasticity in fast-spiking interneurons of primate dorsolateral prefrontal cortex.

    Science.gov (United States)

    Gonzalez-Burgos, G; Kroener, S; Seamans, J K; Lewis, D A; Barrionuevo, G

    2005-12-01

    Dopaminergic regulation of primate dorsolateral prefrontal cortex (PFC) activity is essential for cognitive functions such as working memory. However, the cellular mechanisms of dopamine neuromodulation in PFC are not well understood. We have studied the effects of dopamine receptor activation during persistent stimulation of excitatory inputs onto fast-spiking GABAergic interneurons in monkey PFC. Stimulation at 20 Hz induced short-term excitatory postsynaptic potential (EPSP) depression. The D1 receptor agonist SKF81297 (5 microM) significantly reduced the amplitude of the first EPSP but not of subsequent responses in EPSP trains, which still displayed significant depression. Dopamine (DA; 10 microM) effects were similar to those of SKF81297 and were abolished by the D1 antagonist SCH23390 (5 microM), indicating a D1 receptor-mediated effect. DA did not alter miniature excitatory postsynaptic currents, suggesting that its effects were activity dependent and presynaptic action potential dependent. In contrast to previous findings in pyramidal neurons, in fast-spiking cells, contribution of N-methyl-D-aspartate receptors to EPSPs at subthreshold potentials was not significant and fast-spiking cell depolarization decreased EPSP duration. In addition, DA had no significant effects on temporal summation. The selective decrease in the amplitude of the first EPSP in trains delivered every 10 s suggests that in fast-spiking neurons, DA reduces the amplitude of EPSPs evoked at low frequency but not of EPSPs evoked by repetitive stimulation. DA may therefore improve detection of EPSP bursts above background synaptic activity. EPSP bursts displaying short-term depression may transmit spike-timing-dependent temporal codes contained in presynaptic spike trains. Thus DA neuromodulation may increase the signal-to-noise ratio at fast-spiking cell inputs.

  4. Phase-specific plasticity of synaptic structures in the somatosensory cortex of living mice during neuropathic pain

    Directory of Open Access Journals (Sweden)

    Kim Sun

    2011-11-01

    Full Text Available Abstract Background Postsynaptic dendritic spines in the cortex are highly dynamic, showing rapid morphological changes including elongation/retraction and formation/elimination in response to altered sensory input or neuronal activity, which achieves experience/activity-dependent cortical circuit rewiring. Our previous long-term in vivo two-photon imaging study revealed that spine turnover in the mouse primary somatosensory (S1 cortex markedly increased in an early development phase of neuropathic pain, but was restored in a late maintenance phase of neuropathic pain. However, it remains unknown how spine morphology is altered preceding turnover change and whether gain and loss of presynaptic boutons are changed during neuropathic pain. Findings Here we used short-term (2-hour and long-term (2-week time-lapse in vivo two-photon imaging of individual spines and boutons in the S1 cortical layer 1 of the transgenic mice expressing GFP in pyramidal neurons following partial sciatic nerve ligation (PSL. We found in the short-term imaging that spine motility (Δ length per 30 min significantly increased in the development phase of neuropathic pain, but returned to the baseline in the maintenance phase. Moreover, the proportion of immature (thin and mature (mushroom spines increased and decreased, respectively, only in the development phase. Long-term imaging data showed that formation and elimination of boutons moderately increased and decreased, respectively, during the first 3 days following PSL and was subsequently restored. Conclusions Our results indicate that the S1 synaptic structures are rapidly destabilized and rearranged following PSL and subsequently stabilized in the maintenance phase of neuropathic pain, suggesting a novel therapeutic target in intractable chronic pain.

  5. ESP-102, a Combined Herbal Extract of Angelica gigas, Saururus chinensis, and Schisandra chinensis, Changes Synaptic Plasticity and Attenuates Scopolamine-Induced Memory Impairment in Rat Hippocampus Tissue.

    Science.gov (United States)

    Kim, Hyun-Bum; Hwang, Eun-Sang; Choi, Ga-Young; Lee, Seok; Park, Tae-Suk; Lee, Cheol-Won; Lee, Eun-Suk; Kim, Young-Choong; Kim, Sang Seong; Lee, Sung-Ok; Park, Ji-Ho

    2016-01-01

    ESP-102, an extract from Angelica gigas, Saururus chinensis, and Schisandra chinensis, has been used as herbal medicine and dietary supplement in Korea. Despite the numerous bioactivities in vitro and in vivo studies, its effects on neuronal networks remain elusive. To address the neuronal effect, we examined synaptic plasticity in organotypic hippocampal slice culture with multielectrode array. Our results showed an increase in excitatory postsynaptic potential (EPSP), indicating the induction of long-term potentiation (LTP), in the presence of ESP-102. In addition, the neuroprotective effect of ESP-102 was also tested by application of scopolamine to the hippocampal slice. Interestingly, ESP-102 competitively antagonized the preventative LTP effect induced by scopolamine. The scopolamine-induced reduction in brain-derived neurotrophic factor (BDNF) and GluR-2 expression was also rescued by ESP-102. In terms of mode of action, ESP-102 appears to act on the presynaptic region independent of AMPA/NMDA receptors. Based on these findings, ESP-102 can be suggested as a novel herbal ingredient with memory enhancing as well as neuroprotective effects.

  6. ESP-102, a Combined Herbal Extract of Angelica gigas, Saururus chinensis, and Schisandra chinensis, Changes Synaptic Plasticity and Attenuates Scopolamine-Induced Memory Impairment in Rat Hippocampus Tissue

    Directory of Open Access Journals (Sweden)

    Hyun-Bum Kim

    2016-01-01

    Full Text Available ESP-102, an extract from Angelica gigas, Saururus chinensis, and Schisandra chinensis, has been used as herbal medicine and dietary supplement in Korea. Despite the numerous bioactivities in vitro and in vivo studies, its effects on neuronal networks remain elusive. To address the neuronal effect, we examined synaptic plasticity in organotypic hippocampal slice culture with multielectrode array. Our results showed an increase in excitatory postsynaptic potential (EPSP, indicating the induction of long-term potentiation (LTP, in the presence of ESP-102. In addition, the neuroprotective effect of ESP-102 was also tested by application of scopolamine to the hippocampal slice. Interestingly, ESP-102 competitively antagonized the preventative LTP effect induced by scopolamine. The scopolamine-induced reduction in brain-derived neurotrophic factor (BDNF and GluR-2 expression was also rescued by ESP-102. In terms of mode of action, ESP-102 appears to act on the presynaptic region independent of AMPA/NMDA receptors. Based on these findings, ESP-102 can be suggested as a novel herbal ingredient with memory enhancing as well as neuroprotective effects.

  7. 5-HT(2C) serotonin receptor blockade prevents tau protein hyperphosphorylation and corrects the defect in hippocampal synaptic plasticity caused by a combination of environmental stressors in mice.

    Science.gov (United States)

    Busceti, Carla Letizia; Di Pietro, Paola; Riozzi, Barbara; Traficante, Anna; Biagioni, Francesca; Nisticò, Robert; Fornai, Francesco; Battaglia, Giuseppe; Nicoletti, Ferdinando; Bruno, Valeria

    2015-09-01

    Exposure to multimodal sensory stressors is an everyday occurrence and sometimes becomes very intense, such as during rave parties or other recreational events. A growing body of evidence suggests that strong environmental stressors might cause neuronal dysfunction on their own in addition to their synergistic action with illicit drugs. Mice were exposed to a combination of physical and sensory stressors that are reminiscent of those encountered in a rave party. However, this is not a model of rave because it lacks the rewarding properties of rave. A 14-h exposure to environmental stressors caused an impairment of hippocampal long-term potentiation (LTP) and spatial memory, and an enhanced phosphorylation of tau protein in the CA1 and CA3 regions. These effects were transient and critically depended on the activation of 5-HT2C serotonin receptors, which are highly expressed in the CA1 region. Acute systemic injection of the selective 5-HT2C antagonist, RS-102,221 (2 mg/kg, i.p., 2 min prior the onset of stress), prevented tau hyperphosphorylation and also corrected the defects in hippocampal LTP and spatial memory. These findings suggest that passive exposure to a combination of physical and sensory stressors causes a reversible hippocampal dysfunction, which might compromise mechanisms of synaptic plasticity and spatial memory for a few days. Drugs that block 5-HT2C receptors might protect the hippocampus against the detrimental effect of environmental stressors.

  8. ESP-102, a Combined Herbal Extract of Angelica gigas, Saururus chinensis, and Schisandra chinensis, Changes Synaptic Plasticity and Attenuates Scopolamine-Induced Memory Impairment in Rat Hippocampus Tissue

    Science.gov (United States)

    Kim, Hyun-Bum; Hwang, Eun-Sang; Choi, Ga-Young; Lee, Seok; Park, Tae-Suk; Lee, Cheol-Won; Lee, Eun-Suk; Kim, Young-Choong; Kim, Sang Seong; Lee, Sung-Ok; Park, Ji-Ho

    2016-01-01

    ESP-102, an extract from Angelica gigas, Saururus chinensis, and Schisandra chinensis, has been used as herbal medicine and dietary supplement in Korea. Despite the numerous bioactivities in vitro and in vivo studies, its effects on neuronal networks remain elusive. To address the neuronal effect, we examined synaptic plasticity in organotypic hippocampal slice culture with multielectrode array. Our results showed an increase in excitatory postsynaptic potential (EPSP), indicating the induction of long-term potentiation (LTP), in the presence of ESP-102. In addition, the neuroprotective effect of ESP-102 was also tested by application of scopolamine to the hippocampal slice. Interestingly, ESP-102 competitively antagonized the preventative LTP effect induced by scopolamine. The scopolamine-induced reduction in brain-derived neurotrophic factor (BDNF) and GluR-2 expression was also rescued by ESP-102. In terms of mode of action, ESP-102 appears to act on the presynaptic region independent of AMPA/NMDA receptors. Based on these findings, ESP-102 can be suggested as a novel herbal ingredient with memory enhancing as well as neuroprotective effects. PMID:27298627

  9. Repetitive transcranial magnetic stimulation enhances spatial learning and synaptic plasticity via the VEGF and BDNF-NMDAR pathways in a rat model of vascular dementia.

    Science.gov (United States)

    Zhang, N; Xing, M; Wang, Y; Tao, H; Cheng, Y

    2015-12-17

    This study aimed to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) on learning and memory in a rat model of vascular dementia (VaD) and to analyze the associated mechanisms. Bilateral carotid artery occlusion (2-VO) was used to establish a rat model of VaD. High-frequency (5Hz) rTMS was performed on rats for four weeks. Spatial learning and memory abilities were evaluated using the Morris water maze (MWM), and synaptic plasticity in the hippocampus was assessed via long-term potentiation (LTP). Hippocampal expression of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF) and three subunits of the N-methyl-D-aspartic acid receptor (NMDAR), NR1, NR2A and NR2B, was analyzed by Western blotting. Compared with the VaD group, escape latency was decreased (PCA3-CA1 synapses was enhanced by rTMS (PBDNF, NR1 and NR2B expression was decreased in the VaD group and increased by rTMS (PBDNF and NMDARs. In addition, NR2B may be more important than NR2A for LTP induction in the hippocampus during rTMS treatment of VaD.

