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Sample records for synaptic regulation current

  1. Circadian Regulation of Synaptic Plasticity

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    Marcos G. Frank

    2016-07-01

    Full Text Available Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity.

  2. Klotho regulates CA1 hippocampal synaptic plasticity.

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    Li, Qin; Vo, Hai T; Wang, Jing; Fox-Quick, Stephanie; Dobrunz, Lynn E; King, Gwendalyn D

    2017-04-07

    Global klotho overexpression extends lifespan while global klotho-deficiency shortens it. As well, klotho protein manipulations inversely regulate cognitive function. Mice without klotho develop rapid onset cognitive impairment before they are 2months old. Meanwhile, adult mice overexpressing klotho show enhanced cognitive function, particularly in hippocampal-dependent tasks. The cognitive enhancing effects of klotho extend to humans with a klotho polymorphism that increases circulating klotho and executive function. To affect cognitive function, klotho could act in or on the synapse to modulate synaptic transmission or plasticity. However, it is not yet known if klotho is located at synapses, and little is known about its effects on synaptic function. To test this, we fractionated hippocampi and detected klotho expression in both pre and post-synaptic compartments. We find that loss of klotho enhances both pre and post-synaptic measures of CA1 hippocampal synaptic plasticity at 5weeks of age. However, a rapid loss of synaptic enhancement occurs such that by 7weeks, when mice are cognitively impaired, there is no difference from wild-type controls. Klotho overexpressing mice show no early life effects on synaptic plasticity, but decreased CA1 hippocampal long-term potentiation was measured at 6months of age. Together these data suggest that klotho affects cognition, at least in part, by regulating hippocampal synaptic plasticity. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Lateral regulation of synaptic transmission by astrocytes.

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    Covelo, A; Araque, A

    2016-05-26

    Fifteen years ago the concept of the "tripartite synapse" was proposed to conceptualize the functional view that astrocytes are integral elements of synapses. The signaling exchange between astrocytes and neurons within the tripartite synapse results in the synaptic regulation of synaptic transmission and plasticity through an autocrine form of communication. However, recent evidence indicates that the astrocyte synaptic regulation is not restricted to the active tripartite synapse but can be manifested through astrocyte signaling at synapses relatively distant from active synapses, a process termed lateral astrocyte synaptic regulation. This phenomenon resembles the classical heterosynaptic modulation but is mechanistically different because it involves astrocytes and its properties critically depend on the morphological and functional features of astrocytes. Therefore, the functional concept of the tripartite synapse as a fundamental unit must be expanded to include the interaction between tripartite synapses. Through lateral synaptic regulation, astrocytes serve as an active processing bridge for synaptic interaction and crosstalk between synapses with no direct neuronal connectivity, supporting the idea that neural network function results from the coordinated activity of astrocytes and neurons. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Synaptic regulation of the light-dependent oscillatory currents in starburst amacrine cells of the mouse retina.

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    Petit-Jacques, Jerome; Bloomfield, Stewart A

    2008-08-01

    Responses of on-center starburst amacrine cells to steady light stimuli were recorded in the dark-adapted mouse retina. The response to spots of dim white light appear to show two components, an initial peak that correspond to the onset of the light stimulus and a series of oscillations that ride on top of the initial peak relaxation. The frequency of oscillations during light stimulation was three time higher than the frequency of spontaneous oscillations recorded in the dark. The light-evoked responses in starburst cells were exclusively dependent on the release of glutamate likely from presynaptic bipolar axon terminals and the binding of glutamate to AMPA/kainate receptors because they were blocked by 6-cyano-7-nitroquinoxalene-2,3-dione. The synaptic pathway responsible for the light responses was blocked by AP4, an agonist of metabotropic glutamate receptors that hyperpolarize on-center bipolar cells on activation. Light responses were inhibited by the calcium channel blockers cadmium ions and nifedipine, suggesting that the release of glutamate was calcium dependent. The oscillatory component of the response was specifically inhibited by blocking the glutamate transporter with d-threo-beta-benzyloxyaspartic acid, suggesting that glutamate reuptake is necessary for the oscillatory release. GABAergic antagonists bicuculline, SR 95531, and picrotoxin increased the amplitude of the initial peak while they inhibit the frequency of oscillations. TTX had a similar effect. Strychnine, the blocker of glycine receptors did not affect the initial peak but strongly decreased the oscillations frequency. These inhibitory inputs onto the bipolar axon terminals shape and synchronize the oscillatory component.

  5. Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity

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    Shin, Hyewon; van Riesen, Christoph; Whitcomb, Daniel; Warburton, Julia M.; Jo, Jihoon; Kim, Doyoun; Kim, Sun Gyun; Um, Seung Min; Kwon, Seok-kyu; Kim, Myoung-Hwan; Roh, Junyeop Daniel; Woo, Jooyeon; Jun, Heejung; Lee, Dongmin; Mah, Won; Kim, Hyun; Kaang, Bong-Kiun; Cho, Kwangwook; Rhee, Jeong-Seop; Choquet, Daniel; Kim, Eunjoon

    2016-01-01

    Summary Synaptic adhesion molecules regulate synapse development and plasticity through mechanisms including trans-synaptic adhesion and recruitment of diverse synaptic proteins. We report here that the immunoglobulin superfamily member 11 (IgSF11), a homophilic adhesion molecule preferentially expressed in the brain, is a novel and dual-binding partner of the postsynaptic scaffolding protein PSD-95 and AMPAR glutamate receptors (AMPARs). IgSF11 requires PSD-95 binding for its excitatory synaptic localization. In addition, IgSF11 stabilizes synaptic AMPARs, as shown by IgSF11 knockdown-induced suppression of AMPAR-mediated synaptic transmission and increased surface mobility of AMPARs, measured by high-throughput, single-molecule tracking. IgSF11 deletion in mice leads to suppression of AMPAR-mediated synaptic transmission in the dentate gyrus and long-term potentiation in the CA1 region of the hippocampus. IgSF11 does not regulate the functional characteristics of AMPARs, including desensitization, deactivation, or recovery. These results suggest that IgSF11 regulates excitatory synaptic transmission and plasticity through its tripartite interactions with PSD-95 and AMPARs. PMID:26595655

  6. Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis.

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    Arendt, Kristin L; Zhang, Zhenjie; Ganesan, Subhashree; Hintze, Maik; Shin, Maggie M; Tang, Yitai; Cho, Ahryon; Graef, Isabella A; Chen, Lu

    2015-10-20

    Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca(2+) levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca(2+)-levels to RA synthesis remains unknown. Here we identify the Ca(2+)-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca(2+)-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.

  7. Ubiquitination-dependent mechanisms regulate synaptic growth and function.

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    DiAntonio, A; Haghighi, A P; Portman, S L; Lee, J D; Amaranto, A M; Goodman, C S

    2001-07-26

    The covalent attachment of ubiquitin to cellular proteins is a powerful mechanism for controlling protein activity and localization. Ubiquitination is a reversible modification promoted by ubiquitin ligases and antagonized by deubiquitinating proteases. Ubiquitin-dependent mechanisms regulate many important processes including cell-cycle progression, apoptosis and transcriptional regulation. Here we show that ubiquitin-dependent mechanisms regulate synaptic development at the Drosophila neuromuscular junction (NMJ). Neuronal overexpression of the deubiquitinating protease fat facets leads to a profound disruption of synaptic growth control; there is a large increase in the number of synaptic boutons, an elaboration of the synaptic branching pattern, and a disruption of synaptic function. Antagonizing the ubiquitination pathway in neurons by expression of the yeast deubiquitinating protease UBP2 (ref. 5) also produces synaptic overgrowth and dysfunction. Genetic interactions between fat facets and highwire, a negative regulator of synaptic growth that has structural homology to a family of ubiquitin ligases, suggest that synaptic development may be controlled by the balance between positive and negative regulators of ubiquitination.

  8. Differential regulation of synaptic AP-2/clathrin vesicle uncoating in synaptic plasticity.

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    Candiello, Ermes; Mishra, Ratnakar; Schmidt, Bernhard; Jahn, Olaf; Schu, Peter

    2017-11-17

    AP-1/σ1B-deficiency causes X-linked intellectual disability. AP-1/σ1B -/- mice have impaired synaptic vesicle recycling, fewer synaptic vesicles and enhanced endosome maturation mediated by AP-1/σ1A. Despite defects in synaptic vesicle recycling synapses contain two times more endocytic AP-2 clathrin-coated vesicles. We demonstrate increased formation of two classes of AP-2/clathrin coated vesicles. One which uncoats readily and a second with a stabilised clathrin coat. Coat stabilisation is mediated by three molecular mechanisms: reduced recruitment of Hsc70 and synaptojanin1 and enhanced μ2/AP-2 phosphorylation and activation. Stabilised AP-2 vesicles are enriched in the structural active zone proteins Git1 and stonin2 and synapses contain more Git1. Endocytosis of the synaptic vesicle exocytosis regulating Munc13 isoforms are differentially effected. Regulation of synaptic protein endocytosis by the differential stability of AP-2/clathrin coats is a novel molecular mechanism of synaptic plasticity.

  9. Synaptically evoked glutamate transporter currents in Spinal Dorsal Horn Astrocytes

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    Dougherty Patrick M

    2009-07-01

    Full Text Available Abstract Background Removing and sequestering synaptically released glutamate from the extracellular space is carried out by specific plasma membrane transporters that are primarily located in astrocytes. Glial glutamate transporter function can be monitored by recording the currents that are produced by co-transportation of Na+ ions with the uptake of glutamate. The goal of this study was to characterize glutamate transporter function in astrocytes of the spinal cord dorsal horn in real time by recording synaptically evoked glutamate transporter currents. Results Whole-cell patch clamp recordings were obtained from astrocytes in the spinal substantia gelatinosa (SG area in spinal slices of young adult rats. Glutamate transporter currents were evoked in these cells by electrical stimulation at the spinal dorsal root entry zone in the presence of bicuculline, strychnine, DNQX and D-AP5. Transporter currents were abolished when synaptic transmission was blocked by TTX or Cd2+. Pharmacological studies identified two subtypes of glutamate transporters in spinal astrocytes, GLAST and GLT-1. Glutamate transporter currents were graded with stimulus intensity, reaching peak responses at 4 to 5 times activation threshold, but were reduced following low-frequency (0.1 – 1 Hz repetitive stimulation. Conclusion These results suggest that glutamate transporters of spinal astrocytes could be activated by synaptic activation, and recording glutamate transporter currents may provide a means of examining the real time physiological responses of glial cells in spinal sensory processing, sensitization, hyperalgesia and chronic pain.

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

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    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.

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

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    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 Ca(2+) 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.

  12. Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity.

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    Gerber, Kyle J; Squires, Katherine E; Hepler, John R

    2016-02-01

    The regulator of G protein signaling (RGS) family of proteins serves critical roles in G protein-coupled receptor (GPCR) and heterotrimeric G protein signal transduction. RGS proteins are best understood as negative regulators of GPCR/G protein signaling. They achieve this by acting as GTPase activating proteins (GAPs) for Gα subunits and accelerating the turnoff of G protein signaling. Many RGS proteins also bind additional signaling partners that either regulate their functions or enable them to regulate other important signaling events. At neuronal synapses, GPCRs, G proteins, and RGS proteins work in coordination to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity, which are necessary for central nervous system physiology and behavior. Accumulating evidence has revealed key roles for specific RGS proteins in multiple signaling pathways at neuronal synapses, regulating both pre- and postsynaptic signaling events and synaptic plasticity. Here, we review and highlight the current knowledge of specific RGS proteins (RGS2, RGS4, RGS7, RGS9-2, and RGS14) that have been clearly demonstrated to serve critical roles in modulating synaptic signaling and plasticity throughout the brain, and we consider their potential as future therapeutic targets. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  13. Calcium current homeostasis and synaptic deficits in hippocampal neurons from Kelch-like 1 knockout mice

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    Paula Patricia Perissinotti

    2015-01-01

    Full Text Available Kelch-like 1 (KLHL1 is a neuronal actin-binding protein that modulates voltage-gated CaV2.1 (P/Q-type and CaV3.2 (α1H T-type calcium channels; KLHL1 knockdown experiments (KD cause down-regulation of both channel types and altered synaptic properties in cultured rat hippocampal neurons (Perissinotti et al., 2014. Here, we studied the effect of ablation of KLHL1 on calcium channel function and synaptic properties in cultured hippocampal neurons from KLHL1 knockout (KO mice. Western blot data showed the P/Q-type channel α1A subunit was less abundant in KO hippocampus compared to wildtype (WT; and PQ-type calcium currents were smaller in KO neurons than WT during early days in vitro, although this decrease was compensated for at late stages by increases in L-type calcium current. In contrast, T-type currents did not change in culture. However, biophysical properties and western blot analysis revealed a differential contribution of T-type channel isoforms in the KO, with CaV3.2 α1H subunit being down-regulated and CaV3.1 α1G up-regulated. Synapsin I levels were reduced in the KO hippocampus; cultured neurons displayed a concomitant reduction in synapsin I puncta and decreased miniature excitatory postsynaptic current (mEPSC frequency. In summary, genetic ablation of the calcium channel modulator resulted in compensatory mechanisms to maintain calcium current homeostasis in hippocampal KO neurons; however, synaptic alterations resulted in a reduction of excitatory synapse number, causing an imbalance of the excitatory-inhibitory synaptic input ratio favoring inhibition.