  10. Phospho-regulated Drosophila adducin is a determinant of synaptic plasticity in a complex with Dlg and PIP2 at the larval neuromuscular junction

    Directory of Open Access Journals (Sweden)

    Simon Ji Hau Wang

    2014-11-01

    Full Text Available Adducin is a ubiquitously expressed actin- and spectrin-binding protein involved in cytoskeleton organization, and is regulated through phosphorylation of the myristoylated alanine-rich C-terminal kinase (MARCKS-homology domain by protein kinase C (PKC. We have previously shown that the Drosophila adducin, Hu-li tai shao (Hts, plays a role in larval neuromuscular junction (NMJ growth. Here, we find that the predominant isoforms of Hts at the NMJ contain the MARCKS-homology domain, which is important for interactions with Discs large (Dlg and phosphatidylinositol 4,5-bisphosphate (PIP2. Through the use of Proximity Ligation Assay (PLA, we show that the adducin-like Hts isoforms are in complexes with Dlg and PIP2 at the NMJ. We provide evidence that Hts promotes the phosphorylation and delocalization of Dlg at the NMJ through regulation of the transcript distribution of the PAR-1 and CaMKII kinases in the muscle. We also show that Hts interactions with Dlg and PIP2 are impeded through phosphorylation of the MARCKS-homology domain. These results are further evidence that Hts is a signaling-responsive regulator of synaptic plasticity in Drosophila.

  11. Neonatal Treatment with a Pegylated Leptin Antagonist Induces Sexually Dimorphic Effects on Neurones and Glial Cells, and on Markers of Synaptic Plasticity in the Developing Rat Hippocampal Formation.

    Science.gov (United States)

    López-Gallardo, M; Antón-Fernández, A; Llorente, R; Mela, V; Llorente-Berzal, A; Prada, C; Viveros, M P

    2015-08-01

    The present study aimed to better understand the role of the neonatal leptin surge, which peaks on postnatal day (PND)9-10, on the development of the hippocampal formation. Accordingly, male and female rats were administered with a pegylated leptin antagonist on PND9 and the expression of neurones, glial cells and diverse markers of synaptic plasticity was then analysed by immunohistochemistry in the hippocampal formation. Antagonism of the actions of leptin at this specific postnatal stage altered the number of glial fibrillary acidic protein positive cells, and also affected type 1 cannabinoid receptors, synaptophysin and brain-derived neurotrophic factor (BDNF), with the latter effect being sexually dimorphic. The results indicate that the physiological leptin surge occurring around PND 9-10 is critical for hippocampal formation development and that the dynamics of leptin activity might be different in males and females. The data obtained also suggest that some but not all the previously reported effects of maternal deprivation on hippocampal formation development (which markedly reduces leptin levels at PND 9-10) might be mediated by leptin deficiency in these animals.

  12. Administration of the TrkB receptor agonist 7,8-dihydroxyflavone prevents traumatic stress-induced spatial memory deficits and changes in synaptic plasticity.

    Science.gov (United States)

    Sanz-García, Ancor; Knafo, Shira; Pereda-Pérez, Inmaculada; Esteban, José A; Venero, César; Armario, Antonio

    2016-09-01

    Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic situations and it is characterized by cognitive deficits that include impaired explicit memory. The neurobiological bases of such PTSD-associated memory alterations are yet to be elucidated and no satisfactory treatment for them exists. To address this issue, we first studied whether a single exposure of young adult rats (60 days) to immobilization on boards (IMO), a putative model of PTSD, produces long-term behavioral effects (2-8 days) similar to those found in PTSD patients. Subsequently, we investigated whether the administration of the TrkB agonist 7,8-dihydroxyflavone (DHF) 8 h after stress (therapeutic window) ameliorated the PTSD-like effect of IMO and the associated changes in synaptic plasticity. A single IMO exposure induced a spatial memory impairment similar to that found in other animal models of PTSD or in PTSD patients. IMO also increased spine density and long-term potentiation (LTP) in the CA3-CA1 pathway. Significantly, DHF reverted both spatial memory impairment and the increase in LTP, while it produced no effect in the controls. These data provide novel insights into the possible neurobiological substrate for explicit memory impairment in PTSD patients, supporting the idea that the activation of the BDNF/TrkB pathway fulfils a protective role after severe stress. Administration of DHF in the aftermath of a traumatic experience might be relevant to prevent its long-term consequences. © 2016 Wiley Periodicals, Inc.

  13. Maresin 1 Inhibits TRPV1 in Temporomandibular Joint-Related Trigeminal Nociceptive Neurons and TMJ Inflammation-Induced Synaptic Plasticity in the Trigeminal Nucleus

    Directory of Open Access Journals (Sweden)

    Chul-Kyu Park

    2015-01-01

    Full Text Available In the trigeminal system, disruption of acute resolution processing may lead to uncontrolled inflammation and chronic pain associated with the temporomandibular joint (TMJ. Currently, there are no effective treatments for TMJ pain. Recently, it has been recognized that maresin 1, a newly identified macrophage-derived mediator of inflammation resolution, is a potent analgesic for somatic inflammatory pain without noticeable side effects in mice and a potent endogenous inhibitor of transient receptor potential vanilloid 1 (TRPV1 in the somatic system. However, the molecular mechanisms underlying the analgesic actions of maresin 1 on TMJ pain are unclear in the trigeminal system. Here, by performing TMJ injection of a retrograde labeling tracer DiI (a fluorescent dye, I showed that maresin 1 potently inhibits capsaicin-induced TRPV1 currents and neuronal activity via Gαi-coupled G-protein coupled receptors in DiI-labeled trigeminal nociceptive neurons. Further, maresin 1 blocked TRPV1 agonist-evoked increases in spontaneous excitatory postsynaptic current frequency and abolished TMJ inflammation-induced synaptic plasticity in the trigeminal nucleus. These results demonstrate the potent actions of maresin 1 in regulating TRPV1 in the trigeminal system. Thus, maresin 1 may serve as a novel endogenous inhibitor for treating TMJ-inflammatory pain in the orofacial region.

  14. Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats.

    Science.gov (United States)

    Liu, Su; Liu, Yue-Peng; Huang, Zhi-Jiang; Zhang, Yan-Kai; Song, Angela A; Ma, Ping-Chuan; Song, Xue-Jun

    2015-12-01

    Treating neuropathic pain continues to be a major clinical challenge and underlying mechanisms of neuropathic pain remain elusive. We have recently demonstrated that Wnt signaling, which is important in developmental processes of the nervous systems, plays critical roles in the development of neuropathic pain through the β-catenin-dependent pathway in the spinal cord and the β-catenin-independent pathway in primary sensory neurons after nerve injury. Here, we report that Wnt signaling may contribute to neuropathic pain through the atypical Wnt/Ryk signaling pathway in rats. Sciatic nerve injury causes a rapid-onset and long-lasting expression of Wnt3a, Wnt5b, and Ryk receptors in primary sensory neurons, and dorsal horn neurons and astrocytes. Spinal blocking of the Wnt/Ryk receptor signaling inhibits the induction and persistence of neuropathic pain without affecting normal pain sensitivity and locomotor activity. Blocking activation of the Ryk receptor with anti-Ryk antibody, in vivo or in vitro, greatly suppresses nerve injury-induced increased intracellular Ca and hyperexcitability of the sensory neurons, and also the enhanced plasticity of synapses between afferent C-fibers and the dorsal horn neurons, and activation of the NR2B receptor and the subsequent Ca-dependent signals CaMKII, Src, ERK, PKCγ, and CREB in sensory neurons and the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the Wnt/Ryk signaling may be an effective approach for treating neuropathic pain.

  15. Enhanced Glutamatergic Synaptic Plasticity in the Hippocampal CA1 Field of Food-Restricted Rats: Involvement of CB1 Receptors.

    Science.gov (United States)

    Talani, Giuseppe; Licheri, Valentina; Biggio, Francesca; Locci, Valentina; Mostallino, Maria Cristina; Secci, Pietro Paolo; Melis, Valentina; Dazzi, Laura; Carta, Gianfranca; Banni, Sebastiano; Biggio, Giovanni; Sanna, Enrico

    2016-04-01

    The endogenous endocannabinoid system has a crucial role in regulating appetite and feeding behavior in mammals, as well as working memory and reward mechanisms. In order to elucidate the possible role of cannabinoid type-1 receptors (CB1Rs) in the regulation of hippocampal plasticity in animals exposed to food restriction (FR), we limited the availability of food to a 2-h daily period for 3 weeks in Sprague-Dawley rats. FR rats showed a higher long-term potentiation at hippocampal CA1 excitatory synapses with a parallel increase in glutamate release when compared with animals fed ad libitum. FR rats showed a significant increase in the long-term spatial memory determined by Barnes maze. FR was also associated with a decreased inhibitory effect of the CB1R agonist win55,212-2 on glutamatergic field excitatory postsynaptic potentials, together with a decrease in hippocampal CB1R protein expression. In addition, hippocampal brain-derived neurotrophic factor protein levels and mushroom dendritic spine density were significantly enhanced in FR rats. Altogether, our data suggest that alterations of hippocampal CB1R expression and function in FR rats are associated with dendritic spine remodeling and functional potentiation of CA1 excitatory synapses, and these findings are consistent with increasing evidence supporting the idea that FR may improve cognitive functions.

  16. Neuromodulation and Synaptic Plasticity for the Control of Fast Periodic Movement:Energy Efficiency in Coupled Compliant Joints via PCA

    Directory of Open Access Journals (Sweden)

    Philipp eStratmann

    2016-03-01

    Full Text Available There are multiple indications that the nervous system of animals tunes muscle output to exploit natural dynamics of the elastic locomotor system and the environment. This is an advantageous strategy especially in fast periodic movements, since the elastic elements store energy and increase energy efficiency and movement speed.Experimental evidence suggests that coordination among joints involves proprioceptive input and neuromodulatory influence originating in the brain stem. However, the neural strategies underlying the coordination of fast periodic movements remain poorly understood.Based on robotics control theory, we suggest that the nervous system implements a mechanism to accomplish coordination between joints by a linear coordinate transformation from the multi-dimensional space representing proprioceptive input at the joint level into a one-dimensional controller space. In this one-dimensional subspace, the movements of a whole limb can be driven by a single oscillating unit as simple as a reflex interneuron. The output of the oscillating unit is transformed back to joint space via the same transformation. The transformation weights correspond to the dominant principal component of the movement.In this study, we propose a biologically plausible neural network to exemplify that the central nervous system may encode our controller design. Using theoretical considerations and computer simulations, we demonstrate that spike-timing-dependent plasticity for the input mapping and serotonergic neuromodulation for the output mapping can extract the dominant principal component of sensory signals. Our simulations show that our network can reliably control mechanical systems of different complexity and increase the energy efficiency of ongoing cyclic movements.The proposed network is simple and consistent with previous biologic experiments. Thus, our controller could serve as a candidate to describe the neural control of fast, energy

  17. Neuromodulation and Synaptic Plasticity for the Control of Fast Periodic Movement: Energy Efficiency in Coupled Compliant Joints via PCA.

    Science.gov (United States)

    Stratmann, Philipp; Lakatos, Dominic; Albu-Schäffer, Alin

    2016-01-01

    There are multiple indications that the nervous system of animals tunes muscle output to exploit natural dynamics of the elastic locomotor system and the environment. This is an advantageous strategy especially in fast periodic movements, since the elastic elements store energy and increase energy efficiency and movement speed. Experimental evidence suggests that coordination among joints involves proprioceptive input and neuromodulatory influence originating in the brain stem. However, the neural strategies underlying the coordination of fast periodic movements remain poorly understood. Based on robotics control theory, we suggest that the nervous system implements a mechanism to accomplish coordination between joints by a linear coordinate transformation from the multi-dimensional space representing proprioceptive input at the joint level into a one-dimensional controller space. In this one-dimensional subspace, the movements of a whole limb can be driven by a single oscillating unit as simple as a reflex interneuron. The output of the oscillating unit is transformed back to joint space via the same transformation. The transformation weights correspond to the dominant principal component of the movement. In this study, we propose a biologically plausible neural network to exemplify that the central nervous system (CNS) may encode our controller design. Using theoretical considerations and computer simulations, we demonstrate that spike-timing-dependent plasticity (STDP) for the input mapping and serotonergic neuromodulation for the output mapping can extract the dominant principal component of sensory signals. Our simulations show that our network can reliably control mechanical systems of different complexity and increase the energy efficiency of ongoing cyclic movements. The proposed network is simple and consistent with previous biologic experiments. Thus, our controller could serve as a candidate to describe the neural control of fast, energy

  18. Dendritic GIRK channels gate the integration window, plateau potentials and induction of synaptic plasticity in dorsal but not ventral CA1 neurons.