  14. Synaptic activity regulates AMPA receptor trafficking through different recycling pathways

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    Zheng, Ning; Jeyifous, Okunola; Munro, Charlotte; Montgomery, Johanna M; Green, William N

    2015-01-01

    Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. In this study, we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites. DOI: http://dx.doi.org/10.7554/eLife.06878.001 PMID:25970033

  15. Inter-Synaptic Lateral Diffusion of GABAA Receptors Shapes Inhibitory Synaptic Currents.

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    de Luca, Emanuela; Ravasenga, Tiziana; Petrini, Enrica Maria; Polenghi, Alice; Nieus, Thierry; Guazzi, Stefania; Barberis, Andrea

    2017-07-05

    The lateral mobility of neurotransmitter receptors has been shown to tune synaptic signals. Here we report that GABAA receptors (GABAARs) can diffuse between adjacent dendritic GABAergic synapses in long-living desensitized states, thus laterally spreading "activation memories" between inhibitory synapses. Glutamatergic activity limits this inter-synaptic diffusion by trapping GABAARs at excitatory synapses. This novel form of activity-dependent hetero-synaptic interplay is likely to modulate dendritic synaptic signaling. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  16. F42. CHONDROTIN-6 SULFATE CLUSTERS: ASSOCIATION OF SYNAPTIC DOMAINS AND REGULATION OF SYNAPTIC PLASTICITY DURING FEAR LEARNING

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    Chelini, Gabriele; Berciu, Cristina; Pilobello, Kanoelani; Peter, Durning; Rachel, Jenkins; Kahn, Moazzzam; Ramikie, Teniel; Subramanian, Siva; Ressler, Kerry; Pantazopoulos, Charalampos; Berretta, Sabina

    2018-01-01

    Abstract Background Emerging evidence from our group and others has brought the brain extracellular matrix (ECM) to the forefront of investigations on brain disorders. Our group has shown that organized perisynaptic ECM aggregates, i.e. perineuronal nets (PNNs) are decreased in several brain regions in people with schizophrenia (SZ) and bipolar disorder (BD). PNNs were detected by their expression of specific chondroitin sulfate proteoglycans (CSPGs), main components of the ECM, thought to play a key role in synaptic regulation during development and adulthood. Our studies have also shown that glial cells expressing CSPGs are altered in these disorders, suggesting a link between glial cell and PNN abnormalities. Finally, we have recently shown that novel CSPG structures, bearing a distinct CS-6 sulfation pattern and named CS-6 glial clusters, are decreased in the amygdala of people with SZ and BD. The morphology and function of CS-6 glial clusters is not currently known, but evidence from rodents and on the role of CSPGs in regulating synaptic functions strongly suggest that they may affect synaptic plasticity. We tested this hypothesis using a combination of human postmortem and rodent brain studies. Methods High Resolution electron microscopy was used to investigate the ultrastructural organization of CS-6 glia clusters. A transgenic mouse model expressing green fluorescent protein in a subset of excitatory pyramidal neurons was used to investigate dendritic spines association with CS-6 glia clusters. Mice were exposed to a single session of auditory fear conditioning for a total of 15 minutes. Animals were euthanized 4 hours after behavioral test. Multiplex immunocytochemistry was used to visualize CS-6 clusters. Results In human tissue, we show that CS-6 glia clusters are widespread in several brain regions, including the amygdala, entorhinal cortex, thalamus and hippocampus. Ultrastructural results show that CS-6 glia clusters are formed by CS-6 accumulations

  17. Transcriptional and post-translational regulation of Arc in synaptic plasticity.

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    Carmichael, Ruth E; Henley, Jeremy M

    2017-09-07

    One of the most interesting features of Arc-dependent synaptic plasticity is how multiple types of synaptic activity can converge to alter Arc transcription and then diverge to induce different plasticity outcomes, ranging from AMPA receptor internalisation that promotes long-term depression (LTD), to actin stabilisation that promotes long-term potentiation (LTP). This diversity suggests that there must be numerous levels of control to ensure the temporal profile, abundance, localisation and function of Arc are appropriately regulated to effect learning and memory in the correct contexts. The activity-dependent transcription and post-translational modification of Arc are crucial regulators of synaptic plasticity, fine-tuning the function of this key protein depending on the specific situation. The extensive cross-talk between signalling pathways and the numerous routes of Arc regulation provide a complex interplay of processes in which Arc-mediated plasticity can be broadly induced, but specifically tailored to synaptic activity. Here we provide an overview what is currently known about these processes and potential future directions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Evolution of the aging brain transcriptome and synaptic regulation.

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    Patrick M Loerch

    Full Text Available Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4. However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.

  19. Miniature excitatory synaptic currents in cultured hippocampal neurons.

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    Finch, D M; Fisher, R S; Jackson, M B

    1990-06-04

    We performed patch clamp recordings in the whole cell mode from cultured embryonic mouse hippocampal neurons. In bathing solutions containing tetrodotoxin (TTX), the cells showed spontaneous inward currents (SICs) ranging in size from 1 to 100 pA. Several observations indicated that the SICs were miniature excitatory synaptic currents mediated primarily by non-NMDA (N-methyl-D-aspartate) excitatory amino acid receptors: the rising phase of SICs was fast (1 ms to half amplitude at room temperature) and smooth, suggesting unitary events. The SICs were blocked by the broad-spectrum glutamate receptor antagonist gamma-D-glutamylglycine (DGG), but not by the selective NMDA-receptor antagonist D-2-amino-5-phosphonovaleric acid (5-APV). SICs were also blocked by desensitizing concentrations of quisqualate. Incubating cells in tetanus toxin, which blocks exocytotic transmitter release, eliminated SICs. The presence of SICs was consistent with the morphological arrangement of glutamatergic innervation in the cell cultures demonstrated immunohistochemically. Spontaneous outward currents (SOCs) were blocked by bicuculline and presumed to be mediated by GABAA receptors. This is consistent with immunohistochemical demonstration of GABAergic synapses. SIC frequency was increased in a calcium dependent manner by bathing the cells in a solution high in K+, and application of the dihydropyridine L-type calcium channel agonist BAY K 8644 increased the frequency of SICs. Increases in SIC frequency produced by high K+ solutions were reversed by Cd2+ and omega-conotoxin GVIA, but not by the selective L-type channel antagonist nimodipine. This suggested that presynaptic L-type channels were in a gating mode that was not blocked by nimodipine, and/or that another class of calcium channel makes a dominant contribution to excitatory transmitter release.

  20. On the estimation of population-specific synaptic currents from laminar multielectrode recordings

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    Sergey L Gratiy

    2011-12-01

    Full Text Available Multielectrode array recordings of extracellular electrical field potentials along the depth axis of the cerebral cortex is an up-and-coming approach for investigating activity of cortical neuronal circuits. The low-frequency band of extracellular potential, i.e., the local field potential (LFP, is assumed to reflect the synaptic activity and can be used to extract the current source density (CSD profile. However, physiological interpretation of CSD profiles is uncertain because the analysis does not disambiguate synaptic inputs from passive return currents. Here we present a novel mathematical framework for identifying excited neuronal populations and for separating synaptic input currents from return currents based on LFP recordings. This involves a combination of the linear forward model, which predicts population-specific laminar LFP in response to sinusoidal synaptic inputs applied at different locations along the population cells having realistic morphologies and the linear inverse model, which reconstructs laminar profiles of synaptic inputs from the Fourier spectrum of the laminar LFP data based on the forward prediction. The model allows reconstruction of synaptic input profiles on a spatial scale comparable to known anatomical organization of synaptic projections within a cortical column. Assuming spatial correlation of synaptic inputs within individual populations, the model decomposes the columnar LFP into population-specific contributions. Constraining the solution with a priori knowledge of the spatial distribution of synaptic connectivity further allows prediction of active projections from the composite LFP profile. This modeling framework successfully delineates the main relationships between the synaptic input currents and the evoked LFP and can serve as a foundation for modeling more realistic processing of active dendritic conductances.

  1. The role of sleep in regulating structural plasticity and synaptic strength: Implications for memory and cognitive function.

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    Raven, Frank; Van der Zee, Eddy A; Meerlo, Peter; Havekes, Robbert

    2017-05-18

    Dendritic spines are the major sites of synaptic transmission in the central nervous system. Alterations in the strength of synaptic connections directly affect the neuronal communication, which is crucial for brain function as well as the processing and storage of information. Sleep and sleep loss bidirectionally alter structural plasticity, by affecting spine numbers and morphology, which ultimately can affect the functional output of the brain in terms of alertness, cognition, and mood. Experimental data from studies in rodents suggest that sleep deprivation may impact structural plasticity in different ways. One of the current views, referred to as the synaptic homeostasis hypothesis, suggests that wake promotes synaptic potentiation whereas sleep facilitates synaptic downscaling. On the other hand, several studies have now shown that sleep deprivation can reduce spine density and attenuate synaptic efficacy in the hippocampus. These data are the basis for the view that sleep promotes hippocampal structural plasticity critical for memory formation. Altogether, the impact of sleep and sleep loss may vary between regions of the brain. A better understanding of the role that sleep plays in regulating structural plasticity may ultimately lead to novel therapeutic approaches for brain disorders that are accompanied by sleep disturbances and sleep loss. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. PRRT2: from Paroxysmal Disorders to Regulation of Synaptic Function.

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    Valtorta, Flavia; Benfenati, Fabio; Zara, Federico; Meldolesi, Jacopo

    2016-10-01

    In the past few years, proline-rich transmembrane protein (PRRT)2 has been identified as the causative gene for several paroxysmal neurological disorders. Recently, an important role of PRRT2 in synapse development and function has emerged. Knock down of the protein strongly impairs the formation of synaptic contacts and neurotransmitter release. At the nerve terminal, PRRT2 endows synaptic vesicle exocytosis with Ca 2+ sensitivity by interacting with proteins of the fusion complex and with the Ca 2+ sensors synaptotagmins (Syts). In the postsynaptic compartment, PRRT2 interacts with glutamate receptors. The study of PRRT2 and of its mutations may help in refining our knowledge of the process of synaptic transmission and elucidating the pathogenetic mechanisms leading to derangement of network function in paroxysmal disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. The Histone H3K27 Demethylase UTX Regulates Synaptic Plasticity and Cognitive Behaviors in Mice

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    Gang-Bin Tang

    2017-08-01

    Full Text Available Histone demethylase UTX mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3 to establish a mechanistic switch to activate large sets of genes. Mutation of Utx has recently been shown to be associated with Kabuki syndrome, a rare congenital anomaly syndrome with dementia. However, its biological function in the brain is largely unknown. Here, we observe that deletion of Utx results in increased anxiety-like behaviors and impaired spatial learning and memory in mice. Loss of Utx in the hippocampus leads to reduced long-term potentiation and amplitude of miniature excitatory postsynaptic current, aberrant dendrite development and defective synapse formation. Transcriptional profiling reveals that Utx regulates a subset of genes that are involved in the regulation of dendritic morphology, synaptic transmission, and cognition. Specifically, Utx deletion disrupts expression of neurotransmitter 5-hydroxytryptamine receptor 5B (Htr5b. Restoration of Htr5b expression in newborn hippocampal neurons rescues the defects of neuronal morphology by Utx ablation. Therefore, we provide evidence that Utx plays a critical role in modulating synaptic transmission and cognitive behaviors. Utx cKO mouse models like ours provide a valuable means to study the underlying mechanisms of the etiology of Kabuki syndrome.

  4. Differential regulation of spontaneous and evoked inhibitory synaptic transmission in somatosensory cortex by retinoic acid.

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    Yee, Ada X; Chen, Lu

    2016-11-01

    Retinoic acid (RA), a developmental morphogen, has emerged in recent studies as a novel synaptic signaling molecule that acts in mature hippocampal neurons to modulate excitatory and inhibitory synaptic transmission in the context of homeostatic synaptic plasticity. However, it is unclear whether RA is capable of modulating neural circuits outside of the hippocampus, and if so, whether the mode of RA's action at synapses is similar to that within the hippocampal network. Here we explore for the first time RA's synaptic function outside the hippocampus and uncover a novel function of all-trans retinoic acid at inhibitory synapses. Acute RA treatment increases spontaneous inhibitory synaptic transmission in L2/3 pyramidal neurons of the somatosensory cortex, and this effect requires expression of RA's receptor RARα both pre- and post-synaptically. Intriguingly, RA does not seem to affect evoked inhibitory transmission assayed with either extracellular stimulation or direct activation of action potentials in presynaptic interneurons at connected pairs of interneurons and pyramidal neurons. Taken together, these results suggest that RA's action at synapses is not monotonous, but is diverse depending on the type of synaptic connection (excitatory versus inhibitory) and circuit (hippocampal versus cortical). Thus, synaptic signaling of RA may mediate multi-faceted regulation of synaptic plasticity. In addition to its classic roles in brain development, retinoic acid (RA) has recently been shown to regulate excitatory and inhibitory transmission in the adult brain. Here, the authors show that in layer 2/3 (L2/3) of the somatosensory cortex (S1), acute RA induces increases in spontaneous but not action-potential evoked transmission, and that this requires retinoic acid receptor (RARα) both in presynaptic PV-positive interneurons and postsynaptic pyramidal (PN) neurons. © 2016 Wiley Periodicals, Inc.

  5. Cholinergic synaptic vesicle heterogeneity: evidence for regulation of acetylcholine transport

    International Nuclear Information System (INIS)

    Gracz, L.M.; Wang, W.; Parsons, S.M.

    1988-01-01

    Crude cholinergic synaptic vesicles from a homogenate of the electric organ of Torpedo californica were centrifuged to equilibrium in an isosmotic sucrose density gradient. The classical VP 1 synaptic vesicles banding at 1.055 g/mL actively transported [ 3 H]acetylcholine (AcCh). An organelle banding at about 1.071 g/mL transported even more [ 3 H]AcCh. Transport by both organelles was inhibited by the known AcCh storage blockers trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol, formerly AH5183) and nigericin. Relative to VP 1 vesicles the denser organelle was slightly smaller as shown by size-exclusion chromatography. It is concluded that the denser organelle corresponds to the recycling VP 2 synaptic vesicle originally described in intact Torpedo marmorata electric organ. The properties of the receptor for vesamicol were studied by measuring binding of [ 3 H]vesamicol, and the amount of SV2 antigen characteristic of secretory vesicles was assayed with a monoclonal antibody directed against it. Relative to VP 1 vesicles the VP 2 vesicles had a ratio of [ 3 H]AcCh transport activity to vesamicol receptor concentration that typically was 4-7-fold higher, whereas the ratio of SV2 antigen concentration to vesamicol receptor concentration was about 2-fold higher. The Hill coefficients α/sub H/ and equilibrium dissociation constants K for vesamicol binding to VP 1 and VP 2 vesicles were essentially the same. The positive Hill coefficient suggests that the vesamicol receptor exists as a homotropic oligomeric complex. The results demonstrate that VP 1 and VP 2 synaptic vesicles exhibit functional differences in the AcCh transport system, presumably as a result of regulatory phenomena

  6. Degeneracy in the regulation of short-term plasticity and synaptic filtering by presynaptic mechanisms.

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    Mukunda, Chinmayee L; Narayanan, Rishikesh

    2017-04-15

    We develop a new biophysically rooted, physiologically constrained conductance-based synaptic model to mechanistically account for short-term facilitation and depression, respectively through residual calcium and transmitter depletion kinetics. We address the specific question of how presynaptic components (including voltage-gated ion channels, pumps, buffers and release-handling mechanisms) and interactions among them define synaptic filtering and short-term plasticity profiles. Employing global sensitivity analyses (GSAs), we show that near-identical synaptic filters and short-term plasticity profiles could emerge from disparate presynaptic parametric combinations with weak pairwise correlations. Using virtual knockout models, a technique to address the question of channel-specific contributions within the GSA framework, we unveil the differential and variable impact of each ion channel on synaptic physiology. Our conclusions strengthen the argument that parametric and interactional complexity in biological systems should not be viewed from the limited curse-of-dimensionality standpoint, but from the evolutionarily advantageous perspective of providing functional robustness through degeneracy. Information processing in neurons is known to emerge as a gestalt of pre- and post-synaptic filtering. However, the impact of presynaptic mechanisms on synaptic filters has not been quantitatively assessed. Here, we developed a biophysically rooted, conductance-based model synapse that was endowed with six different voltage-gated ion channels, calcium pumps, calcium buffer and neurotransmitter-replenishment mechanisms in the presynaptic terminal. We tuned our model to match the short-term plasticity profile and band-pass structure of Schaffer collateral synapses, and performed sensitivity analyses to demonstrate that presynaptic voltage-gated ion channels regulated synaptic filters through changes in excitability and associated calcium influx. These sensitivity analyses

  7. Cortactin Is a Regulator of Activity-Dependent Synaptic Plasticity Controlled by Wingless.

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    Alicea, Daniel; Perez, Marizabeth; Maldonado, Carolina; Dominicci-Cotto, Carihann; Marie, Bruno

    2017-02-22

    Major signaling molecules initially characterized as key early developmental regulators are also essential for the plasticity of the nervous system. Previously, the Wingless (Wg)/Wnt pathway was shown to underlie the structural and electrophysiological changes during activity-dependent synaptic plasticity at the Drosophila neuromuscular junction. A challenge remains to understand how this signal mediates the cellular changes underlying this plasticity. Here, we focus on the actin regulator Cortactin, a major organizer of protrusion, membrane mobility, and invasiveness, and define its new role in synaptic plasticity. We show that Cortactin is present presynaptically and postsynaptically at the Drosophila NMJ and that it is a presynaptic regulator of rapid activity-dependent modifications in synaptic structure. Furthermore, animals lacking presynaptic Cortactin show a decrease in spontaneous release frequency, and presynaptic Cortactin is necessary for the rapid potentiation of spontaneous release frequency that takes place during activity-dependent plasticity. Most interestingly, Cortactin levels increase at stimulated synaptic terminals and this increase requires neuronal activity, de novo transcription and depends on Wg/Wnt expression. Because it is not simply the presence of Cortactin in the presynaptic terminal but its increase that is necessary for the full range of activity-dependent plasticity, we conclude that it probably plays a direct and important role in the regulation of this process. SIGNIFICANCE STATEMENT In the nervous system, changes in activity that lead to modifications in synaptic structure and function are referred to as synaptic plasticity and are thought to be the basis of learning and memory. The secreted Wingless/Wnt molecule is a potent regulator of synaptic plasticity in both vertebrates and invertebrates. Understanding the molecular mechanisms that underlie these plastic changes is a major gap in our knowledge. Here, we identify a

  8. Opposing Synaptic Regulation of Amyloid-β Metabolism by NMDA Receptors In Vivo

    Science.gov (United States)

    Verges, Deborah K.; Restivo, Jessica L.; Goebel, Whitney D.; Holtzman, David M.; Cirrito, John R.

    2012-01-01

    The concentration of amyloid-β (Aβ) within the brain extracellular space is one determinant of whether the peptide will aggregate into toxic species that are important in Alzheimer’s disease (AD) pathogenesis. Some types of synaptic activity can regulate Aβ levels. Here we demonstrate two distinct mechanisms that are simultaneously activated by NMDA receptors and regulate brain interstitial fluid (ISF) Aβ levels in opposite directions in the living mouse. Depending on the dose of NMDA administered locally to the brain, ISF Aβ levels either increase or decrease. Low doses of NMDA increase action potentials and synaptic transmission which leads to an elevation in synaptic Aβ generation. In contrast, high doses of NMDA activate signaling pathways that lead to ERK (extracellular-regulated kinase) activation, which reduces processing of APP into Aβ. This depression in Aβ via APP processing occurs despite dramatically elevated synaptic activity. Both of these synaptic mechanisms are simultaneously active, with the balance between them determining whether ISF Aβ levels will increase or decrease. NMDA receptor antagonists increase ISF Aβ levels, suggesting that basal activity at these receptors normally suppresses Aβ levels in vivo. This has implications for understanding normal Aβ metabolism as well as AD pathogenesis. PMID:21813692

  9. KV7 Channels Regulate Firing during Synaptic Integration in GABAergic Striatal Neurons

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    M. Belén Pérez-Ramírez

    2015-01-01

    Full Text Available Striatal projection neurons (SPNs process motor and cognitive information. Their activity is affected by Parkinson’s disease, in which dopamine concentration is decreased and acetylcholine concentration is increased. Acetylcholine activates muscarinic receptors in SPNs. Its main source is the cholinergic interneuron that responds with a briefer latency than SPNs during a cortical command. Therefore, an important question is whether muscarinic G-protein coupled receptors and their signaling cascades are fast enough to intervene during synaptic responses to regulate synaptic integration and firing. One of the most known voltage dependent channels regulated by muscarinic receptors is the KV7/KCNQ channel. It is not known whether these channels regulate the integration of suprathreshold corticostriatal responses. Here, we study the impact of cholinergic muscarinic modulation on the synaptic response of SPNs by regulating KV7 channels. We found that KV7 channels regulate corticostriatal synaptic integration and that this modulation occurs in the dendritic/spines compartment. In contrast, it is negligible in the somatic compartment. This modulation occurs on sub- and suprathreshold responses and lasts during the whole duration of the responses, hundreds of milliseconds, greatly altering SPNs firing properties. This modulation affected the behavior of the striatal microcircuit.

  10. SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks.

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    Chih-Chieh Wang

    Full Text Available Disrupting the balance between excitatory and inhibitory neurotransmission in the developing brain has been causally linked with intellectual disability (ID and autism spectrum disorders (ASD. Excitatory synapse strength is regulated in the central nervous system by controlling the number of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs. De novo genetic mutations of the synaptic GTPase-activating protein (SynGAP are associated with ID and ASD. SynGAP is enriched at excitatory synapses and genetic suppression of SynGAP increases excitatory synaptic strength. However, exactly how SynGAP acts to maintain synaptic AMPAR content is unclear. We show here that SynGAP limits excitatory synaptic strength, in part, by suppressing protein synthesis in cortical neurons. The data presented here from in vitro, rat and mouse cortical networks, demonstrate that regulation of translation by SynGAP involves ERK, mTOR, and the small GTP-binding protein Rheb. Furthermore, these data show that GluN2B-containing NMDARs and the cognitive kinase CaMKII act upstream of SynGAP and that this signaling cascade is required for proper translation-dependent homeostatic synaptic plasticity of excitatory synapses in developing cortical networks.

  11. Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila

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    Samuel H. Friedman

    2013-11-01

    Fragile X syndrome (FXS, the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1 gene product (FMRP, an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1 null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs: GPI-anchored glypican Dally-like protein (Dlp and transmembrane Syndecan (Sdc. Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg ligand abundance and downstream Frizzled-2 (Fz2 receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb, and downstream ERK phosphorylation (dpERK are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb and downstream signaling via phosphorylation of the transcription factor MAD (pMAD seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1 Wg and Jeb trans-synaptic signaling, and (2 synaptic architecture and transmission strength back to wild-type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS disease state.

  12. Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens.

    Science.gov (United States)

    Ishikawa, Masago; Otaka, Mami; Neumann, Peter A; Wang, Zhijian; Cook, James M; Schlüter, Oliver M; Dong, Yan; Huang, Yanhua H

    2013-10-01

    Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway, a neural circuit that mediates behavioural responses elicited by natural rewards as well as by cocaine and other drugs of abuse. In addition to the well-known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, directly regulating NAc medium spiny neurons (MSNs). However, the cellular nature of VTA-to-NAc fast synaptic transmission and its roles in drug-induced adaptations are not well understood. Using viral-mediated in vivo expression of channelrhodopsin 2, the present study dissected fast excitatory and inhibitory synaptic transmission from the VTA to NAc MSNs in rats. Our results suggest that, following repeated exposure to cocaine (15 mg kg(-1) day(-1) × 5 days, i.p., 1 or 21 day withdrawal), a presynaptic enhancement of excitatory transmission and suppression of inhibitory transmission occurred at different withdrawal time points at VTA-to-NAc core synapses. In contrast, no postsynaptic alterations were detected at either type of synapse. These results suggest that changes in VTA-to-NAc fast excitatory and inhibitory synaptic transmissions may contribute to cocaine-induced alteration of the brain reward circuitry.