    Science.gov (United States)

    Malik, Ruchi; Johnston, Daniel

    2017-03-09

    Studies comparing neuronal activity at the dorsal and ventral poles of the hippocampus have shown that the scale of spatial information increases and the precision with which space is represented declines from the dorsal to ventral end. These dorsoventral differences in neuronal output and spatial representation could arise due to differences in computations performed by dorsal and ventral CA1 neurons. In this study, we tested this hypothesis by quantifying the differences in dendritic integration and synaptic plasticity between dorsal and ventral CA1 pyramidal neurons of rat hippocampus. Using a combination of somatic and dendritic patch clamp recordings, we show that the threshold for LTP induction is higher in dorsal CA1 neurons and that a G protein-coupled inward-rectifying potassium channel (GIRK) mediated regulation of dendritic plateau potentials and dendritic excitability underlies this gating. By contrast, similar regulation of LTP is absent in ventral CA1 neurons. Additionally, we show that generation of plateau potentials and LTP induction in dorsal CA1 neurons depends on the coincident activation of Schaffer collateral and temporoammonic inputs at the distal apical dendrites. The ventral CA1 dendrites, however, can generate plateau potentials in response to temporally dispersed excitatory inputs. Overall, our results highlight the dorsoventral differences in dendritic computation that could account for the dorsoventral differences in spatial representation.SIGNIFICANCE STATEMENTThe dorsal and ventral parts of the hippocampus encode spatial information at very different scales. While the place specific firing fields are small and precise at the dorsal end of the hippocampus, neurons at the ventral end have comparatively larger place fields. Here, we show that the dorsal CA1 neurons have a higher threshold for long-term potentiation (LTP) and require coincident timing of excitatory synaptic inputs for the generation of dendritic plateau potentials. By

  19. Adolescent alcohol exposure: Burden of epigenetic reprogramming, synaptic remodeling, and adult psychopathology

    Directory of Open Access Journals (Sweden)

    Evan J Kyzar

    2016-05-01

    Full Text Available Adolescence represents a crucial phase of synaptic maturation characterized by molecular changes in the developing brain that shape normal behavioral patterns. Epigenetic mechanisms play an important role in these neuromaturation processes. Perturbations of normal epigenetic programming during adolescence by ethanol can delay these molecular events, leading to synaptic remodeling and abnormal adult behaviors. Repeated exposure to binge levels of alcohol increases the risk for alcohol use disorder (AUD and comorbid psychopathology including anxiety in adulthood. Recent studies in the field clearly suggest that adolescent alcohol exposure causes widespread and persistent changes in epigenetic, neurotrophic, and neuroimmune pathways in the brain. These changes are manifested by altered synaptic remodeling and neurogenesis in key brain regions leading to adult psychopathology such as anxiety and alcoholism. This review details the molecular mechanisms underlying adolescent alcohol exposure-induced changes in synaptic plasticity and the development of alcohol addiction-related phenotypes in adulthood.

  20. Increased Synaptic Excitation and Abnormal Dendritic Structure of Prefrontal Cortex Layer V Pyramidal Neurons following Prolonged Binge-Like Consumption of Ethanol

    Science.gov (United States)

    Klenowski, Paul M.; Fogarty, Matthew J.; Shariff, Masroor; Belmer, Arnauld

    2016-01-01

    Abstract Long-term alcohol use causes a multitude of neurochemical changes in cortical regions that facilitate the transition to dependence. Therefore, we used a model of long-term, binge-like ethanol consumption in rats to determine the effects on morphology and synaptic physiology of medial prefrontal cortex (mPFC) layer V pyramidal neurons. Following 10 weeks of ethanol consumption, we recorded synaptic currents from mPFC neurons and used neurobiotin filling to analyze their morphology. We then compared these data to measurements obtained from age-matched, water-drinking control rats. We found that long-term ethanol consumption caused a significant increase in total dendrite arbor length of mPFC layer V pyramidal neurons. Dendritic restructuring was primarily observed in basal dendrite arbors, with mPFC neurons from animals engaged in long-term ethanol drinking having significantly larger and more complex basal arbors compared with controls. These changes were accompanied by significantly increased total spine densities and spontaneous postsynaptic excitatory current frequency, suggesting that long-term binge-like ethanol consumption enhances basal excitatory synaptic transmission in mPFC layer V pyramidal neurons. Our results provide insights into the morphological and functional changes in mPFC layer V pyramidal neuronal physiology following prolonged exposure to ethanol and support changes in mPFC activity during the development of alcohol dependence. PMID:28032119

  1. Kindling-Induced Changes in Plasticity of the Rat Amygdala and Hippocampus

    Science.gov (United States)

    Schubert, Manja; Siegmund, Herbert; Pape, Hans-Christian; Albrecht, Doris

    2005-01-01

    Temporal lobe epilepsy (TLE) is often accompanied by interictal behavioral abnormalities, such as fear and memory impairment. To identify possible underlying substrates, we analyzed long-term synaptic plasticity in two relevant brain regions, the lateral amygdala (LA) and the CA1 region of the hippocampus, in the kindling model of epilepsy. Wistar…

  2. Pathological Plasticity in Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Brandon S. Martin

    2012-01-01

    Full Text Available Deficits in neuronal plasticity are common hallmarks of many neurodevelopmental disorders. In the case of fragile-X syndrome (FXS, disruption in the function of a single gene, FMR1, results in a variety of neurological consequences directly related to problems with the development, maintenance, and capacity of plastic neuronal networks. In this paper, we discuss current research illustrating the mechanisms underlying plasticity deficits in FXS. These processes include synaptic, cell intrinsic, and homeostatic mechanisms both dependent on and independent of abnormal metabotropic glutamate receptor transmission. We place particular emphasis on how identified deficits may play a role in developmental critical periods to produce neuronal networks with permanently decreased capacity to dynamically respond to changes in activity central to learning, memory, and cognition in patients with FXS. Characterizing early developmental deficits in plasticity is fundamental to develop therapies that not only treat symptoms but also minimize the developmental pathology of the disease.

  3. Neuroprotective effect of β-asarone against Alzheimer’s disease: regulation of synaptic plasticity by increased expression of SYP and GluR1

    Directory of Open Access Journals (Sweden)

    Liu SJ

    2016-04-01

    cells was detected by Western blot assay in the hippocampus and brain cortex tissues of mice.Results: β-asarone at a high dose reduced escape latency and upregulated SYP and GluR1 expression at both medium and high doses. Cell morphology evaluation showed that β-asarone treatment did not result in obvious cell surface spots and cytoplasmic granularity. β-asarone had a dose-dependent effect on cell proliferation.Conclusion: β-asarone antagonized the Aβ neurotoxicity in vivo, improved the learning and memory ability of APP/PS1 mice, and increased the expression of SYP and GluR1 both in vivo and in vitro. Thus, β-asarone may be a potential drug for the treatment of Alzheimer’s disease.Keywords: neuroprotective effect, β-asarone, synaptic plasticity, synaptophysin, glutamatergic receptor 1

  4. Transcranial magnetic stimulation provides means to assess cortical plasticity and excitability in humans with fragile X syndrome and autism spectrum disorder

    Directory of Open Access Journals (Sweden)

    Lindsay M Oberman

    2010-06-01

    Full Text Available Fragile X Syndrome (FXS is the most common heritable cause of intellectual disability. In vitro electrophysiologic data from mouse models of FXS suggest that loss of Fragile X Mental Retardation Protein (FMRP affects intracortical excitability and synaptic plasticity. Specifically, the cortex appears hyperexcitable, and use-dependent long-term potentiation (LTP and long-term depression (LTD of synaptic strength are abnormal. Though animal models provide important information, FXS and other neurodevelopmental disorders are human diseases and as such translational research to evaluate cortical excitability and plasticity must be applied in the human. Transcranial magnetic stimulation (TMS paradigms have recently been developed to noninvasively investigate cortical excitability using paired-pulse stimulation, as well as LTP- and LTD-like synaptic plasticity in response to theta burst stimulation (TBS in vivo in the human. TBS applied on consecutive days can be used to measure metaplasticity (the ability of the synapse to undergo a second plastic change following a recent induction of plasticity. The current study investigated intracortical inhibition, plasticity and metaplasticity in full mutation females with FXS, participants with autism spectrum disorders (ASD, and neurotypical controls. Results suggest that intracortical inhibition is normal in participants with FXS, while plasticity and metaplasticity appear abnormal. ASD participants showed abnormalities in plasticity and metaplasticity, as well as heterogeneity in intracortical inhibition. Our findings highlight the utility of noninvasive neurophysiological measures to translate insights from animal models to humans with neurodevelopmental disorders, and thus provide direct confirmation of cortical dysfunction in patients with FXS and ASD.

  5. Synaptic encoding of temporal contiguity

    Directory of Open Access Journals (Sweden)

    Srdjan eOstojic

    2013-04-01

    Full Text Available Often we need to perform tasks in an environment that changes stochastically. In these situations it is important to learn the statistics of sequences of events in order to predict the future and the outcome of our actions. The statistical description of many of these sequences can be reduced to the set of probabilities that a particular event follows another event (temporal contiguity. Under these conditions, it is important to encode and store in our memory these transition probabilities. Here we show that for a large class of synaptic plasticity models, the distribution of synaptic strengths encodes transitions probabilities. Specifically, when the synaptic dynamics depend on pairs of contiguous events and the synapses can remember multiple instances of the transitions, then the average synaptic weights are a monotonic function of the transition probabilities. The synaptic weights converge to the distribution encoding the probabilities also when the correlations between consecutive synaptic modifications are considered. We studied how this distribution depends on the number of synaptic states for a specific model of a multi-state synapse with hard bounds. In the case of bistable synapses, the average synaptic weights are a smooth function of the transition probabilities and the accuracy of the encoding depends on the learning rate. As the number of synaptic states increases, the average synaptic weights become a step function of the transition probabilities. We finally show that the information stored in the synaptic weights can be read out by a simple rate-based neural network. Our study shows that synapses encode transition probabilities under general assumptions and this indicates that temporal contiguity is likely to be encoded and harnessed in almost every neural circuit in the brain.

  6. 海马神经元突触可塑性在抑郁症发病机制中的研究%A systematic review of neuron synaptic plasticity in hioppocampus in the pathogenesis of depression

    Institute of Scientific and Technical Information of China (English)

    刘聪; 韩金红; 王长虹

    2015-01-01

    Objective To review the neuron synaptic plasticity in hioppocampus in the pathogenesis of depression in present studies,and expected to provide reference and basis for study of depression in clinic and model.Methods The words " depression"," antidepression"," chronic unpredictable stimulate"," hippocampus"," synapse","plasticity" were used as index words.Analysis the relationship of depression or antidepression and synaptic plasticity in hippocampus from the results of researches enrolled at home or abroad.Summarize the effect of neuron synaptic plasticity in hioppocampus in the pathogenesis of depression.Result Totally 37 articles enrolled.They show the onset of depression or antidepressant processes always combine with the damage or recover of neuron synaptic plasticity.Conclusion The reduction or damage in synaptic plasticity in hippocampus is likely to be the pathogenesis of depression,like the changes of function or expression of SYN-1,MAP-2,SYT-1,PSD-95 or any other synapse-associated proteins.Meanwhile,studies of using enrich environment to treat depression indicated that depression is likely related to the synaptic plasticity in hippocampus in another way.But who are the synapse-associated proteins related to synaptic plasticity in depression? How to design the enrich environment.? These still need further study.%目的 本文基于目前抑郁症发病机制中海马神经元突触可塑性的研究结果归纳总结,期望为抑郁症的临床和动物实验等研究提供参考和依据.方法 2014年4月在Pubmed、中国知网、万方数据知识服务平台以“抑郁”、“抗抑郁”、“丰富环境”、“慢性不可预见性刺激”、“海马”、“突触”、“可塑性”、“突触素(SYN-1)”、“微管相关蛋白-2(MAP-2)”、“突触结合蛋白-1(SYT-1)”、“突触后致密物-95(PSD-95)”等作为检索词,分析国内外相关研究结果中抑郁与海马神经元突触可塑性、抗抑郁与海马神经元突

  7. Differential alterations of synaptic plasticity in dentate gyrus and CA1 hippocampal area of Calbindin-D28K knockout mice

    NARCIS (Netherlands)

    Westerink, R.H.S.; Beekwilder, J.P.; Wadman, W.J.

    2012-01-01

    Regulation of the intracellular calcium concentration ([Ca(2+)](i)) is of critical importance for synaptic function. Therefore, neurons buffer [Ca(2+)](i) using intracellular Ca(2+)-binding proteins (CaBPs). Previous evidence suggests that Calbindin-D(28K) (CB), an abundantly expressed endogenous fa

  8. Deafferentation-Induced Plasticity of Visual Callosal Connections: Predicting Critical Periods and Analyzing Cortical Abnormalities Using Diffusion Tensor Imaging

    Directory of Open Access Journals (Sweden)

    Jaime F. Olavarria

    2012-01-01

    Full Text Available Callosal connections form elaborate patterns that bear close association with striate and extrastriate visual areas. Although it is known that retinal input is required for normal callosal development, there is little information regarding the period during which the retina is critically needed and whether this period correlates with the same developmental stage across species. Here we review the timing of this critical period, identified in rodents and ferrets by the effects that timed enucleations have on mature callosal connections, and compare it to other developmental milestones in these species. Subsequently, we compare these events to diffusion tensor imaging (DTI measurements of water diffusion anisotropy within developing cerebral cortex. We observed that the relationship between the timing of the critical period and the DTI-characterized developmental trajectory is strikingly similar in rodents and ferrets, which opens the possibility of using cortical DTI trajectories for predicting the critical period in species, such as humans, in which this period likely occurs prenatally. Last, we discuss the potential of utilizing DTI to distinguish normal from abnormal cerebral cortical development, both within the context of aberrant connectivity induced by early retinal deafferentation, and more generally as a potential tool for detecting abnormalities associated with neurodevelopmental disorders.

  9. 漆黄素逆转慢性应激鼠认知损害突触可塑性研究%Synaptic plasticity following fisetin’s reversion of cognitive impairment provoked by chronic stress in mice

    Institute of Scientific and Technical Information of China (English)

    杨仙萍; 涂传龙; 庄聪文; 石晓磊; 翁向群

    2016-01-01

    目的:探讨漆黄素逆转慢性束缚应激小鼠认知损害的突触可塑性研究。方法用 CD1小鼠建立慢性束缚应激模型,漆黄素(25 mg·kg -1·d -1)灌胃给药,漆黄素给药前30 min 双侧背侧海马微量注射 U0126(0.5μg/侧)。场电生理研究海马CA1区长时程增强(LTP)的变化,高尔基染色观察树突棘数量改变,Western blot 检测突触膜蛋白表达。结果漆黄素逆转慢性应激鼠海马 CA1区 LTP 损害,提高海马树突棘数量,ERK 特异性阻断剂 U0126阻断其效应。结论漆黄素逆转慢性应激鼠海马突触可塑性损害,可能与 ERK 通路有关。%Objective To investigate synaptic plasticity following the prevention of cognitive deficits by fisetin treatment provoked by chronic stress in mice.Methods Mice were subjected to chronic restraint stress for 21 days.Stressed mice received repeated gavage of 25 mg·kg -1 fisetin once daily for 14 consecutive days.Mice were injected with U0126(0.5 μg/side)30 min before fisetin treatment. Effects of fisetin on long-term potentiation (LTP)in mouse hippocampal slices were investigated by electrophysiological methods.The expressive levels of proteins in the hippocampus of mice were analyzed by Western blot.The spine density in mice was investigated by Golgi staining.Results Fisetin reversed hippocampal LTP in stressed mice,increased the density of dendritic spines.However,pre-treatment with U0126,a specific ERK inhibitor,blocked the restoration of synaptic plasticity by fisetin in stressed mice.Conclusions Chronic oral administration of fisetin restores synaptic plasticity in stressed mice,which may be related to ERK signaling pathway in-volved in the hippocampus.

  10. 小鼠海马CAl区高频刺激诱发的突触可塑性分析%Analysis of high-frequency stimulation-evoked synaptic plasticity in mouse hippocampal CA1 region

    Institute of Scientific and Technical Information of China (English)

    刘喜娟; 黄汾生; 黄辰; 杨章民; 冯新正

    2008-01-01

    Extracellular recordings of field excitatory postsynaptic potential (fEPSP) is one of the most common ways for studies ofsynaptic plasticity, such as long-term potentiation (LTP) and paired-pulse plasticity (PPP). The measurement of the changes in thedifferent components of fEPSP waveform, such as the initial slope, initial area, peak amplitude and whole area, were commonly usedas criteria for the judgement of potentiation or depression of synaptic plasticity. However, the differences in the conclusions drawnfrom measuring different components of fEPSP waveform at the same recording have still been largely ignored. Here we compared high-frequency stimulation (HFS)-evoked synaptic plasticity, both LTP and PPP, by measuring different components of fEPSP waveform,including the initial slope, initial area, peak amplitude, whole area and time course. The results not only indicated the acceleration of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor kinetics underlies LTP in hippocampal CAI region of mice,but also showed that different measurements of fEPSP waveform at the same recording'result in different magnitudes of LTP anddifferent forms of PPP in hippocampal CAl region of mice. After HFS, the paired-pulse ratio was slightly decreased by measurementof the initial area, but obviously increased by measurement of the initial slope of the pair fEPSPs. These results might draw apparentlycontradictory conclusions. Therefore, careful and complete analysis of the data from different parts of fEPSP waveforms is importantfor reflection of the faithful changes in synaptic plasticity.%通过细胞外记录方法记录场兴奋性突触后电位(field excitatory postsynaptic potential,fEPSP)的变化是研究突触可塑性,诸如长时程增强(long-term potentiation,LTP)和双脉冲可塑性(paired.pulse plasticity,PPP)的最常见方法之一.fEPSP波形的起始斜率、起始面积、峰值及总面积等的变化常用作判断突触可塑性增强

  11. The effect of acute swim stress and training in the water maze on hippocampal synaptic activity as well as plasticity in the dentate gyrus of freely moving rats: revisiting swim-induced LTP reinforcement.

    Science.gov (United States)

    Tabassum, Heena; Frey, Julietta U

    2013-12-01

    Hippocampal long-term potentiation (LTP) is a cellular model of learning and memory. An early form of LTP (E-LTP) can be reinforced into its late form (L-LTP) by various behavioral interactions within a specific time window ("behavioral LTP-reinforcement"). Depending on the type and procedure used, various studies have shown that stress differentially affects synaptic plasticity. Under low stress, such as novelty detection or mild foot shocks, E-LTP can be transformed into L-LTP in the rat dentate gyrus (DG). A reinforcing effect of a 2-min swim, however, has only been shown in (Korz and Frey (2003) J Neurosci 23:7281-7287; Korz and Frey (2005) J Neurosci 25:7393-7400; Ahmed et al. (2006) J Neurosci 26:3951-3958; Sajikumar et al., (2007) J Physiol 584.2:389-400) so far. We have reinvestigated these studies using the same as well as an improved recording technique which allowed the recording of field excitatory postsynaptic potentials (fEPSP) and the population spike amplitude (PSA) at their places of generation in freely moving rats. We show that acute swim stress led to a long-term depression (LTD) in baseline values of PSA and partially fEPSP. In contrast to earlier studies a LTP-reinforcement by swimming could never be reproduced. Our results indicate that 2-min swim stress influenced synaptic potentials as well as E-LTP negatively.

  12. Synaptic consolidation across multiple timescales

    Directory of Open Access Journals (Sweden)

    Lorric Ziegler

    2014-03-01

    Full Text Available The brain is bombarded with a continuous stream of sensory events, but retains only a small subset in memory. The selectivity of memory formation prevents our memory from being overloaded with irrelevant items that would rapidly bring the brain to its storage limit; moreover, selectivity also prevents overwriting previously formed memories with new ones. Memory formation in the hippocampus, as well as in other brain regions, is thought to be linked to changes in the synaptic connections between neurons. In this view, sensory events imprint traces at the level of synapses that reflect potential memory items. The question of memory selectivity can therefore be reformulated as follows: what are the reasons and conditions that some synaptic traces fade away whereas others are consolidated and persist? Experimentally, changes in synaptic strength induced by 'Hebbian' protocols fade away over a few hours (early long-term potentiation or e-LTP, unless these changes are consolidated. The experiments and conceptual theory of synaptic tagging and capture (STC provide a mechanistic explanation for the processes involved in consolidation. This theory suggests that the initial trace of synaptic plasticity sets a tag at the synapse, which then serves as a marker for potential consolidation of the changes in synaptic efficacy. The actual consolidation processes, transforming e-LTP into late LTP (l-LTP, require the capture of plasticity-related proteins (PRP. We translate the above conceptual model into a compact computational model that accounts for a wealth of in vitro data including experiments on cross-tagging, tag-resetting and depotentiation. A central ingredient is that synaptic traces are described with several variables that evolve on different time scales. Consolidation requires the transmission of information from a 'fast' synaptic trace to a 'slow' one through a 'write' process, including the formation of tags and the production of PRP for the

  13. AMPA receptor inhibition by synaptically released zinc.

    Science.gov (United States)

    Kalappa, Bopanna I; Anderson, Charles T; Goldberg, Jacob M; Lippard, Stephen J; Tzounopoulos, Thanos

    2015-12-22

    The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.

  14. 动态STDP突触系统模型设计与验证%Design and Verification of Dynamic Synaptic Modeling with Spike-time Dependent Plasticity

    Institute of Scientific and Technical Information of China (English)

    林凌鹏; 林水生; 黄乐天; 刘培龙

    2011-01-01

    神经突触的STDP(Spike Timing Dependent Plasticity)机制被认为是脑神经网络中最重要的机制之一,最有效的模拟STDP神经突触的方法是建立神经突触的离子通道的动力学模型。目前的STDP突触系统建模均存在一定的缺陷,不能很好地解释STDP机制的细胞分子生物反应原理或者得到STDP的时间非对称实验结果。提出一种新型的STDP神经突触系统模型,通过两个重要的输入信号用以验证该模型。仿真和验证结果表明,所提曲的模型不仅反应7STDP神经突触实际的生理学机理,而且还得到STDP神经突融的时阃非对称结果,%STDP (Spike Timing Dependent Plasticity) mechanism of synapses is considered to be one of the most important mechanisms of neural network, and the most effective method of emulated STDP synapse is to establishing the kinetic model of synaptic ion channels. However, most of the existing modeling of STDP synaptic mechanism have some certain defects, they either can't well explained the biomolecular reactions at a cellular level which is responsible for STDP, or acquired asymmetric STDP responses. A new modeling of STDP synaptic system was proposed. Two significant synaptic inputs were designed which were used to make the verification of the system. The simulation and verification results show that the new modeling not only reflects the actual physiological mechanism of STDP synapses, but also asymmetric STDP responses are obtained.

  15. Sensitivity of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials and synaptic plasticity to TCN 201 and TCN 213 in rat hippocampal slices.