  13. A Novel Egr-1-Agrin Pathway and Potential Implications for Regulation of Synaptic Physiology and Homeostasis at the Neuromuscular Junction

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    Ryen MacDonald

    2017-08-01

    Full Text Available Synaptic transmission requires intricate coordination of the components involved in processing of incoming signals, formation and stabilization of synaptic machinery, neurotransmission and in all related signaling pathways. Changes to any of these components cause synaptic imbalance and disruption of neuronal circuitry. Extensive studies at the neuromuscular junction (NMJ have greatly aided in the current understanding of synapses and served to elucidate the underlying physiology as well as associated adaptive and homeostatic processes. The heparan sulfate proteoglycan agrin is a vital component of the NMJ, mediating synaptic formation and maintenance in both brain and muscle, but very little is known about direct control of its expression. Here, we investigated the relationship between agrin and transcription factor early growth response-1 (Egr-1, as Egr-1 regulates the expression of many genes involved in synaptic homeostasis and plasticity. Using chromatin immunoprecipitation (ChIP, cell culture with cell lines derived from brain and muscle, and animal models, we show that Egr-1 binds to the AGRN gene locus and suppresses its expression. When compared with wild type (WT, mice deficient in Egr-1 (Egr-1−/− display a marked increase in AGRN mRNA and agrin full-length and cleavage fragment protein levels, including the 22 kDa, C-terminal fragment in brain and muscle tissue homogenate. Because agrin is a crucial component of the NMJ, we explored possible physiological implications of the Egr-1-agrin relationship. In the diaphragm, Egr-1−/− mice display increased NMJ motor endplate density, individual area and area of innervation. In addition to increased density, soleus NMJs also display an increase in fragmented and faint endplates in Egr-1−/− vs. WT mice. Moreover, the soleus NMJ electrophysiology of Egr-1−/− mice revealed increased quantal content and motor testing showed decreased movement and limb muscle strength compared with

  14. 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. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Dopamine Regulates Aversive Contextual Learning and Associated In Vivo Synaptic Plasticity in the Hippocampus

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    John I. Broussard

    2016-03-01

    Full Text Available Dopamine release during reward-driven behaviors influences synaptic plasticity. However, dopamine innervation and release in the hippocampus and its role during aversive behaviors are controversial. Here, we show that in vivo hippocampal synaptic plasticity in the CA3-CA1 circuit underlies contextual learning during inhibitory avoidance (IA training. Immunohistochemistry and molecular techniques verified sparse dopaminergic innervation of the hippocampus from the midbrain. The long-term synaptic potentiation (LTP underlying the learning of IA was assessed with a D1-like dopamine receptor agonist or antagonist in ex vivo hippocampal slices and in vivo in freely moving mice. Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction. The results indicate that dopamine-receptor signaling during an aversive contextual task regulates aversive memory retention and regulates associated synaptic mechanisms in the hippocampus that likely underlie learning.

  16. Short-Term Synaptic Plasticity Regulation in Solution-Gated Indium-Gallium-Zinc-Oxide Electric-Double-Layer Transistors.

    Science.gov (United States)

    Wan, Chang Jin; Liu, Yang Hui; Zhu, Li Qiang; Feng, Ping; Shi, Yi; Wan, Qing

    2016-04-20

    In the biological nervous system, synaptic plasticity regulation is based on the modulation of ionic fluxes, and such regulation was regarded as the fundamental mechanism underlying memory and learning. Inspired by such biological strategies, indium-gallium-zinc-oxide (IGZO) electric-double-layer (EDL) transistors gated by aqueous solutions were proposed for synaptic behavior emulations. Short-term synaptic plasticity, such as paired-pulse facilitation, high-pass filtering, and orientation tuning, was experimentally emulated in these EDL transistors. Most importantly, we found that such short-term synaptic plasticity can be effectively regulated by alcohol (ethyl alcohol) and salt (potassium chloride) additives. Our results suggest that solution gated oxide-based EDL transistors could act as the platforms for short-term synaptic plasticity emulation.

  17. Altered gene regulation and synaptic morphology in Drosophila learning and memory mutants

    Science.gov (United States)

    Guan, Zhuo; Buhl, Lauren K.; Quinn, William G.; Littleton, J. Troy

    2011-01-01

    Genetic studies in Drosophila have revealed two separable long-term memory pathways defined as anesthesia-resistant memory (ARM) and long-lasting long-term memory (LLTM). ARM is disrupted in radish (rsh) mutants, whereas LLTM requires CREB-dependent protein synthesis. Although the downstream effectors of ARM and LLTM are distinct, pathways leading to these forms of memory may share the cAMP cascade critical for associative learning. Dunce, which encodes a cAMP-specific phosphodiesterase, and rutabaga, which encodes an adenylyl cyclase, both disrupt short-term memory. Amnesiac encodes a pituitary adenylyl cyclase-activating peptide homolog and is required for middle-term memory. Here, we demonstrate that the Radish protein localizes to the cytoplasm and nucleus and is a PKA phosphorylation target in vitro. To characterize how these plasticity pathways may manifest at the synaptic level, we assayed synaptic connectivity and performed an expression analysis to detect altered transcriptional networks in rutabaga, dunce, amnesiac, and radish mutants. All four mutants disrupt specific aspects of synaptic connectivity at larval neuromuscular junctions (NMJs). Genome-wide DNA microarray analysis revealed ∼375 transcripts that are altered in these mutants, suggesting defects in multiple neuronal signaling pathways. In particular, the transcriptional target Lapsyn, which encodes a leucine-rich repeat cell adhesion protein, localizes to synapses and regulates synaptic growth. This analysis provides insights into the Radish-dependent ARM pathway and novel transcriptional targets that may contribute to memory processing in Drosophila. PMID:21422168

  18. pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract

    Science.gov (United States)

    McCrimmon, Donald R.; Martina, Marco

    2013-01-01

    The nucleus of the solitary tract (NTS) is the major site for termination of visceral sensory afferents contributing to homeostatic regulation of, for example, arterial pressure, gastric motility, and breathing. Whereas much is known about how different neuronal populations influence these functions, information about the role of glia remains scant. In this article, we propose that glia may contribute to NTS functions by modulating excitatory neurotransmission. We found that acidification (pH 7.0) depolarizes NTS glia by inhibiting K+-selective membrane currents. NTS glia also showed functional expression of voltage-sensitive glutamate transporters, suggesting that extracellular acidification regulates synaptic transmission by compromising glial glutamate uptake. To test this hypothesis, we evoked glutamatergic slow excitatory potentials (SEPs) in NTS neurons with repetitive stimulation (20 pulses at 10 Hz) of the solitary tract. This SEP depends on accumulation of glutamate following repetitive stimulation, since it was potentiated by blocking glutamate uptake with dl-threo-β-benzyloxyaspartic acid (TBOA) or a glia-specific glutamate transport blocker, dihydrokainate (DHK). Importantly, extracellular acidification (pH 7.0) also potentiated the SEP. This effect appeared to be mediated through a depolarization-induced inhibition of glial transporter activity, because it was occluded by TBOA and DHK. In agreement, pH 7.0 did not directly alter d-aspartate-induced responses in NTS glia or properties of presynaptic glutamate release. Thus acidification-dependent regulation of glial function affects synaptic transmission within the NTS. These results suggest that glia play a modulatory role in the NTS by integrating local tissue signals (such as pH) with synaptic inputs from peripheral afferents. PMID:23615553

  19. Conserved properties of Drosophila Insomniac link sleep regulation and synaptic function.

    Science.gov (United States)

    Li, Qiuling; Kellner, David A; Hatch, Hayden A M; Yumita, Tomohiro; Sanchez, Sandrine; Machold, Robert P; Frank, C Andrew; Stavropoulos, Nicholas

    2017-05-01

    Sleep is an ancient animal behavior that is regulated similarly in species ranging from flies to humans. Various genes that regulate sleep have been identified in invertebrates, but whether the functions of these genes are conserved in mammals remains poorly explored. Drosophila insomniac (inc) mutants exhibit severely shortened and fragmented sleep. Inc protein physically associates with the Cullin-3 (Cul3) ubiquitin ligase, and neuronal depletion of Inc or Cul3 strongly curtails sleep, suggesting that Inc is a Cul3 adaptor that directs the ubiquitination of neuronal substrates that impact sleep. Three proteins similar to Inc exist in vertebrates-KCTD2, KCTD5, and KCTD17-but are uncharacterized within the nervous system and their functional conservation with Inc has not been addressed. Here we show that Inc and its mouse orthologs exhibit striking biochemical and functional interchangeability within Cul3 complexes. Remarkably, KCTD2 and KCTD5 restore sleep to inc mutants, indicating that they can substitute for Inc in vivo and engage its neuronal targets relevant to sleep. Inc and its orthologs localize similarly within fly and mammalian neurons and can traffic to synapses, suggesting that their substrates may include synaptic proteins. Consistent with such a mechanism, inc mutants exhibit defects in synaptic structure and physiology, indicating that Inc is essential for both sleep and synaptic function. Our findings reveal that molecular functions of Inc are conserved through ~600 million years of evolution and support the hypothesis that Inc and its orthologs participate in an evolutionarily conserved ubiquitination pathway that links synaptic function and sleep regulation.

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

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    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.

  1. Control of Homeostatic Synaptic Plasticity by AKAP-Anchored Kinase and Phosphatase Regulation of Ca2+-Permeable AMPA Receptors.

    Science.gov (United States)

    Sanderson, Jennifer L; Scott, John D; Dell'Acqua, Mark L

    2018-02-13

    Neuronal information processing requires multiple forms of synaptic plasticity mediated by NMDA and AMPA-type glutamate receptors (NMDAR, AMPAR). These plasticity mechanisms include long-term potentiation (LTP) and depression (LTD), which are Hebbian, homosynaptic mechanisms locally regulating synaptic strength of specific inputs, and homeostatic synaptic scaling, which is a heterosynaptic mechanism globally regulating synaptic strength across all inputs. In many cases, LTP and homeostatic scaling regulate AMPAR subunit composition to increase synaptic strength via incorporation of Ca 2+ -permeable receptors (CP-AMPAR) containing GluA1, but lacking GluA2, subunits. Previous work by our group and others demonstrated that anchoring of the kinase PKA and the phosphatase calcineurin (CaN) to A-kinase anchoring protein (AKAP) 150 play opposing roles in regulation of GluA1 Ser845 phosphorylation and CP-AMPAR synaptic incorporation during hippocampal LTP and LTD. Here, using both male and female knock-in mice that are deficient in PKA or CaN anchoring, we show that AKAP150-anchored PKA and CaN also play novel roles in controlling CP-AMPAR synaptic incorporation during homeostatic plasticity in hippocampal neurons. We found that genetic disruption of AKAP-PKA anchoring prevented increases in Ser845 phosphorylation and CP-AMPAR synaptic recruitment during rapid homeostatic synaptic scaling-up induced by combined blockade of action potential firing and NMDAR activity. In contrast, genetic disruption of AKAP-CaN anchoring resulted in basal increases in Ser845 phosphorylation and CP-AMPAR synaptic activity that blocked subsequent scaling-up by preventing additional CP-AMPAR recruitment. Thus, the balanced, opposing phospho-regulation provided by AKAP-anchored PKA and CaN is essential for control of both Hebbian and homeostatic plasticity mechanisms that require CP-AMPARs. Significance statement: Neuronal circuit function is shaped by multiple forms of activity

  2. Differential Regulation of Synaptic Vesicle Tethering and Docking by UNC-18 and TOM-1.

    Science.gov (United States)

    Gracheva, Elena O; Maryon, Ed B; Berthelot-Grosjean, Martine; Richmond, Janet E

    2010-01-01

    The assembly of SNARE complexes between syntaxin, SNAP-25 and synaptobrevin is required to prime synaptic vesicles for fusion. Since Munc18 and tomosyn compete for syntaxin interactions, the interplay between these proteins is predicted to be important in regulating synaptic transmission. We explored this possibility, by examining genetic interactions between C. elegans unc-18(Munc18), unc-64(syntaxin) and tom-1(tomosyn). We have previously demonstrated that unc-18 mutants have reduced synaptic transmission, whereas tom-1 mutants exhibit enhanced release. Here we show that the unc-18 mutant release defect is associated with loss of two morphologically distinct vesicle pools; those tethered within 25 nm of the plasma membrane and those docked with the plasma membrane. In contrast, priming defective unc-13 mutants accumulate tethered vesicles, while docked vesicles are greatly reduced, indicating tethering is UNC-18-dependent and occurs in the absence of priming. C. elegans unc-64 mutants phenocopy unc-18 mutants, losing both tethered and docked vesicles, whereas overexpression of open syntaxin preferentially increases vesicle docking, suggesting UNC-18/closed syntaxin interactions are responsible for vesicle tethering. Given the competition between vertebrate tomosyn and Munc18, for syntaxin binding, we hypothesized that C. elegans TOM-1 may inhibit both UNC-18-dependent vesicle targeting steps. Consistent with this hypothesis, tom-1 mutants exhibit enhanced UNC-18 plasma membrane localization and a concomitant increase in both tethered and docked synaptic vesicles. Furthermore, in tom-1;unc-18 double mutants the docked, primed vesicle pool is preferentially rescued relative to unc-18 single mutants. Together these data provide evidence for the differential regulation of two vesicle targeting steps by UNC-18 and TOM-1 through competitive interactions with syntaxin.