    Science.gov (United States)

    Izumi, Yukitoshi; Zorumski, Charles F

    2015-02-01

    Whereas ifenprodil has been used as a selective GluN1/GluN2B (NR1/NR2B, B-type) receptor antagonist to distinguish between GluN2B (NR2B) and GluN2A (NR2A)-containing N-methyl-d-aspartate receptors (NMDARs), TCN 201 (3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide) and TCN 213 [N-(cyclohexylmethyl)-2-[{5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio]acetamide] have been found to be selective GluN1/GluN2A (NR1/NR2A, A-type) antagonists. Based on the premise that A- and B-types are major synaptic NMDARs, we examined whether inhibition of NMDAR excitatory postsynaptic potentials (EPSPs) by the TCN compounds and ifenprodil are complementary. Contrary to this prediction, inhibition of NMDAR EPSPs by the TCN compounds and ifenprodil were largely overlapping in the CA1 region of hippocampal slices from 30-day-old rats. After partial inhibition by ifenprodil, TCN compounds produced little further suppression of NMDAR EPSPs. Similarly, after partial inhibition by TCN compounds ifenprodil failed to further suppress NMDAR EPSPs. However, low micromolar d-2-amino-5-phosphonovalerate, a competitive NMDAR antagonist, which alone only partially inhibits NMDAR EPSPs, markedly suppresses residual NMDAR responses in the presence of ifenprodil or the TCNs, suggesting that low 2-amino-5-phosphonovalerate antagonizes both ifenprodil- and TCN-insensitive synaptic NMDARs. These observations can be most readily interpreted if ifenprodil and TCNs act on a similar population of synaptic NMDARs. Recent lines of evidence suggest that the majority of hippocampal synaptic NMDARs are triheteromers. If so, modulation of GluN2A, and not just GluN2B NMDARs, could dampen long-term depression (LTD). Indeed, both TCNs, like ifenprodil, blocked LTD, suggesting the involvement of ifenprodil- and TCN-sensitive NMDARs in LTD induction. However, the TCNs plus ifenprodil failed to inhibit long-term potentiation (LTP), suggesting that neither ifenprodil- nor TCN

  16. The Effect of Castration on the Synaptic Plasticity of HVC-RA in Adult Male Zebra Finch (Taeniopygia Guttata)%去势对成年雄性斑胸草雀HVC-RA突触可塑性的影响

    Institute of Scientific and Technical Information of China (English)

    陈小鑫; 王松华; 李东风

    2016-01-01

    应用在体电生理方法研究了去势前后成年雄性斑胸草雀发声运动通路中HVC-RA 突触的可塑性变化,进一步探讨雄激素在调节鸣唱行为中的作用和机制。结果表明:低频刺激可引起 HVC-RA突触群体峰电位幅度的短时程抑制( Short-term depression, STD),高频刺激可引起群体峰电位幅度的长时程抑制( Long-term depression, LTD)。而去势后30 d,鸣曲稳定时再给予同样的条件刺激,发现无论低频或高频刺激,HVC-RA 突触的短时程抑制和长时程抑制现象同时消失。研究结果显示:鸣曲稳定性可能依赖于HVC-RA通路的突触可塑性,雄激素在维持鸣曲稳定过程中发挥重要作用。%Songbirds are animal with the ability of vocal learning like human, and the neural basis of vocal learning is similar to the language learning of human. This study investigated the changes in synaptic plasticity of HVC-RA synapses in adult male zebra finches after castration with in vivo electrophysiology technique, analysed the potential functions and mechanisms of androgen in the process of modulating courtship song and song maintaining. The re-sults showed that low frequency stimulation induced short-term depression, high frequency stimulation induced long-term depression in HVC-RA synapses of adult male zebra finches. When the singing was stable after castration, we found that low or high frequency stimulation could not induce long-term or short-term synaptic depression. These re-sults suggested that the stability of singing may depend on HVC-RA synaptic plasticity, and androgens may play an important role in the song stability.

  17. Effect of castration on the susceptibility of male rats to the sleep deprivation-induced impairment of behavioral and synaptic plasticity.

    Science.gov (United States)

    Hajali, Vahid; Sheibani, Vahid; Ghazvini, Hamed; Ghadiri, Tahereh; Valizadeh, Toktam; Saadati, Hakimeh; Shabani, Mohammad

    2015-09-01

    In both human and animal studies, the effect of sleep deficiency on cognitive performances has mostly been studied during adulthood in males, but very little data exist concerning the effects of poor sleep in gonadal hormones-depleted status, such as aging or gonadectomized (GDX) male animal models. The present study investigated the potential modulatory effects of the endogenous male sex hormones on the 48h REM sleep deprivation (SD)-induced cognitive and synaptic impairments by comparing the gonadally intact with castrated male rats, a rodent model of androgen-deprived male animals. The multiple platform method was used for inducing REM-SD and spatial performances were evaluated using Morris water maze (MWM) task. Early long-term potentiation (E-LTP) was measured in area CA1 of the hippocampus and PCR and western blotting assays were employed to assess brain derived neurotrophic factor (BDNF) gene and protein expression in the hippocampus. To reveal any influence of sleep loss on stress level, we also evaluated the plasma corticosterone levels of animals. Regardless of reproductive status, REM-SD significantly disrupted short-term memory and LTP, as well as hippocampal BDNF expression. The corticosterone levels were not significantly changed following REM-SD neither in intact nor in GDX male rats. These findings suggest that depletion of male sex steroid hormones by castration does not lead to any heightened sensitivity of male animals to the deleterious effects of 48h REM-SD on cognitive and synaptic performances.

  18. Involvement of TrkB- and p75NTR-signaling pathways in two contrasting forms of long-lasting synaptic plasticity

    Science.gov (United States)

    Sakuragi, Shigeo; Tominaga-Yoshino, Keiko; Ogura, Akihiko

    2013-11-01

    The repetition of experience is often necessary to establish long-lasting memory. However, the cellular mechanisms underlying this repetition-dependent consolidation of memory remain unclear. We previously observed in organotypic slice cultures of the rodent hippocampus that repeated inductions of long-term potentiation (LTP) led to a slowly developing long-lasting synaptic enhancement coupled with synaptogenesis. We also reported that repeated inductions of long-term depression (LTD) produced a long-lasting synaptic suppression coupled with synapse elimination. We proposed these phenomena as useful in vitro models for analyzing repetition-dependent consolidation. Here, we hypothesized that the enhancement and suppression are mediated by the brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway and the proBDNF-p75NTR pathway, respectively. When we masked the respective pathways, reversals of the enhancement and suppression resulted. These results suggest the alternative activation of the p75NTR pathway by BDNF under TrkB-masking conditions and of the TrkB pathway by proBDNF under p75NTR-masking conditions, thus supporting the aforementioned hypothesis.

  19. Control of Abnormal Synchronization in Neurological Disorders

    Directory of Open Access Journals (Sweden)

    Oleksandr V. Popovych

    2014-12-01

    Full Text Available In the nervous system synchronization processes play an important role, e.g., in the context of information processing and motor control. However, pathological, excessive synchronization may strongly impair brain function and is a hallmark of several neurological disorders. This focused review addresses the question of how an abnormal neuronal synchronization can specifically be counteracted by invasive and non-invasive brain stimulation as, for instance, by deep brain stimulation for the treatment of Parkinson's disease, or by acoustic stimulation for the treatment of tinnitus. On the example of coordinated reset (CR neuromodulation we illustrate how insights into the dynamics of complex systems contribute to successful model-based approaches, which use methods from synergetics, nonlinear dynamics, and statistical physics, for the development of novel therapies for normalization of brain function and synaptic connectivity. Based on the intrinsic multistability of the neuronal populations induced by spike timing-dependent plasticity (STDP,CR neuromodulation utilizes the mutual interdependence between synaptic connectivity and dynamics of the neuronal networks in order to restore more physiological patterns of connectivity via desynchronization of neuronal activity. The very goal is to shift the neuronal population by stimulation from anabnormally coupled and synchronized state to a desynchronized regime with normalized synaptic connectivity, which significantly outlasts the stimulation cessation, so that long-lasting therapeutic effects can be achieved.

  20. GluN2B-containing NMDA receptors contribute to the beneficial effects of hydrogen sulfide on cognitive and synaptic plasticity deficits in APP/PS1 transgenic mice.

    Science.gov (United States)

    Yang, Yuan-Jian; Zhao, Ying; Yu, Bin; Xu, Guo-Gang; Wang, Wei; Zhan, Jin-Qiong; Tang, Zhen-Yu; Wang, Ting; Wei, Bo

    2016-10-29

    Alzheimer's disease (AD) is the most common type of clinical dementia. Previous studies have demonstrated that hydrogen sulfide (H2S) is implicated with the pathology of AD, and exogenous H2S attenuates spatial memory impairments in AD animal models. However, the molecular mechanism by which H2S improves cognition in AD has not been fully explored. Here, we report that chronic administration of sodium hydrosulfide (NaHS, a H2S donor) elevated hippocampal H2S levels and enhanced hippocampus-dependent contextual fear memory and novel object recognition in amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice. In parallel with these behavioral results, treating transgenic mice with NaHS reversed impaired hippocampal long-term potentiation (LTP), which is deemed as the neurobiological basis of learning and memory. At the molecular level, we found that treatment with NaHS did not affect the expression of the GluN1 and GluN2A subunits of NMDA receptor (NMDAR), but did prevent the downregulation of GluN2B subunit and restored its synaptic abundance, response and downstream signaling in the hippocampus in transgenic mice. Moreover, applying Ro 25-6981, a specific GluN2B antagonist, abolished the beneficial effects of NaHS on cognitive performance and hippocampal LTP in transgenic mice. Collectively, our results indicate that H2S can reverse cognitive and synaptic plasticity deficits in AD model mice by restoring surface GluN2B expression and the function of GluN2B-containing NMDARs.

  1. Synaptic vesicle pools and dynamics.

    Science.gov (United States)

    Alabi, AbdulRasheed A; Tsien, Richard W

    2012-08-01

    Synaptic vesicles release neurotransmitter at chemical synapses, thus initiating the flow of information in neural networks. To achieve this, vesicles undergo a dynamic cycle of fusion and retrieval to maintain the structural and functional integrity of the presynaptic terminals in which they reside. Moreover, compelling evidence indicates these vesicles differ in their availability for release and mobilization in response to stimuli, prompting classification into at least three different functional pools. Ongoing studies of the molecular and cellular bases for this heterogeneity attempt to link structure to physiology and clarify how regulation of vesicle pools influences synaptic strength and presynaptic plasticity. We discuss prevailing perspectives on vesicle pools, the role they play in shaping synaptic transmission, and the open questions that challenge current understanding.

  2. BRP-170 and BRP190 Isoforms of Bruchpilot Protein Differentially Contribute to the Frequency of Synapses and Synaptic Circadian Plasticity in the Visual System of Drosophila

    Directory of Open Access Journals (Sweden)

    Olga eWoznicka

    2015-06-01

    Full Text Available In the first optic neuropil (lamina of the optic lobe of Drosophila melanogaster, two classes of synapses, tetrad and feedback, show daily rhythms in the number and size of presynaptic profiles examined at the level of transmission electron microscopy (TEM. Number of tetrad presynaptic profiles increases twice a day, once in the morning and again in the evening, and their presynaptic ribbons are largest in the evening. In contrast, feedback synapses peak at night. The frequency of synapses is correlated with size of the presynaptic element measured as the platform size of so-called T-bars, with T-bar platforms being largest with increasing synapse frequency. The large scaffold protein Bruchpilot (BRP is a major essential constituent of T-bars, with two major isoforms of 190 and 170 kD forming T-bars of the peripheral NMJ synapses and in the brain. In addition to the analysis of cyclic plasticity of tetrad and feedback synapses in wild-type flies, we used TEM to examine daily changes in the size and distribution of synapses within isoform-specific BRP mutants, expressing BRP-190 (BRP170 or BRP-170 (BRP190 only. We found that the number and circadian plasticity of synapses depends on both isoforms. In the BRP190 lacking BRP-190 there was almost 50% less tetrad synapses demonstrable than when both isoforms were present. The lack of BRP-170 and BRP-190 increased and decreased, respectively the number of feedback synapses, indicating that BRP-190 forms most of the feedback synapses. In both mutants, the daily plasticity of tetrad and feedback presynaptic profiles was abolished, except for feedback synapses in BRP190. The oscillations in the number and size of presynaptic elements seem to depend on a different contribution of BRP isoforms in a presynaptic element at different time during the day and night and at various synapse types. The participation of both BRP isoforms may vary in different classes of synapses.

  3. Alteration in synaptic junction proteins following traumatic brain injury.

    Science.gov (United States)

    Merlo, Lucia; Cimino, Francesco; Angileri, Filippo Flavio; La Torre, Domenico; Conti, Alfredo; Cardali, Salvatore Massimiliano; Saija, Antonella; Germanò, Antonino

    2014-08-15

    Extensive research and scientific efforts have been focused on the elucidation of the pathobiology of cellular and axonal damage following traumatic brain injury (TBI). Conversely, few studies have specifically addressed the issue of synaptic dysfunction. Synaptic junction proteins may be involved in post-TBI alterations, leading to synaptic loss or disrupted plasticity. A Synapse Protein Database on synapse ontology identified 109 domains implicated in synaptic activities and over 5000 proteins, but few of these demonstrated to play a role in the synaptic dysfunction after TBI. These proteins are involved in neuroplasticity and neuromodulation and, most importantly, may be used as novel neuronal markers of TBI for specific intervention.

  4. Dynamic DNA methylation controls glutamate receptor trafficking and synaptic scaling.

    Science.gov (United States)

    Sweatt, J David

    2016-05-01

    Hebbian plasticity, including long-term potentiation and long-term depression, has long been regarded as important for local circuit refinement in the context of memory formation and stabilization. However, circuit development and stabilization additionally relies on non-Hebbian, homeostatic, forms of plasticity such as synaptic scaling. Synaptic scaling is induced by chronic increases or decreases in neuronal activity. Synaptic scaling is associated with cell-wide adjustments in postsynaptic receptor density, and can occur in a multiplicative manner resulting in preservation of relative synaptic strengths across the entire neuron's population of synapses. Both active DNA methylation and demethylation have been validated as crucial regulators of gene transcription during learning, and synaptic scaling is known to be transcriptionally dependent. However, it has been unclear whether homeostatic forms of plasticity such as synaptic scaling are regulated via epigenetic mechanisms. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously largely considered separately: DNA methylation, homeostatic plasticity, and glutamate receptor trafficking. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously considered separately: glutamate receptor trafficking, DNA methylation, and homeostatic plasticity.

  5. ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.

    Science.gov (United States)

    Hirata, Hiromi; Nanda, Indrajit; van Riesen, Anne; McMichael, Gai; Hu, Hao; Hambrock, Melanie; Papon, Marie-Amélie; Fischer, Ute; Marouillat, Sylviane; Ding, Can; Alirol, Servane; Bienek, Melanie; Preisler-Adams, Sabine; Grimme, Astrid; Seelow, Dominik; Webster, Richard; Haan, Eric; MacLennan, Alastair; Stenzel, Werner; Yap, Tzu Ying; Gardner, Alison; Nguyen, Lam Son; Shaw, Marie; Lebrun, Nicolas; Haas, Stefan A; Kress, Wolfram; Haaf, Thomas; Schellenberger, Elke; Chelly, Jamel; Viot, Géraldine; Shaffer, Lisa G; Rosenfeld, Jill A; Kramer, Nancy; Falk, Rena; El-Khechen, Dima; Escobar, Luis F; Hennekam, Raoul; Wieacker, Peter; Hübner, Christoph; Ropers, Hans-Hilger; Gecz, Jozef; Schuelke, Markus; Laumonnier, Frédéric; Kalscheuer, Vera M

    2013-05-02

    Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two ZC4H2 deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired α-motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that ZC4H2 point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes. Our results highlight the importance of ZC4H2 for genetic testing of individuals presenting with ID plus muscle weakness and minor or major forms of AMC.

  6. Meiotic abnormalities in infertile males.

    Science.gov (United States)

    Egozcue, J; Sarrate, Z; Codina-Pascual, M; Egozcue, S; Oliver-Bonet, M; Blanco, J; Navarro, J; Benet, J; Vidal, F

    2005-01-01

    Meiotic anomalies, as reviewed here, are synaptic chromosome abnormalities, limited to germ cells that cannot be detected through the study of the karyotype. Although the importance of synaptic errors has been underestimated for many years, their presence is related to many cases of human male infertility. Synaptic anomalies can be studied by immunostaining of synaptonemal complexes (SCs), but in this case their frequency is probably underestimated due to the phenomenon of synaptic adjustment. They can also be studied in classic meiotic preparations, which, from a clinical point of view, is still the best approach, especially if multiplex fluorescence in situ hybridization is at hand to solve difficult cases. Sperm chromosome FISH studies also provide indirect evidence of their presence. Synaptic anomalies can affect the rate of recombination of all bivalents, produce achiasmate small univalents, partially achiasmate medium-sized or large bivalents, or affect all bivalents in the cell. The frequency is variable, interindividually and intraindividually. The baseline incidence of synaptic anomalies is 6-8%, which may be increased to 17.6% in males with a severe oligozoospermia, and to 27% in normozoospermic males with one or more previous IVF failures. The clinical consequences are the production of abnormal spermatozoa that will produce a higher number of chromosomally abnormal embryos. The indications for a meiotic study in testicular biopsy are provided.

  7. Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission.

    Science.gov (United States)

    Weston, Matthew C; Chen, Hongmei; Swann, John W

    2012-08-15

    The mammalian target of rapamycin (mTOR) signaling pathway in neurons integrates a variety of extracellular signals to produce appropriate translational responses. mTOR signaling is hyperactive in neurological syndromes in both humans and mouse models that are characterized by epilepsy, autism, and cognitive disturbances. In addition, rapamycin, a clinically important immunosuppressant, is a specific and potent inhibitor of mTOR signaling. While mTOR is known to regulate growth and synaptic plasticity of glutamatergic neurons, its effects on basic parameters of synaptic transmission are less well studied, and its role in regulating GABAergic transmission is unexplored. We therefore performed an electrophysiological and morphological comparison of glutamatergic and GABAergic neurons in which mTOR signaling was either increased by loss of the repressor Pten or decreased by treatment with rapamycin. We found that hyperactive mTOR signaling increased evoked synaptic responses in both glutamatergic and GABAergic neurons by ∼50%, due to an increase in the number of synaptic vesicles available for release, the number of synapses formed, and the miniature event size. Prolonged (72 h) rapamycin treatment prevented these abnormalities and also decreased synaptic transmission in wild-type glutamatergic, but not GABAergic, neurons. Further analyses suggested that hyperactivation of the mTOR pathway also impairs presynaptic function, possibly by interfering with vesicle fusion. Despite this presynaptic impairment, the net effect of Pten loss is enhanced synaptic transmission in both GABAergic and glutamatergic neurons, which has numerous implications, depending on where in the brain mutations of an mTOR suppressor gene occur.

  8. 基于神经元突触可塑性机制图像边缘检测方法%Image edge detection method based on synaptic plasticity mechanism

    Institute of Scientific and Technical Information of China (English)

    方芳; 范影乐; 廖进文; 张梦楠

    2015-01-01

    To extract the image edge information effectively,a new method of image edge detection based on spike time dependent plasticity (STDP)and other visual mechanism was proposed.Firstly, the color opponent-process characteristic was realized by image intensity and chromaticity coding mechanism.Secondly,Log-Gabor filter was adopted to realize the orientation selectivity of visual sys-tem.Then,a neuronal population network with the characteristic of STDP was proposed,which used the relevance of the asynchronous pulse spiking between neurons and visual contour to strengthen the edge information.Finally,spiking times were recorded for the first spiking time decoding to obtain the edge information.Taking the micrograph for example,the result shows the new method is effec-tive in extracting edge information distinctly and completely and can retain more small details,which proposes a new way for synaptic plasticity to be applied into image processing.%针对图像边缘信息的有效提取问题,提出了基于脉冲时间相关突触可塑性(STDP)机制的边缘检测新方法。首先通过亮度和色度编码实现颜色拮抗特性;利用 Log-Gabor 滤波器提取符合人类视觉特性的特定方向图像信息;接着建立了一种具有突触 STDP 特性的神经元网络模型,利用神经元之间非同步放电与视觉轮廓的关联性强化边缘信息;最后通过首次放电时间解码获取边缘信息。以微生物显微图像为例进行实验研究,结果表明:所提方法获取的图像边缘信息清晰完整,并且保留了更多的微弱细节;为突触可塑性机制在图像处理中的应用提供新思路。

  9. Short term synaptic depression imposes a frequency dependent filter on synaptic information transfer.

    Science.gov (United States)

    Rosenbaum, Robert; Rubin, Jonathan; Doiron, Brent

    2012-01-01

    Depletion of synaptic neurotransmitter vesicles induces a form of short term depression in synapses throughout the nervous system. This plasticity affects how synapses filter presynaptic spike trains. The filtering properties of short term depression are often studied using a deterministic synapse model that predicts the mean synaptic response to a presynaptic spike train, but ignores variability introduced by the probabilistic nature of vesicle release and stochasticity in synaptic recovery time. We show that this additional variability has important consequences for the synaptic filtering of presynaptic information. In particular, a synapse model with stochastic vesicle dynamics suppresses information encoded at lower frequencies more than information encoded at higher frequencies, while a model that ignores this stochasticity transfers information encoded at any frequency equally well. This distinction between the two models persists even when large numbers of synaptic contacts are considered. Our study provides strong evidence that the stochastic nature neurotransmitter vesicle dynamics must be considered when analyzing the information flow across a synapse.

  10. Plastic Bronchitis.

    Science.gov (United States)

    Rubin, Bruce K

    2016-09-01

    Plastic bronchitis is an uncommon and probably underrecognized disorder, diagnosed by the expectoration or bronchoscopic removal of firm, cohesive, branching casts. It should not be confused with purulent mucous plugging of the airway as seen in patients with cystic fibrosis or bronchiectasis. Few medications have been shown to be effective and some are now recognized as potentially harmful. Current research directions in plastic bronchitis research include understanding the genetics of lymphatic development and maldevelopment, determining how abnormal lymphatic malformations contribute to cast formation, and developing new treatments.

  11. Meiotic abnormalities and spermatogenic parameters in severe oligoasthenozoospermia.

    Science.gov (United States)

    Vendrell, J M; García, F; Veiga, A; Calderón, G; Egozcue, S; Egozcue, J; Barri, P N

    1999-02-01

    The incidence of meiotic abnormalities and their relationship with different spermatogenic parameters was assessed in 103 male patients with presumably idiopathic severe oligoasthenozoospermia (motile sperm concentration Meiotic patterns included normal meiosis and two meiotic abnormalities, i.e. severe arrest and synaptic anomalies. A normal pattern was found in 64 (62.1%), severe arrest in 21 (20.4%) and synaptic anomalies in 18 (17.5%). The overall rate of meiotic abnormalities was 37.9%. Most (66.7%) meiotic abnormalities occurred in patients with a sperm concentration meiotic abnormalities were found in 57.8% of the patients; of these, 26.7% had synaptic anomalies. When the sperm concentration was meiotic abnormalities occurred in 54.8% (synaptic anomalies in 22.6%). There were statistically significant differences among the three meiotic patterns in relation to sperm concentration (P 10 IU/l were the only predictors of meiotic abnormalities.