  3. Differential regulation of synaptic vesicle tethering and docking by UNC-18 and TOM-1

    Directory of Open Access Journals (Sweden)

    Elena O Gracheva

    2010-10-01

    Full Text Available The assembly of SNARE complexes between syntaxin, SNAP-25 and synaptobrevin is required to prime synaptic vesicles for fusion. Since Munc18 and tomosyn compete for syntaxin interactions, the interplay between these proteins is predicted to be important in regulating synaptic transmission. We explored this possibility, by examining genetic interactions between C. elegans unc-18(Munc18, unc-64(syntaxin and tom-1(tomosyn. We have previously demonstrated that unc-18 mutants have reduced synaptic transmission, whereas tom-1 mutants exhibit enhanced release. Here we show that the unc-18 mutant release defect is associated with loss of two morphologically distinct vesicle pools; those tethered within 25nm of the plasma membrane and those docked with the plasma membrane. In contrast, priming defective unc-13 mutants accumulate tethered vesicles, while docked vesicles are greatly reduced, indicating tethering is UNC-18-dependent and occurs in the absence of priming. C. elegans unc-64 mutants phenocopy unc-18 mutants, losing both tethered and docked vesicles, whereas overexpression of open syntaxin preferentially increases vesicle docking, suggesting UNC-18/closed syntaxin interactions are responsible for vesicle tethering. Given the competition between vertebrate tomosyn and Munc18, for syntaxin binding, we hypothesized that C. elegans TOM-1 may inhibit both UNC-18-dependent vesicle targeting steps. Consistent with this hypothesis, tom-1 mutants exhibit enhanced UNC-18 plasma membrane localization and a concomitant increase in both tethered and docked synaptic vesicles. Furthermore, in tom-1;unc-18 double mutants the docked, primed vesicle pool is preferentially rescued relative to unc-18 single mutants. Together these data provide evidence for the differential regulation of two vesicle targeting steps by UNC-18 and TOM-1 through competitive interactions with syntaxin

  4. DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth

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    DiAntonio Aaron

    2007-08-01

    Full Text Available Abstract Background The growth of new synapses shapes the initial formation and subsequent rearrangement of neural circuitry. Genetic studies have demonstrated that the ubiquitin ligase Highwire restrains synaptic terminal growth by down-regulating the MAP kinase kinase kinase Wallenda/dual leucine zipper kinase (DLK. To investigate the mechanism of Highwire action, we have identified DFsn as a binding partner of Highwire and characterized the roles of DFsn in synapse development, synaptic transmission, and the regulation of Wallenda/DLK kinase abundance. Results We identified DFsn as an F-box protein that binds to the RING-domain ubiquitin ligase Highwire and that can localize to the Drosophila neuromuscular junction. Loss-of-function mutants for DFsn have a phenotype that is very similar to highwire mutants – there is a dramatic overgrowth of synaptic termini, with a large increase in the number of synaptic boutons and branches. In addition, synaptic transmission is impaired in DFsn mutants. Genetic interactions between DFsn and highwire mutants indicate that DFsn and Highwire collaborate to restrain synaptic terminal growth. Finally, DFsn regulates the levels of the Wallenda/DLK kinase, and wallenda is necessary for DFsn-dependent synaptic terminal overgrowth. Conclusion The F-box protein DFsn binds the ubiquitin ligase Highwire and is required to down-regulate the levels of the Wallenda/DLK kinase and restrain synaptic terminal growth. We propose that DFsn and Highwire participate in an evolutionarily conserved ubiquitin ligase complex whose substrates regulate the structure and function of synapses.

  5. Dendritic Branch Intersections Are Structurally Regulated Targets for Efficient Axonal Wiring and Synaptic Clustering

    Science.gov (United States)

    Pinchas, Monika; Baranes, Danny

    2013-01-01

    Synaptic clustering on dendritic branches enhances plasticity, input integration and neuronal firing. However, the mechanisms guiding axons to cluster synapses at appropriate sites along dendritic branches are poorly understood. We searched for such a mechanism by investigating the structural overlap between dendritic branches and axons in a simplified model of neuronal networks - the hippocampal cell culture. Using newly developed software, we converted images of meshes of overlapping axonal and dendrites into topological maps of intersections, enabling quantitative study of overlapping neuritic geometry at the resolution of single dendritic branch-to-branch and axon-to-branch crossings. Among dendro-dendritic crossing configurations, it was revealed that the orientations through which dendritic branches cross is a regulated attribute. While crossing angle distribution among branches thinner than 1 µm appeared to be random, dendritic branches 1 µm or wider showed a preference for crossing each other at angle ranges of either 50°–70° or 80°–90°. It was then found that the dendro-dendritic crossings themselves, as well as their selective angles, both affected the path of axonal growth. Axons displayed 4 fold stronger tendency to traverse within 2 µm of dendro-dendritic intersections than at farther distances, probably to minimize wiring length. Moreover, almost 70% of the 50°–70° dendro-denritic crossings were traversed by axons from the obtuse angle’s zone, whereas only 15% traversed through the acute angle’s zone. By contrast, axons showed no orientation restriction when traversing 80°–90° crossings. When such traverse behavior was repeated by many axons, they converged in the vicinity of dendro-dendritic intersections, thereby clustering their synaptic connections. Thus, the vicinity of dendritic branch-to-branch crossings appears to be a regulated structure used by axons as a target for efficient wiring and as a preferred site for synaptic

  6. Synaptic dynamics regulation in response to high frequency stimulation in neuronal networks

    Science.gov (United States)

    Su, Fei; Wang, Jiang; Li, Huiyan; Wei, Xile; Yu, Haitao; Deng, Bin

    2018-02-01

    High frequency stimulation (HFS) has confirmed its ability in modulating the pathological neural activities. However its detailed mechanism is unclear. This study aims to explore the effects of HFS on neuronal networks dynamics. First, the two-neuron FitzHugh-Nagumo (FHN) networks with static coupling strength and the small-world FHN networks with spike-time-dependent plasticity (STDP) modulated synaptic coupling strength are constructed. Then, the multi-scale method is used to transform the network models into equivalent averaged models, where the HFS intensity is modeled as the ratio between stimulation amplitude and frequency. Results show that in static two-neuron networks, there is still synaptic current projected to the postsynaptic neuron even if the presynaptic neuron is blocked by the HFS. In the small-world networks, the effects of the STDP adjusting rate parameter on the inactivation ratio and synchrony degree increase with the increase of HFS intensity. However, only when the HFS intensity becomes very large can the STDP time window parameter affect the inactivation ratio and synchrony index. Both simulation and numerical analysis demonstrate that the effects of HFS on neuronal network dynamics are realized through the adjustment of synaptic variable and conductance.

  7. Estimation of Synaptic Conductances in Presence of Nonlinear Effects Caused by Subthreshold Ionic Currents

    DEFF Research Database (Denmark)

    Vich, Catalina; Berg, Rune W.; Guillamon, Antoni

    2017-01-01

    Subthreshold fluctuations in neuronal membrane potential traces contain nonlinear components, and employing nonlinear models might improve the statistical inference. We propose a new strategy to estimate synaptic conductances, which has been tested using in silico data and applied to in vivo...... recordings. The model is constructed to capture the nonlinearities caused by subthreshold activated currents, and the estimation procedure can discern between excitatory and inhibitory conductances using only one membrane potential trace. More precisely, we perform second order approximations of biophysical...... models to capture the subthreshold nonlinearities, resulting in quadratic integrate-and-fire models, and apply approximate maximum likelihood estimation where we only suppose that conductances are stationary in a 50–100 ms time window. The results show an improvement compared to existent procedures...

  8. Kek-6: A truncated-Trk-like receptor for Drosophila neurotrophin 2 regulates structural synaptic plasticity.

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    Suzana Ulian-Benitez

    2017-08-01

    Full Text Available Neurotrophism, structural plasticity, learning and long-term memory in mammals critically depend on neurotrophins binding Trk receptors to activate tyrosine kinase (TyrK signaling, but Drosophila lacks full-length Trks, raising the question of how these processes occur in the fly. Paradoxically, truncated Trk isoforms lacking the TyrK predominate in the adult human brain, but whether they have neuronal functions independently of full-length Trks is unknown. Drosophila has TyrK-less Trk-family receptors, encoded by the kekkon (kek genes, suggesting that evolutionarily conserved functions for this receptor class may exist. Here, we asked whether Keks function together with Drosophila neurotrophins (DNTs at the larval glutamatergic neuromuscular junction (NMJ. We tested the eleven LRR and Ig-containing (LIG proteins encoded in the Drosophila genome for expression in the central nervous system (CNS and potential interaction with DNTs. Kek-6 is expressed in the CNS, interacts genetically with DNTs and can bind DNT2 in signaling assays and co-immunoprecipitations. Ligand binding is promiscuous, as Kek-6 can also bind DNT1, and Kek-2 and Kek-5 can also bind DNT2. In vivo, Kek-6 is found presynaptically in motoneurons, and DNT2 is produced by the muscle to function as a retrograde factor at the NMJ. Kek-6 and DNT2 regulate NMJ growth and synaptic structure. Evidence indicates that Kek-6 does not antagonise the alternative DNT2 receptor Toll-6. Instead, Kek-6 and Toll-6 interact physically, and together regulate structural synaptic plasticity and homeostasis. Using pull-down assays, we identified and validated CaMKII and VAP33A as intracellular partners of Kek-6, and show that they regulate NMJ growth and active zone formation downstream of DNT2 and Kek-6. The synaptic functions of Kek-6 could be evolutionarily conserved. This raises the intriguing possibility that a novel mechanism of structural synaptic plasticity involving truncated Trk

  9. Sex-Dependent Regulation of Aromatase-Mediated Synaptic Plasticity in the Basolateral Amygdala.

    Science.gov (United States)

    Bender, Roland A; Zhou, Lepu; Vierk, Ricardo; Brandt, Nicola; Keller, Alexander; Gee, Christine E; Schäfer, Michael K E; Rune, Gabriele M

    2017-02-08

    The basolateral amygdala (BLA) integrates sensory input from cortical and subcortical regions, a function that requires marked synaptic plasticity. Here we provide evidence that cytochrome P450 aromatase (AROM), the enzyme converting testosterone to 17β-estradiol (E2), contributes to the regulation of this plasticity in a sex-specific manner. We show that AROM is expressed in the BLA, particularly in the basolateral nucleus (BL), in male and female rodents. Systemic administration of the AROM inhibitor letrozole reduced spine synapse density in the BL of adult female mice but not in the BL of male mice. Similarly, in organotypic corticoamygdalar slice cultures from immature rats, treatment with letrozole significantly reduced spine synapses in the BL only in cultures derived from females. In addition, letrozole sex-specifically altered synaptic properties in the BL: in acute slices from juvenile (prepubertal) female rats, wash-in of letrozole virtually abolished long-term potentiation (LTP), whereas it did not prevent the generation of LTP in the slices from males. Together, these data indicate that neuron-derived E2 modulates synaptic plasticity in rodent BLA sex-dependently. As protein expression levels of AROM, estrogen and androgen receptors did not differ between males and females and were not sex-specifically altered by letrozole, the findings suggest sex-specific mechanisms of E2 signaling. SIGNIFICANCE STATEMENT The basolateral amygdala (BLA) is a key structure of the fear circuit. This research reveals a sexually dimorphic regulation of synaptic plasticity in the BLA involving neuronal aromatase, which produces the neurosteroid 17β-estradiol (E2). As male and female neurons in rodent BLA responded differently to aromatase inhibition both in vivo and in vitro , our findings suggest that E2 signaling in BLA neurons is regulated sex-dependently, presumably via mechanisms that have been established during sexual determination. These findings could be

  10. Electroacupuncture Regulates Hippocampal Synaptic Plasticity via miR-134-Mediated LIMK1 Function in Rats with Ischemic Stroke.