  12. Theory of Synaptic Plasticity in Visual Cortex.

    Science.gov (United States)

    1992-12-23

    1977), found, using intracellular recording, that geniculo- cortical synapses on inhibitory interneurons are more resistant to monocular deprivation...the CAI population EPSP that persisted without signs of recovery for > 1 hour following cessation of the conditioning stimulation. This long-term

  13. Nicotinic Receptor Activity Alters Synaptic Plasticity

    Directory of Open Access Journals (Sweden)

    John A. Dani

    2001-01-01

    Full Text Available Studies using specific agonists, antagonists, and lesions have shown that nicotinic cholinergic systems participate in attention, learning, and memory[1,2]. The nicotinic manipulations usually have the greatest influence on difficult tasks or on cognitively impaired subjects[2]. For example, Alzheimer's disease is characterized by a loss of cholinergic projections and nicotinic acetylcholine receptors (nAChRs in the cortex and hippocampus[3]. Nicotine skin patches can improve learning rates and attention in Alzheimer's patients[4].

  14. Bursting and synaptic plasticity in neuronal networks

    NARCIS (Netherlands)

    Stegenga, Jan

    2010-01-01

    Networks of neonatal cortical neurons, cultured on multi electrode arrays (MEAs) exhibit spontaneous action potential firings. The electrodes embedded in the glass surface of a MEA can be used to record and stimulate activity at 60 sites in a network of ~50.000 neurons. Such in-vitro networks enable

  15. 侧脑室注射氯胺酮降低成年SD大鼠海马区突触可塑性%Effect of ketamine injected into cerebro ventriles on synaptic plasticity of hippocampus in adult SD rats

    Institute of Scientific and Technical Information of China (English)

    郭东勇; 谭涛; 田心; 王国林

    2012-01-01

    Objective: To observe the effect of ketamine of intracerebroventricular injection to adult SD rats on LTP of hippocampus. Methods: 12 adult SD rats were randomly divided into group C and C-I. LTP was recorded after NS or ketamine(50μg) 5μL were injected into cerebro ventriles respectively. Results: 30 min after stimulation, PS amplitude in group C and C—I were (216.29±12.11)% and (138.04±6.50)% (P<0.05). 60 min after stimulation, PS amplitude were (202.33±11.53)% and (149.60±10.86)%(P<0.05). LTP in group C-I reduced obviously. Conclusion: Ketamine of intracerebroventricular injection reduces synaptic plasticity of hippocampus in adult SD rats.%目的:研究侧脑室注射氯胺酮对成年SD大鼠在体海马区长时程增强(LTP)的影响.方法:成年SD大鼠12只,随机分为实验组(C-1组)和对照组(C组),前者经右侧脑室注射50μg氯胺酮(生理盐水稀释至5μL),后者注射等量生理盐水后,记录在体海马区LTP.结果:高频刺激后30min时,C组和C-1组分别为条件刺激PS幅值的(216.29±12.11)%和(138.04±6.50)%(P<0.05);刺激后60min时,分别为(202.33±11.53)%和(149.60±10.86)%(P<0.05),C-1组LTP突触可塑性改变程度较对照组显著降低.结论:侧脑室注射氯胺酮可显著降低成年大鼠海马区突触可塑性.

  16. Regulation of NMDA-receptor synaptic transmission by Wnt signaling

    Science.gov (United States)

    Cerpa, Waldo; Gambrill, Abigail; Inestrosa, Nibaldo C.; Barria, Andres

    2011-01-01

    Wnt ligands are secreted glycoproteins controlling gene expression and cytoskeleton reorganization involved in embryonic development of the nervous system. However, their role in later stages of brain development, particularly in the regulation of established synaptic connections is not known. We found that Wnt-5a acutely and specifically up-regulates synaptic NMDAR currents in rat hippocampal slices facilitating induction of LTP, a cellular model of learning and memory. This effect requires an increase in postsynaptic Ca2+ and activation of non-canonical downstream effectors of the Wnt signaling pathway. In contrast, Wnt-7a, an activator of the canonical Wnt signaling pathway, has no effect on NMDAR mediated synaptic transmission. Moreover, endogenous Wnt ligands are necessary to maintain basal NMDAR synaptic transmission adjusting the threshold for synaptic potentiation. This novel role for Wnt ligands provides a mechanism for Wnt signaling to acutely modulate synaptic plasticity and brain function in later stages of development and in the mature organism. PMID:21715611

  17. Synaptic vesicle endocytosis.

    Science.gov (United States)

    Saheki, Yasunori; De Camilli, Pietro

    2012-09-01

    Neurons can sustain high rates of synaptic transmission without exhausting their supply of synaptic vesicles. This property relies on a highly efficient local endocytic recycling of synaptic vesicle membranes, which can be reused for hundreds, possibly thousands, of exo-endocytic cycles. Morphological, physiological, molecular, and genetic studies over the last four decades have provided insight into the membrane traffic reactions that govern this recycling and its regulation. These studies have shown that synaptic vesicle endocytosis capitalizes on fundamental and general endocytic mechanisms but also involves neuron-specific adaptations of such mechanisms. Thus, investigations of these processes have advanced not only the field of synaptic transmission but also, more generally, the field of endocytosis. This article summarizes current information on synaptic vesicle endocytosis with an emphasis on the underlying molecular mechanisms and with a special focus on clathrin-mediated endocytosis, the predominant pathway of synaptic vesicle protein internalization.

  18. Adult myelination:wrapping up neuronal plasticity

    Institute of Scientific and Technical Information of China (English)

    Megan ORourke; Robert Gasperini; Kaylene M.Young

    2014-01-01

    In this review, we outline the major neural plasticity mechanisms that have been identiifed in the adult central nervous system (CNS), and offer a perspective on how they regulate CNS function. In particular we examine how myelin plasticity can operate alongside neurogenesis and synaptic plasticity to inlfuence information processing and transfer in the mature CNS.

  19. Spindle Activity Orchestrates Plasticity during Development and Sleep

    Directory of Open Access Journals (Sweden)

    Christoph Lindemann

    2016-01-01

    Full Text Available Spindle oscillations have been described during early brain development and in the adult brain. Besides similarities in temporal patterns and involved brain areas, neonatal spindle bursts (NSBs and adult sleep spindles (ASSs show differences in their occurrence, spatial distribution, and underlying mechanisms. While NSBs have been proposed to coordinate the refinement of the maturating neuronal network, ASSs are associated with the implementation of acquired information within existing networks. Along with these functional differences, separate synaptic plasticity mechanisms seem to be recruited. Here, we review the generation of spindle oscillations in the developing and adult brain and discuss possible implications of their differences for synaptic plasticity. The first part of the review is dedicated to the generation and function of ASSs with a particular focus on their role in healthy and impaired neuronal networks. The second part overviews the present knowledge of spindle activity during development and the ability of NSBs to organize immature circuits. Studies linking abnormal maturation of brain wiring with neurological and neuropsychiatric disorders highlight the importance to better elucidate neonatal plasticity rules in future research.

  20. Extracellular ATP hydrolysis inhibits synaptic transmission by increasing ph buffering in the synaptic cleft.

    Directory of Open Access Journals (Sweden)

    Rozan Vroman

    2014-05-01

    Full Text Available Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (τ≈200 ms, highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca²⁺ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form

  1. Visual Cortex Plasticity Following Peripheral Damage To The Visual System: fMRI Evidence.

    Science.gov (United States)

    Lemos, João; Pereira, Daniela; Castelo-Branco, Miguel

    2016-10-01

    Over the last two decades, functional magnetic resonance imaging (fMRI) has become a powerful research method to investigate cortical visual plasticity. Abnormal fMRI response patterns have been occasionally detected in the visually deprived cortex of patients with bilateral retinal diseases. Controversy remains whether these observations indicate structural reorganization of the visual cortex or unmasking of previously silent cortico-cortical connections. In optic nerve diseases, there is weak evidence showing that early visual cortex seems to lack reorganization, while higher-order visual areas undergo plastic changes which may contribute to optimise visual function. There is however accumulating imaging evidence demonstrating trans-synaptic degeneration of the visual cortex in patients with disease of the anterior visual pathways. This may preclude the use of restorative treatments in these patients. Here, we review and update the body of fMRI evidence on visual cortical plasticity.

  2. Growth hormone rescues hippocampal synaptic function after sleep deprivation

    OpenAIRE

    Kim, EunYoung; Grover, Lawrence M; Bertolotti, Don; Green, Todd L.

    2010-01-01

    Sleep is required for, and sleep loss impairs, normal hippocampal synaptic N-methyl-d-aspartate (NMDA) glutamate receptor function and expression, hippocampal NMDA receptor-dependent synaptic plasticity, and hippocampal-dependent memory function. Although sleep is essential, the signals linking sleep to hippocampal function are not known. One potential signal is growth hormone. Growth hormone is released during sleep, and its release is suppressed during sleep deprivation. If growth hormone l...

  3. Synaptic connectivity in engineered neuronal networks.

    Science.gov (United States)

    Molnar, Peter; Kang, Jung-Fong; Bhargava, Neelima; Das, Mainak; Hickman, James J

    2014-01-01

    We have developed a method to organize cells in dissociated cultures using engineered chemical clues on a culture surface and determined their connectivity patterns. Although almost all elements of the synaptic transmission machinery can be studied separately in single cell models in dissociated cultures, the complex physiological interactions between these elements are usually lost. Thus, factors affecting synaptic transmission are generally studied in organotypic cultures, brain slices, or in vivo where the cellular architecture generally remains intact. However, by utilizing engineered neuronal networks complex phenomenon such as synaptic transmission or synaptic plasticity can be studied in a simple, functional, cell culture-based system. We have utilized self-assembled monolayers and photolithography to create the surface templates. Embryonic hippocampal cells, plated on the resultant patterns in serum-free medium, followed the surface clues and formed the engineered neuronal networks. Basic whole-cell patch-clamp electrophysiology was applied to characterize the synaptic connectivity in these engineered two-cell networks. The same technology has been used to pattern other cell types such as cardiomyocytes or skeletal muscle fibers.

  4. Progress in neural plasticity

    Institute of Scientific and Technical Information of China (English)

    POO; Mu-Ming

    2010-01-01

    One of the properties of the nervous system is the use-dependent plasticity of neural circuits.The structure and function of neural circuits are susceptible to changes induced by prior neuronal activity,as reflected by short-and long-term modifications of synaptic efficacy and neuronal excitability.Regarded as the most attractive cellular mechanism underlying higher cognitive functions such as learning and memory,activity-dependent synaptic plasticity has been in the spotlight of modern neuroscience since 1973 when activity-induced long-term potentiation(LTP) of hippocampal synapses was first discovered.Over the last 10 years,Chinese neuroscientists have made notable contributions to the study of the cellular and molecular mechanisms of synaptic plasticity,as well as of the plasticity beyond synapses,including activity-dependent changes in intrinsic neuronal excitability,dendritic integration functions,neuron-glia signaling,and neural network activity.This work highlight some of these significant findings.

  5. Abnormal fear conditioning and amygdala processing in an animal model of autism

    DEFF Research Database (Denmark)

    Markram, Kamila; Rinaldi, Tania; La Mendola, Deborah

    2008-01-01

    A core feature of autism spectrum disorders is the impairment in social interactions. Among other brain regions, a deficit in amygdala processing has been suggested to underlie this impairment, but whether the amygdala is processing fear abnormally in autism, is yet not clear. We used the valproic......-treated animals displayed several symptoms common to autism, among them impaired social interactions and increased repetitive behaviors. Furthermore, VPA-treated rats were more anxious and exhibited abnormally high and longer lasting fear memories, which were overgeneralized and harder to extinguish....... On the cellular level, the amygdala was hyperreactive to electrical stimulation and displayed boosted synaptic plasticity as well as a deficit in inhibition. We show for the first time enhanced, overgeneralized and resistant conditioned fear memories in an animal model of autism. Such hyperfear could be caused...

  6. The Spacing Principle for Unlearning Abnormal Neuronal Synchrony

    OpenAIRE

    Popovych, Oleksandr V.; Markos N Xenakis; Tass, Peter A.