    Science.gov (United States)

    Liu, Weilin; Wu, Jie; Huang, Jia; Zhuo, Peiyuan; Lin, Yunjiao; Wang, Lulu; Lin, Ruhui; Chen, Lidian; Tao, Jing

    2017-01-01

    MircoRNAs (miRs) have been implicated in learning and memory, by regulating LIM domain kinase (LIMK1) to induce synaptic-dendritic plasticity. The study aimed to investigate whether miRNAs/LIMK1 signaling was involved in electroacupuncture- (EA-) mediated synaptic-dendritic plasticity in a rat model of middle cerebral artery occlusion induced cognitive deficit (MICD). Compared to untreatment or non-acupoint-EA treatment, EA at DU20 and DU24 acupoints could shorten escape latency and increase the frequency of crossing platform in Morris water maze test. T2-weighted imaging showed that the MICD rat brain lesions were located in cortex, hippocampus, corpus striatum, and thalamus regions and injured volumes were reduced after EA. Furthermore, we found that the density of dendritic spine and the number of synapses in the hippocampal CA1 pyramidal cells were obviously reduced at Day 14 after MICD. However, synaptic-dendritic loss could be rescued after EA. Moreover, the synaptic-dendritic plasticity was associated with increases of the total LIMK1 and phospho-LIMK1 levels in hippocampal CA1 region, wherein EA decreased the expression of miR-134, negatively regulating LIMK1 to enhance synaptic-dendritic plasticity. Therefore, miR-134-mediated LIMK1 was involved in EA-induced hippocampal synaptic plasticity, which served as a contributor to improving learning and memory during the recovery stage of ischemic stroke.

  11. Regulation of neuromodulator receptor efficacy--implications for whole-neuron and synaptic plasticity.

    Science.gov (United States)

    Scheler, Gabriele

    2004-04-01

    Membrane receptors for neuromodulators (NM) are highly regulated in their distribution and efficacy-a phenomenon which influences the individual cell's response to central signals of NM release. Even though NM receptor regulation is implicated in the pharmacological action of many drugs, and is also known to be influenced by various environmental factors, its functional consequences and modes of action are not well understood. In this paper we summarize relevant experimental evidence on NM receptor regulation (specifically dopamine D1 and D2 receptors) in order to explore its significance for neural and synaptic plasticity. We identify the relevant components of NM receptor regulation (receptor phosphorylation, receptor trafficking and sensitization of second-messenger pathways) gained from studies on cultured cells. Key principles in the regulation and control of short-term plasticity (sensitization) are identified, and a model is presented which employs direct and indirect feedback regulation of receptor efficacy. We also discuss long-term plasticity which involves shifts in receptor sensitivity and loss of responsivity to NM signals. Finally, we discuss the implications of NM receptor regulation for models of brain plasticity and memorization. We emphasize that a realistic model of brain plasticity will have to go beyond Hebbian models of long-term potentiation and depression. Plasticity in the distribution and efficacy of NM receptors may provide another important source of functional plasticity with implications for learning and memory.

  12. Phospho-dependent binding of the clathrin AP2 adaptor complex to GABAA receptors regulates the efficacy of inhibitory synaptic transmission.

    Science.gov (United States)

    Kittler, Josef T; Chen, Guojun; Honing, Stephan; Bogdanov, Yury; McAinsh, Kristina; Arancibia-Carcamo, I Lorena; Jovanovic, Jasmina N; Pangalos, Menelas N; Haucke, Volker; Yan, Zhen; Moss, Stephen J

    2005-10-11

    The efficacy of synaptic inhibition depends on the number of gamma-aminobutyric acid type A receptors (GABA(A)Rs) expressed on the cell surface of neurons. The clathrin adaptor protein 2 (AP2) complex is a critical regulator of GABA(A)R endocytosis and, hence, surface receptor number. Here, we identify a previously uncharacterized atypical AP2 binding motif conserved within the intracellular domains of all GABA(A)R beta subunit isoforms. This AP2 binding motif (KTHLRRRSSQLK in the beta3 subunit) incorporates the major sites of serine phosphorylation within receptor beta subunits, and phosphorylation within this site inhibits AP2 binding. Furthermore, by using surface plasmon resonance, we establish that a peptide (pepbeta3) corresponding to the AP2 binding motif in the GABA(A)R beta3 subunit binds to AP2 with high affinity only when dephosphorylated. Moreover, the pepbeta3 peptide, but not its phosphorylated equivalent (pepbeta3-phos), enhanced the amplitude of miniature inhibitory synaptic current and whole cell GABA(A)R current. These effects of pepbeta3 on GABA(A)R current were occluded by inhibitors of dynamin-dependent endocytosis supporting an action of pepbeta3 on GABA(A)R endocytosis. Therefore phospho-dependent regulation of AP2 binding to GABA(A)Rs provides a mechanism to specify receptor cell surface number and the efficacy of inhibitory synaptic transmission.

  13. Syncrip/hnRNP Q influences synaptic transmission and regulates BMP signaling at the Drosophila neuromuscular synapse

    Directory of Open Access Journals (Sweden)

    James M. Halstead

    2014-08-01

    Full Text Available Synaptic plasticity involves the modulation of synaptic connections in response to neuronal activity via multiple pathways. One mechanism modulates synaptic transmission by retrograde signals from the post-synapse that influence the probability of vesicle release in the pre-synapse. Despite its importance, very few factors required for the expression of retrograde signals, and proper synaptic transmission, have been identified. Here, we identify the conserved RNA binding protein Syncrip as a new factor that modulates the efficiency of vesicle release from the motoneuron and is required for correct synapse structure. We show that syncrip is required genetically and its protein product is detected only in the muscle and not in the motoneuron itself. This unexpected non-autonomy is at least partly explained by the fact that Syncrip modulates retrograde BMP signals from the muscle back to the motoneuron. We show that Syncrip influences the levels of the Bone Morphogenic Protein ligand Glass Bottom Boat from the post-synapse and regulates the pre-synapse. Our results highlight the RNA-binding protein Syncrip as a novel regulator of synaptic output. Given its known role in regulating translation, we propose that Syncrip is important for maintaining a balance between the strength of presynaptic vesicle release and postsynaptic translation.

  14. Cryptochrome Is a Regulator of Synaptic Plasticity in the Visual System of Drosophila melanogaster

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    Milena Damulewicz

    2017-05-01

    Full Text Available Drosophila CRYPTOCHROME (CRY is a blue light sensitive protein with a key role in circadian photoreception. A main feature of CRY is that light promotes an interaction with the circadian protein TIMELESS (TIM resulting in their ubiquitination and degradation, a mechanism that contributes to the synchronization of the circadian clock to the environment. Moreover, CRY participates in non-circadian functions such as magnetoreception, modulation of neuronal firing, phototransduction and regulation of synaptic plasticity. In the present study we used co-immunoprecipitation, yeast 2 hybrid (Y2H and in situ proximity ligation assay (PLA to show that CRY can physically associate with the presynaptic protein BRUCHPILOT (BRP and that CRY-BRP complexes are located mainly in the visual system. Additionally, we present evidence that light-activated CRY may decrease BRP levels in photoreceptor termini in the distal lamina, probably targeting BRP for degradation.

  15. Selective Enhancement of Synaptic Inhibition by Hypocretin (Orexin) in Rat Vagal Motor Neurons: Implications for Autonomic Regulation

    Science.gov (United States)

    Davis, Scott F.; Williams, Kevin W.; Xu, Weiye; Glatzer, Nicholas R.; Smith, Bret N.

    2012-01-01

    The hypocretins (orexins) are hypothalamic neuropeptides implicated in feeding, arousal, and autonomic regulation. These studies were designed to determine the actions of hypocretin peptides on synaptic transmission in the dorsal motor nucleus of the vagus nerve (DMV). Whole-cell patch-clamp recordings were made from DMV neurons in transverse slices of rat brainstem. Some of the neurons were identified as gastric-related by retrograde labeling after inoculation of the stomach wall with pseudorabies virus 152, a viral label that reports enhanced green fluorescent protein. Consistent with previous findings, hypocretins caused an inward current (6–68 pA) in most neurons at holding potentials near rest. In addition, the frequency of spontaneous IPSCs was increased in a concentration-related manner (up to 477%), with little change in EPSCs. This effect was preserved in the presence of tetrodotoxin, suggesting a presynaptic site of action. Hypocretins increased the amplitude of IPSCs evoked by electrical stimulation of the nucleus tractus solitarius (NTS) but not evoked EPSCs. Hypocretin-induced increases in the frequency of IPSCs evoked by photoactivation of caged glutamate within the NTS were also observed. Identical effects of the peptides were observed in identified gastric-related and unlabeled DMV neurons. In contrast to some previous studies, which have reported primarily excitatory actions of the hypocretins in many regions of the CNS, these data support a role for hypocretin in preferentially enhancing synaptic inhibition, including inhibitory inputs arising from neurons in the NTS. These findings indicate that the hypocretins can modulate and coordinate visceral autonomic output by acting directly on central vagal circuits. PMID:12736355

  16. Glutamatergic synaptic currents of nigral dopaminergic neurons follow a postnatal developmental sequence

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    Edouard ePearlstein

    2015-05-01

    Full Text Available The spontaneous activity pattern of adult dopaminergic (DA neurons of the substantia nigra pars compacta (SNc results from interactions between intrinsic membrane conductances and afferent inputs. In adult SNc DA neurons, low-frequency tonic background activity is generated by intrinsic pacemaker mechanisms, whereas burst generation depends on intact synaptic inputs in particular the glutamatergic ones. Tonic DA release in the striatum during pacemaking is required to maintain motor activity, and burst firing evokes phasic DA release, necessary for cue-dependent learning tasks. However, it is still unknown how the firing properties of SNc DA neurons mature during postnatal development before reaching the adult state. We studied the postnatal developmental profile of spontaneous and evoked AMPA and NMDA receptor-mediated excitatory postsynaptic currents (EPSCs in SNc DA neurons in brain slices from immature (postnatal days P4-10 and young adult (P30-50 tyrosine hydroxylase (TH-GFP mice. We found that somato-dendritic fields of SNc DA neurons are already mature at P4-10. In contrast, spontaneous glutamatergic EPSCs show a developmental sequence. Spontaneous NMDA EPSCs in particular are larger and more frequent in immature SNc DA neurons than in young adult ones and have a bursty pattern. They are mediated by GluN2B and GluN2D subunit-containing NMDA receptors. The latter generate long-lasting, DQP1105-sensitive, spontaneous EPSCs, which are transiently recorded during this early period. Due to high NMDA activity, immature SNc DA neurons generate large and long lasting NMDA receptor-dependent (APV-sensitive bursts in response to the stimulation of the subthalamic nucleus. We conclude that the transient high NMDA activity allows calcium influx into the dendrites of developing SNc DA neurons.

  17. The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons.

    Science.gov (United States)

    Yamakawa, Hidekuni; Cheng, Jemmie; Penney, Jay; Gao, Fan; Rueda, Richard; Wang, Jun; Yamakawa, Satoko; Kritskiy, Oleg; Gjoneska, Elizabeta; Tsai, Li-Huei

    2017-08-08

    The histone deacetylase HDAC2, which negatively regulates synaptic gene expression and neuronal plasticity, is upregulated in Alzheimer's disease (AD) patients and mouse models. Therapeutics targeting HDAC2 hold promise for ameliorating AD-related cognitive impairment; however, attempts to generate HDAC2-specific inhibitors have failed. Here, we take an integrative genomics approach to identify proteins that mediate HDAC2 recruitment to synaptic plasticity genes. Functional screening revealed that knockdown of the transcription factor Sp3 phenocopied HDAC2 knockdown and that Sp3 facilitated recruitment of HDAC2 to synaptic genes. Importantly, like HDAC2, Sp3 expression was elevated in AD patients and mouse models, where Sp3 knockdown ameliorated synaptic dysfunction. Furthermore, exogenous expression of an HDAC2 fragment containing the Sp3-binding domain restored synaptic plasticity and memory in a mouse model with severe neurodegeneration. Our findings indicate that targeting the HDAC2-Sp3 complex could enhance cognitive function without affecting HDAC2 function in other processes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Synaptic adaptations by alcohol and drugs of abuse: changes in microRNA expression and mRNA regulation

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    Dana eMost

    2014-12-01

    Full Text Available Local translation of mRNAs is a mechanism by which cells can rapidly remodel synaptic structure and function. There is ample evidence for a role of synaptic translation in the neuroadaptations resulting from chronic drug use and abuse. Persistent and coordinated changes of many mRNAs, globally and locally, may have a causal role in complex disorders such as addiction. In this review we examine the evidence that translational regulation by microRNAs drives synaptic remodeling and mRNA expression, which may regulate the transition from recreational to compulsive drug use.MicroRNAs are small, non-coding RNAs that control the translation of mRNAs in the cell and within spatially restricted sites such as the synapse. MicroRNAs typically repress the translation of mRNAs into protein by binding to the 3’UTR of their targets. As ‘master regulators’ of many mRNAs, changes in microRNAs could account for the systemic alterations in mRNA and protein expression observed with drug abuse and dependence. Recent studies indicate that manipulation of microRNAs affects addiction-related behaviors such as the rewarding properties of cocaine, cocaine-seeking behavior and self-administration rates of alcohol. There is limited evidence, however, regarding how synaptic microRNAs control local mRNA translation during chronic drug exposure and how this contributes to the development of dependence.Here, we discuss research supporting microRNA regulation of local mRNA translation and how drugs of abuse may target this process. The ability of synaptic microRNAs to rapidly regulate mRNAs provides a discrete, localized system that could potentially be used as diagnostic and treatment tools for alcohol and other addiction disorders.

  19. Molecular machines regulating the release probability of synaptic vesicles at the active zone.

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    Christoph eKoerber

    2016-03-01

    Full Text Available The fusion of synaptic vesicles (SVs with the plasma membrane of the active zone (AZ upon arrival of an action potential (AP at the presynaptic compartment is a tightly regulated probabil-istic process crucial for information transfer. The probability of a SV to release its transmitter content in response to an AP, termed release probability (Pr, is highly diverse both at the level of entire synapses and individual SVs at a given synapse. Differences in Pr exist between different types of synapses, between synapses of the same type, synapses originating from the same axon and even between different SV subpopulations within the same presynaptic terminal. The Pr of SVs at the AZ is set by a complex interplay of different presynaptic properties including the availability of release-ready SVs, the location of the SVs relative to the voltage-gated calcium channels (VGCCs at the AZ, the magnitude of calcium influx upon arrival of the AP, the buffer-ing of calcium ions as well as the identity and sensitivity of the calcium sensor. These properties are not only interconnected, but can also be regulated dynamically to match the requirements of activity patterns mediated by the synapse. Here, we review recent advances in identifying mole-cules and molecular machines taking part in the determination of vesicular Pr at the AZ.

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

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    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.

  1. Reduced Levels of the Synaptic Functional Regulator FMRP in Dentate Gyrus of the Aging Sprague-Dawley Rat

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    Roman Smidak

    2017-11-01

    Full Text Available Fragile X mental retardation protein (FMRP encoded by Fragile X mental retardation 1 (FMR1 gene is a RNA-binding regulator of mRNA translation, transport and stability with multiple targets responsible for proper synaptic function. Epigenetic silencing of FMR1 gene expression leads to the development of Fragile X syndrome (FXS that is characterized by intellectual disability and other behavioral problems including autism. In the rat FXS model, the lack of FMRP caused a deficit in hippocampal-dependent memory. However, the hippocampal changes of FMRP in aging rats are not fully elucidated. The current study addresses the changes in FMRP levels in dentate gyrus (DG from young (17 weeks and aging (22 months Sprague – Dawley rats. The aging animal group showed significant decline in spatial reference memory. Protein samples from five rats per each group were analyzed by quantitative proteomic analysis resulting in 153 significantly changed proteins. FMRP showed significant reduction in aging animals which was confirmed by immunoblotting and immunofluorescence microscopy. Furthermore, bioinformatic analysis of the differential protein dataset revealed several functionally related protein groups with individual interactions with FMRP. These include high representation of the RNA translation and processing machinery connected to FMRP and other RNA-binding regulators including CAPRIN1, the members of Pumilio (PUM and CUG-BP, Elav-like (CELF family, and YTH N(6-methyladenosine RNA-binding proteins (YTHDF. The results of the current study point to the important role of FMRP and regulation of RNA processing in the rat DG and memory decline during the aging process.

  2. Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus.

    Science.gov (United States)

    Isaacson, J S; Nicoll, R A

    1991-12-01

    Aniracetam is a nootropic drug that has been shown to selectively enhance quisqualate receptor-mediated responses in Xenopus oocytes injected with brain mRNA and in hippocampal pyramidal cells [Ito, I., Tanabe, S., Kohda, A. & Sugiyama, H. (1990) J. Physiol. (London) 424, 533-544]. We have used patch clamp recording techniques in hippocampal slices to elucidate the mechanism for this selective action. We find that aniracetam enhances glutamate-evoked currents in whole-cell recordings and, in outside-out patches, strongly reduces glutamate receptor desensitization. In addition, aniracetam selectively prolongs the time course and increases the peak amplitude of fast synaptic currents. These findings indicate that aniracetam slows the kinetics of fast synaptic transmission and are consistent with the proposal [Trussell, L. O. & Fischbach, G. D. (1989) Neuron 3, 209-218; Tang, C.-M., Dichter, M. & Morad, M. (1989) Science 243, 1474-1477] that receptor desensitization governs the strength of fast excitatory synaptic transmission in the brain.

  3. Characterization of spontaneous excitatory synaptic currents in salamander retinal ganglion cells.

    Science.gov (United States)

    Taylor, W R; Chen, E; Copenhagen, D R

    1995-01-01

    1. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded under voltage-clamp conditions. Consistent with activation of non-NMDA-type glutamate receptors, the sEPSCs reversed at potentials above 0 mV, were blocked by 1 microM CNQX and prolonged by 2 mM aniracetam. 2. The peak conductance of the averaged sEPSCs (n = 70-400) was 130 +/- 60 pS (mean +/- S.D.; 17 cells, ranging from 70 to 290 pS). Amplitude distributions were skewed towards larger amplitudes. 3. The decay of individual and mean sEPSCs was exponential with a mean time constant (tau d) of 3.75 +/- 0.84 ms (n = 13), which was voltage independent. The 10-90% rise time of the sEPSCs was 1.30 +/- 0.44 ms (n = 13). There was no correlation between sEPSC rise time and tau d suggesting that dendritic filtering alone did not shape the time course of sEPSCs. 4. Light-evoked EPSCs in these retinal ganglion cells are mediated by concomitant activation of NMDA and non-NMDA receptors; however, no NMDA component was discerned in the sEPSCs, even when recording at -96 mV in Mg(2+)-free solutions. The decay time course was not altered by 20 microM AP7, an NMDA antagonist, nor was an NMDA component unmasked by adding glycine or D-serine. These results suggest that NMDA and non-NMDA receptors are not coactivated by a single vesicle of transmitter during spontaneous release, and thus are probably not colocalized in the postsynaptic membrane at the sites of spontaneous release. 5. The sEPSCs were an order of magnitude faster than the non-NMDA receptor-mediated EPSCs evoked by light stimuli, and it is proposed that the EPSC time course is determined largely by the extended time course of release of synaptic vesicles from bipolar cells. The quantal content of a light-evoked non-NMDA receptor-mediated EPSC in an on-off cell is about 200 quanta. Images Figure 6 PMID:7562636

  4. The Molecular Chaperone Hsc70 Interacts with Tyrosine Hydroxylase to Regulate Enzyme Activity and Synaptic Vesicle Localization.

    Science.gov (United States)

    Parra, Leonardo A; Baust, Tracy B; Smith, Amanda D; Jaumotte, Juliann D; Zigmond, Michael J; Torres, Soledad; Leak, Rehana K; Pino, Jose A; Torres, Gonzalo E

    2016-08-19

    We previously reported that the vesicular monoamine transporter 2 (VMAT2) is physically and functionally coupled with Hsc70 as well as with the dopamine synthesis enzymes tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase, providing a novel mechanism for dopamine homeostasis regulation. Here we expand those findings to demonstrate that Hsc70 physically and functionally interacts with TH to regulate the enzyme activity and synaptic vesicle targeting. Co-immunoprecipitation assays performed in brain tissue and heterologous cells demonstrated that Hsc70 interacts with TH and aromatic amino acid decarboxylase. Furthermore, in vitro binding assays showed that TH directly binds the substrate binding and carboxyl-terminal domains of Hsc70. Immunocytochemical studies indicated that Hsc70 and TH co-localize in midbrain dopaminergic neurons. The functional significance of the Hsc70-TH interaction was then investigated using TH activity assays. In both dopaminergic MN9D cells and mouse brain synaptic vesicles, purified Hsc70 facilitated an increase in TH activity. Neither the closely related protein Hsp70 nor the unrelated Hsp60 altered TH activity, confirming the specificity of the Hsc70 effect. Overexpression of Hsc70 in dopaminergic MN9D cells consistently resulted in increased TH activity whereas knockdown of Hsc70 by short hairpin RNA resulted in decreased TH activity and dopamine levels. Finally, in cells with reduced levels of Hsc70, the amount of TH associated with synaptic vesicles was decreased. This effect was rescued by addition of purified Hsc70. Together, these data demonstrate a novel interaction between Hsc70 and TH that regulates the activity and localization of the enzyme to synaptic vesicles, suggesting an important role for Hsc70 in dopamine homeostasis. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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

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    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.

  6. TGF-β Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning

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    Sarah X. Luo

    2016-12-01

    Full Text Available Neural circuits involving midbrain dopaminergic (DA neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor β (TGF-β signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-β type II receptor in DA neurons also disrupts the balance in TGF-β1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-β signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus-reward associations. These results support a role for TGF-β in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders.

  7. Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell

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    Regina A. Mangieri

    2017-08-01

    Full Text Available Anaplastic lymphoma kinase (ALK is a receptor tyrosine kinase recently implicated in biochemical, physiological, and behavioral responses to ethanol. Thus, manipulation of ALK signaling may represent a novel approach to treating alcohol use disorder (AUD. Ethanol induces adaptations in glutamatergic synapses onto nucleus accumbens shell (NAcSh medium spiny neurons (MSNs, and putative targets for treating AUD may be validated for further development by assessing how their manipulation modulates accumbal glutamatergic synaptic transmission and plasticity. Here, we report that Alk knockout (AlkKO mice consumed greater doses of ethanol, relative to wild-type (AlkWT mice, in an operant self-administration model. Using ex vivo electrophysiology to examine excitatory synaptic transmission and plasticity at NAcSh MSNs that express dopamine D1 receptors (D1MSNs, we found that the amplitude of spontaneous excitatory post-synaptic currents (EPSCs in NAcSh D1MSNs was elevated in AlkKO mice and in the presence of an ALK inhibitor, TAE684. Furthermore, when ALK was absent or inhibited, glutamatergic synaptic plasticity – long-term depression of evoked EPSCs – in D1MSNs was attenuated. Thus, loss of ALK activity in mice is associated with elevated ethanol consumption and enhanced excitatory transmission in NAcSh D1MSNs. These findings add to the mounting evidence of a relationship between excitatory synaptic transmission onto NAcSh D1MSNs and ethanol consumption, point toward ALK as one important molecular mediator of this interaction, and further validate ALK as a target for therapeutic intervention in the treatment of AUD.

  8. ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization.

    Science.gov (United States)

    Tindi, Jaafar O; Chávez, Andrés E; Cvejic, Svetlana; Calvo-Ochoa, Erika; Castillo, Pablo E; Jordan, Bryen A

    2015-06-17

    NMDA receptors (NMDARs) are key mediators of glutamatergic transmission and synaptic plasticity, and their dysregulation has been linked to diverse neuropsychiatric and neurodegenerative disorders. While normal NMDAR function requires regulated expression and trafficking of its different subunits, the molecular mechanisms underlying these processes are not fully understood. Here we report that the amyloid precursor protein intracellular domain associated-1 protein (AIDA-1), which associates with NMDARs and is encoded by ANKS1B, a gene recently linked to schizophrenia, regulates synaptic NMDAR subunit composition. Forebrain-specific AIDA-1 conditional knock-out (cKO) mice exhibit reduced GluN2B-mediated and increased GluN2A-mediated synaptic transmission, and biochemical analyses show AIDA-1 cKO mice have low GluN2B and high GluN2A protein levels at isolated hippocampal synaptic junctions compared with controls. These results are corroborated by immunocytochemical and electrophysiological analyses in primary neuronal cultures following acute lentiviral shRNA-mediated knockdown of AIDA-1. Moreover, hippocampal NMDAR-dependent but not metabotropic glutamate receptor-dependent plasticity is impaired in AIDA-1 cKO mice, further supporting a role for AIDA-1 in synaptic NMDAR function. We also demonstrate that AIDA-1 preferentially associates with GluN2B and with the adaptor protein Ca(2+)/calmodulin-dependent serine protein kinase and kinesin KIF17, which regulate the transport of GluN2B-containing NMDARs from the endoplasmic reticulum (ER) to synapses. Consistent with this function, GluN2B accumulates in ER-enriched fractions in AIDA-1 cKO mice. These findings suggest that AIDA-1 regulates NMDAR subunit composition at synapses by facilitating transport of GluN2B from the ER to synapses, which is critical for NMDAR plasticity. Our work provides an explanation for how AIDA-1 dysfunction might contribute to neuropsychiatric conditions, such as schizophrenia. Copyright

  9. Myosin IIb-dependent Regulation of Actin Dynamics Is Required for N-Methyl-D-aspartate Receptor Trafficking during Synaptic Plasticity.