    2015-01-01

    Desynchronizing stimulation techniques were developed to specifically counteract abnormal neuronal synchronization relevant to several neurological and psychiatric disorders. The goal of our approach is to achieve an anti-kindling, where the affected neural networks unlearn abnormal synaptic connectivity and, hence, abnormal neuronal synchrony, by means of desynchronizing stimulation, in particular, Coordinated Reset (CR) stimulation. As known from neuroscience, psychology and education, lear...

  7. Basic mechanisms for recognition and transport of synaptic cargos

    Directory of Open Access Journals (Sweden)

    Schlager Max A

    2009-08-01

    Full Text Available Abstract Synaptic cargo trafficking is essential for synapse formation, function and plasticity. In order to transport synaptic cargo, such as synaptic vesicle precursors, mitochondria, neurotransmitter receptors and signaling proteins to their site of action, neurons make use of molecular motor proteins. These motors operate on the microtubule and actin cytoskeleton and are highly regulated so that different cargos can be transported to distinct synaptic specializations at both pre- and post-synaptic sites. How synaptic cargos achieve specificity, directionality and timing of transport is a developing area of investigation. Recent studies demonstrate that the docking of motors to their cargos is a key control point. Moreover, precise spatial and temporal regulation of motor-cargo interactions is important for transport specificity and cargo recruitment. Local signaling pathways – Ca2+ influx, CaMKII signaling and Rab GTPase activity – regulate motor activity and cargo release at synaptic locations. We discuss here how different motors recognize their synaptic cargo and how motor-cargo interactions are regulated by neuronal activity.

  8. Brain region specific pre-synaptic and post-synaptic degeneration are early components of neuropathology in prion disease.

    Directory of Open Access Journals (Sweden)

    Zuzana Šišková

    Full Text Available Synaptic abnormalities, one of the key features of prion disease pathogenesis, gives rise to functional deficits and contributes to the devastating clinical outcome. The synaptic compartment is the first to succumb in several neurodegenerative diseases linked with protein misfolding but the mechanisms underpinning this are poorly defined. In our current study we document that a focal intrahippocampal injection of the mouse-adapted 22L scrapie strain produces a complex, region-specific pathology in the brain. Our findings reveal that early synaptic changes in the stratum radiatum of the hippocampus, identical to those observed with the ME7 strain, occur when 22L strain is introduced into the hippocampus. The pathology was defined by degenerating Type I pre-synaptic elements progressively enveloped by the post-synaptic density of the dendritic spine. In contrast, the pathology in the cerebellum suggested that dendritic disintegration rather than pre-synaptic abnormalities dominate the early degenerative changes associated with the Purkinje cells. Indeed, both of the major synaptic inputs into the cerebellum, which arise from the parallel and climbing fibers, remained intact even at late stage disease. Immunolabeling with pathway selective antibodies reinforced these findings. These observations demonstrate that neuronal vulnerability to pathological protein misfolding is strongly dependent on the structure and function of the target neurons.

  9. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses

    OpenAIRE

    Hartmann, Matthias; Heumann, Rolf; Lessmann, Volkmar

    2001-01-01

    The protein brain-derived neurotrophic factor (BDNF) has been postulated to be a retrograde or paracrine synaptic messenger in long-term potentiation and other forms of activity-dependent synaptic plasticity. Although crucial for this concept, direct evidence for the activity-dependent synaptic release of BDNF is lacking. Here we investigate secretion of BDNF labelled with green fluorescent protein (BDNF–GFP) by monitoring the changes in fluorescence intensity of dendritic BDNF–GFP vesicles a...

  10. Absence of PTHrP nuclear localization and carboxyl terminus sequences leads to abnormal brain development and function.

    Directory of Open Access Journals (Sweden)

    Zhen Gu

    Full Text Available We assessed whether the nuclear localization sequences (NLS and C terminus of parathyroid hormone-related protein (PTHrP play critical roles in brain development and function. We used histology, immunohistochemistry, histomorphometry, Western blots and electrophysiological recordings to compare the proliferation and differentiation of neural stem cells, neuronal hippocampal synaptic transmission, and brain phenotypes including shape and structures, in Pthrp knock-in mice, which express PTHrP (1-84, a truncated form of the protein that is missing the NLS and the C-terminal region of the protein, and their wild-type littermates. Results showed that Pthrp knock-in mice display abnormal brain shape and structures; decreased neural cell proliferative capacity and increased apoptosis associated with up-regulation of cyclin dependent kinase inhibitors p16, p21, p27 and p53 and down-regulation of the Bmi-1 oncogene; delayed neural cell differentiation; and impaired hippocampal synaptic transmission and plasticity. These findings provide in vivo experimental evidence that the NLS and C-terminus of PTHrP are essential not only for the regulation of neural cell proliferation and differentiation, but also for the maintenance of normal neuronal synaptic transmission and plasticity.

  11. cAMP Signals in Drosophila Motor Neurons Are Confined to Single Synaptic Boutons

    Directory of Open Access Journals (Sweden)

    Isabella Maiellaro

    2016-10-01

    Full Text Available The second messenger cyclic AMP (cAMP plays an important role in synaptic plasticity. Although there is evidence for local control of synaptic transmission and plasticity, it is less clear whether a similar spatial confinement of cAMP signaling exists. Here, we suggest a possible biophysical basis for the site-specific regulation of synaptic plasticity by cAMP, a highly diffusible small molecule that transforms the physiology of synapses in a local and specific manner. By exploiting the octopaminergic system of Drosophila, which mediates structural synaptic plasticity via a cAMP-dependent pathway, we demonstrate the existence of local cAMP signaling compartments of micrometer dimensions within single motor neurons. In addition, we provide evidence that heterogeneous octopamine receptor localization, coupled with local differences in phosphodiesterase activity, underlies the observed differences in cAMP signaling in the axon, cell body, and boutons.

  12. Meiotic abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  13. Astrocyte-Synapse Structural Plasticity

    Directory of Open Access Journals (Sweden)

    Yann Bernardinelli

    2014-01-01

    Full Text Available The function and efficacy of synaptic transmission are determined not only by the composition and activity of pre- and postsynaptic components but also by the environment in which a synapse is embedded. Glial cells constitute an important part of this environment and participate in several aspects of synaptic functions. Among the glial cell family, the roles played by astrocytes at the synaptic level are particularly important, ranging from the trophic support to the fine-tuning of transmission. Astrocytic structures are frequently observed in close association with glutamatergic synapses, providing a morphological entity for bidirectional interactions with synapses. Experimental evidence indicates that astrocytes sense neuronal activity by elevating their intracellular calcium in response to neurotransmitters and may communicate with neurons. The precise role of astrocytes in regulating synaptic properties, function, and plasticity remains however a subject of intense debate and many aspects of their interactions with neurons remain to be investigated. A particularly intriguing aspect is their ability to rapidly restructure their processes and modify their coverage of the synaptic elements. The present review summarizes some of these findings with a particular focus on the mechanisms driving this form of structural plasticity and its possible impact on synaptic structure and function.

  14. Targeting synaptic dysfunction in Alzheimer's disease therapy.

    Science.gov (United States)

    Nisticò, Robert; Pignatelli, Marco; Piccinin, Sonia; Mercuri, Nicola B; Collingridge, Graham

    2012-12-01

    In the past years, major efforts have been made to understand the genetics and molecular pathogenesis of Alzheimer's disease (AD), which has been translated into extensive experimental approaches aimed at slowing down or halting disease progression. Advances in transgenic (Tg) technologies allowed the engineering of different mouse models of AD recapitulating a range of AD-like features. These Tg models provided excellent opportunities to analyze the bases for the temporal evolution of the disease. Several lines of evidence point to synaptic dysfunction as a cause of AD and that synapse loss is a pathological correlate associated with cognitive decline. Therefore, the phenotypic characterization of these animals has included electrophysiological studies to analyze hippocampal synaptic transmission and long-term potentiation, a widely recognized cellular model for learning and memory. Transgenic mice, along with non-Tg models derived mainly from exogenous application of Aβ, have also been useful experimental tools to test the various therapeutic approaches. As a result, numerous pharmacological interventions have been reported to attenuate synaptic dysfunction and improve behavior in the different AD models. To date, however, very few of these findings have resulted in target validation or successful translation into disease-modifying compounds in humans. Here, we will briefly review the synaptic alterations across the different animal models and we will recapitulate the pharmacological strategies aimed at rescuing hippocampal plasticity phenotypes. Finally, we will highlight intrinsic limitations in the use of experimental systems and related challenges in translating preclinical studies into human clinical trials.

  15. The interplay between neuronal activity and actin dynamics mimic the setting of an LTD synaptic tag

    OpenAIRE

    Szabó, Eszter C.; Manguinhas, Rita; Fonseca, Rosalina

    2016-01-01

    Persistent forms of plasticity, such as long-term depression (LTD), are dependent on the interplay between activity-dependent synaptic tags and the capture of plasticity-related proteins. We propose that the synaptic tag represents a structural alteration that turns synapses permissive to change. We found that modulation of actin dynamics has different roles in the induction and maintenance of LTD. Inhibition of either actin depolymerisation or polymerization blocks LTD induction whereas only...

  16. A trans-synaptic nanocolumn aligns neurotransmitter release to receptors.

    Science.gov (United States)

    Tang, Ai-Hui; Chen, Haiwen; Li, Tuo P; Metzbower, Sarah R; MacGillavry, Harold D; Blanpied, Thomas A

    2016-08-11

    Synaptic transmission is maintained by a delicate, sub-synaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity and pathological disorders. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresponds to the position of receptors in the postsynaptic density. However, while it has long been recognized that this spatial relationship modulates synaptic strength, it has not been precisely described, owing in part to the limited resolution of light microscopy. Using localization microscopy, here we show that key proteins mediating vesicle priming and fusion are mutually co-enriched within nanometre-scale subregions of the presynaptic active zone. Through development of a new method to map vesicle fusion positions within single synapses in cultured rat hippocampal neurons, we find that action-potential-evoked fusion is guided by this protein gradient and occurs preferentially in confined areas with higher local density of Rab3-interacting molecule (RIM) within the active zones. These presynaptic RIM nanoclusters closely align with concentrated postsynaptic receptors and scaffolding proteins, suggesting the existence of a trans-synaptic molecular 'nanocolumn'. Thus, we propose that the nanoarchitecture of the active zone directs action-potential-evoked vesicle fusion to occur preferentially at sites directly opposing postsynaptic receptor-scaffold ensembles. Remarkably, NMDA receptor activation triggered distinct phases of plasticity in which postsynaptic reorganization was followed by trans-synaptic nanoscale realignment. This architecture suggests a simple organizational principle of central nervous system synapses to maintain and modulate synaptic efficiency.

  17. Short term synaptic depression imposes a frequency dependent filter on synaptic information transfer.

    Directory of Open Access Journals (Sweden)

    Robert Rosenbaum

    Full Text Available Depletion of synaptic neurotransmitter vesicles induces a form of short term depression in synapses throughout the nervous system. This plasticity affects how synapses filter presynaptic spike trains. The filtering properties of short term depression are often studied using a deterministic synapse model that predicts the mean synaptic response to a presynaptic spike train, but ignores variability introduced by the probabilistic nature of vesicle release and stochasticity in synaptic recovery time. We show that this additional variability has important consequences for the synaptic filtering of presynaptic information. In particular, a synapse model with stochastic vesicle dynamics suppresses information encoded at lower frequencies more than information encoded at higher frequencies, while a model that ignores this stochasticity transfers information encoded at any frequency equally well. This distinction between the two models persists even when large numbers of synaptic contacts are considered. Our study provides strong evidence that the stochastic nature neurotransmitter vesicle dynamics must be considered when analyzing the information flow across a synapse.

  18. Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex.

    Science.gov (United States)

    Pinto, Joshua G A; Jones, David G; Williams, C Kate; Murphy, Kathryn M

    2015-01-01

    Although many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin) and found that synaptic development in human primary visual cortex (V1) continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of