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    Bu, Yunfei; Wang, Ning; Wang, Shaoli; Sheng, Tao; Tian, Tian; Chen, Linlin; Pan, Weiwei; Zhu, Minsheng; Luo, Jianhong; Lu, Wei

    2015-10-16

    N-Methyl-d-aspartate receptor (NMDAR) synaptic incorporation changes the number of NMDARs at synapses and is thus critical to various NMDAR-dependent brain functions. To date, the molecules involved in NMDAR trafficking and the underlying mechanisms are poorly understood. Here, we report that myosin IIb is an essential molecule in NMDAR synaptic incorporation during PKC- or θ burst stimulation-induced synaptic plasticity. Moreover, we demonstrate that myosin light chain kinase (MLCK)-dependent actin reorganization contributes to NMDAR trafficking. The findings from additional mutual occlusion experiments demonstrate that PKC and MLCK share a common signaling pathway in NMDAR-mediated synaptic regulation. Because myosin IIb is the primary substrate of MLCK and can regulate actin dynamics during synaptic plasticity, we propose that the MLCK- and myosin IIb-dependent regulation of actin dynamics is required for NMDAR trafficking during synaptic plasticity. This study provides important insights into a mechanical framework for understanding NMDAR trafficking associated with synaptic plasticity. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Regulation of synaptic scaling by action potential-independent miniature neurotransmission.

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    Gonzalez-Islas, Carlos; Bülow, Pernille; Wenner, Peter

    2018-03-01

    Synaptic scaling represents a homeostatic adjustment in synaptic strength that was first identified as a cell-wide mechanism to achieve firing rate homeostasis after perturbations to spiking activity levels. In this review, we consider a form of synaptic scaling that is triggered by changes in action potential-independent neurotransmitter release. This plasticity appears to be both triggered and expressed locally at the dendritic site of the synapse that experiences a perturbation. A discussion of different forms of scaling triggered by different perturbations is presented. We consider work from multiple groups supporting this form of scaling, which we call neurotransmission-based scaling. This class of homeostatic synaptic plasticity is compared in studies using hippocampal and cortical cultures, as well as in vivo work in the embryonic chick spinal cord. Despite differences in the tissues examined, there are clear similarities in neurotransmission-based scaling, which appear to be molecularly distinct from the originally described spike-based scaling. © 2017 Wiley Periodicals, Inc.

  11. Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage.

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    Carolin Wippel

    Full Text Available Streptococcus pneumoniae (pneumococcal meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial layers of the frontal neocortex of post-mortem brain samples from individuals with pneumococcal meningitis. A similar effect was observed in mice with pneumococcal meningitis only when the bacteria expressed the pore-forming cholesterol-dependent cytolysin pneumolysin. Exposure of acute mouse brain slices to only pore-competent pneumolysin at disease-relevant, non-lytic concentrations caused permanent dendritic swelling, dendritic spine elimination and synaptic loss. The NMDA glutamate receptor antagonists MK801 and D-AP5 reduced this pathology. Pneumolysin increased glutamate levels within the mouse brain slices. In mouse astrocytes, pneumolysin initiated the release of glutamate in a calcium-dependent manner. We propose that pneumolysin plays a significant synapto- and dendritotoxic role in pneumococcal meningitis by initiating glutamate release from astrocytes, leading to subsequent glutamate-dependent synaptic damage. We outline for the first time the occurrence of synaptic pathology in pneumococcal meningitis and demonstrate that a bacterial cytolysin can dysregulate the control of glutamate in the brain, inducing excitotoxic damage.

  12. Neuron-wide RNA transport combines with netrin-mediated local translation to spatially regulate the synaptic proteome.

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    Kim, Sangmok; Martin, Kelsey C

    2015-01-08

    The persistence of experience-dependent changes in brain connectivity requires RNA localization and protein synthesis. Previous studies have demonstrated a role for local translation in altering the structure and function of synapses during synapse formation and experience-dependent synaptic plasticity. In this study, we ask whether in addition to promoting local translation, local stimulation also triggers directed trafficking of RNAs from nucleus to stimulated synapses. Imaging of RNA localization and translation in cultured Aplysia sensory-motor neurons revealed that RNAs were delivered throughout the arbor of the sensory neuron, but that translation was enriched only at sites of synaptic contact and/or synaptic stimulation. Investigation of the mechanisms that trigger local translation revealed a role for calcium-dependent retrograde netrin-1/DCC receptor signaling. Spatially restricting gene expression by regulating local translation rather than by directing the delivery of mRNAs from nucleus to stimulated synapses maximizes the readiness of the entire neuronal arbor to respond to local cues.

  13. Differential regulation of wild-type and mutant alpha-synuclein binding to synaptic membranes by cytosolic factors

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    Figeys Daniel

    2008-09-01

    Full Text Available Abstract Background Alpha-Synuclein (α-syn, a 140 amino acid protein associated with presynaptic membranes in brain, is a major constituent of Lewy bodies in Parkinson's disease (PD. Three missense mutations (A30P, A53T and E46K in the α-syn gene are associated with rare autosomal dominant forms of familial PD. However, the regulation of α-syn's cellular localization in neurons and the effects of the PD-linked mutations are poorly understood. Results In the present study, we analysed the ability of cytosolic factors to regulate α-syn binding to synaptic membranes. We show that co-incubation with brain cytosol significantly increases the membrane binding of normal and PD-linked mutant α-syn. To characterize cytosolic factor(s that modulate α-syn binding properties, we investigated the ability of proteins, lipids, ATP and calcium to modulate α-syn membrane interactions. We report that lipids and ATP are two of the principal cytosolic components that modulate Wt and A53T α-syn binding to the synaptic membrane. We further show that 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF is one of the principal lipids found in complex with cytosolic proteins and is required to enhance α-syn interaction with synaptic membrane. In addition, the impaired membrane binding observed for A30P α-syn was significantly mitigated by the presence of protease-sensitive factors in brain cytosol. Conclusion These findings suggest that endogenous brain cytosolic factors regulate Wt and mutant α-syn membrane binding, and could represent potential targets to influence α-syn solubility in brain.

  14. Rapid Turnover of Cortical NCAM1 Regulates Synaptic Reorganization after Peripheral Nerve Injury

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    Hyoung-Gon Ko

    2018-01-01

    Full Text Available Peripheral nerve injury can induce pathological conditions that lead to persistent sensitized nociception. Although there is evidence that plastic changes in the cortex contribute to this process, the underlying molecular mechanisms are unclear. Here, we find that activation of the anterior cingulate cortex (ACC induced by peripheral nerve injury increases the turnover of specific synaptic proteins in a persistent manner. We demonstrate that neural cell adhesion molecule 1 (NCAM1 is one of the molecules involved and show that it mediates spine reorganization and contributes to the behavioral sensitization. We show striking parallels in the underlying mechanism with the maintenance of NMDA-receptor- and protein-synthesis-dependent long-term potentiation (LTP in the ACC. Our results, therefore, demonstrate a synaptic mechanism for cortical reorganization and suggest potential avenues for neuropathic pain treatment.

  15. Rapid Turnover of Cortical NCAM1 Regulates Synaptic Reorganization after Peripheral Nerve Injury.

    Science.gov (United States)

    Ko, Hyoung-Gon; Choi, Jun-Hyeok; Park, Dong Ik; Kang, SukJae Joshua; Lim, Chae-Seok; Sim, Su-Eon; Shim, Jaehoon; Kim, Ji-Il; Kim, Siyong; Choi, Tae-Hyeok; Ye, Sanghyun; Lee, Jaehyun; Park, Pojeong; Kim, Somi; Do, Jeehaeh; Park, Jihye; Islam, Md Ariful; Kim, Hyun Jeong; Turck, Christoph W; Collingridge, Graham L; Zhuo, Min; Kaang, Bong-Kiun

    2018-01-16

    Peripheral nerve injury can induce pathological conditions that lead to persistent sensitized nociception. Although there is evidence that plastic changes in the cortex contribute to this process, the underlying molecular mechanisms are unclear. Here, we find that activation of the anterior cingulate cortex (ACC) induced by peripheral nerve injury increases the turnover of specific synaptic proteins in a persistent manner. We demonstrate that neural cell adhesion molecule 1 (NCAM1) is one of the molecules involved and show that it mediates spine reorganization and contributes to the behavioral sensitization. We show striking parallels in the underlying mechanism with the maintenance of NMDA-receptor- and protein-synthesis-dependent long-term potentiation (LTP) in the ACC. Our results, therefore, demonstrate a synaptic mechanism for cortical reorganization and suggest potential avenues for neuropathic pain treatment. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  16. Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse.

    Science.gov (United States)

    Gocel, James; Larson, John

    2012-09-27

    Fragile X syndrome is a neurodevelopmental condition caused by the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. The Fmr1 knockout (KO) mouse exhibits age-dependent deficits in long term potentiation (LTP) at association (ASSN) synapses in anterior piriform cortex (APC). To investigate the mechanisms for this, whole-cell voltage-clamp recordings of ASSN stimulation-evoked synaptic currents were made in APC of slices from adult Fmr1-KO and wild-type (WT) mice, using the competitive N-methyl-D-aspartate (NMDA) receptor antagonist, CPP, to distinguish currents mediated by NMDA and AMPA receptors. NMDA/AMPA current ratios were lower in Fmr1-KO mice than in WT mice, at ages ranging from 3-18months. Since amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) mediated by AMPA receptors were no different in Fmr1-KO and WT mice at these ages, the results suggest that NMDA receptor-mediated currents are selectively reduced in Fmr1-KO mice. Analyses of voltage-dependence and decay kinetics of NMDA receptor-mediated currents did not reveal differences between Fmr1-KO and WT mice, suggesting that reduced NMDA currents in Fmr1-KO mice are due to fewer synaptic receptors rather than differences in receptor subunit composition. Reduced NMDA receptor signaling may help to explain the LTP deficit seen at APC ASSN synapses in Fmr1-KO mice at 6-18months of age, but does not explain normal LTP at these synapses in mice 3-6months old. Evoked currents and mEPSCs were also examined in senescent Fmr1-KO and WT mice at 24-28months of age. NMDA/AMPA ratios were similar in senescent WT and Fmr1-KO mice, due to a decrease in the ratio in the WT mice, without significant change in AMPA receptor-mediated mEPSCs. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Behavior control in the sensorimotor loop with short-term synaptic dynamics induced by self-regulating neurons

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    Hazem eToutounji

    2014-05-01

    Full Text Available The behavior and skills of living systems depend on the distributed control provided by specialized and highly recurrent neural networks. Learning and memory in these systems is mediated by a set of adaptation mechanisms, known collectively as neuronal plasticity. Translating principles of recurrent neural control and plasticity to artificial agents has seen major strides, but is usually hampered by the complex interactions between the agent's body and its environment. One of the important standing issues is for the agent to support multiple stable states of behavior, so that its behavioral repertoire matches the requirements imposed by these interactions. The agent also must have the capacity to switch between these states in time scales that are comparable to those by which sensory stimulation varies. Achieving this requires a mechanism of short-term memory that allows the neurocontroller to keep track of the recent history of its input, which finds its biological counterpart in short-term synaptic plasticity. This issue is approached here by deriving synaptic dynamics in recurrent neural networks. Neurons are introduced as self-regulating units with a rich repertoire of dynamics. They exhibit homeostatic properties for certain parameter domains, which result in a set of stable states and the required short-term memory. They can also operate as oscillators, which allow them to surpass the level of activity imposed by their homeostatic operation conditions. Neural systems endowed with the derived synaptic dynamics can be utilized for the neural behavior control of autonomous mobile agents. The resulting behavior depends also on the underlying network structure, which is either engineered, or developed by evolutionary techniques. The effectiveness of these self-regulating units is demonstrated by controlling locomotion of a hexapod with eighteen degrees of freedom, and obstacle-avoidance of a wheel-driven robot.

  18. Firing-rate response of linear and nonlinear integrate-and-fire neurons to modulated current-based and conductance-based synaptic drive.

    Science.gov (United States)

    Richardson, Magnus J E

    2007-08-01

    Integrate-and-fire models are mainstays of the study of single-neuron response properties and emergent states of recurrent networks of spiking neurons. They also provide an analytical base for perturbative approaches that treat important biological details, such as synaptic filtering, synaptic conductance increase, and voltage-activated currents. Steady-state firing rates of both linear and nonlinear integrate-and-fire models, receiving fluctuating synaptic drive, can be calculated from the time-independent Fokker-Planck equation. The dynamic firing-rate response is less easy to extract, even at the first-order level of a weak modulation of the model parameters, but is an important determinant of neuronal response and network stability. For the linear integrate-and-fire model the response to modulations of current-based synaptic drive can be written in terms of hypergeometric functions. For the nonlinear exponential and quadratic models no such analytical forms for the response are available. Here it is demonstrated that a rather simple numerical method can be used to obtain the steady-state and dynamic response for both linear and nonlinear models to parameter modulation in the presence of current-based or conductance-based synaptic fluctuations. To complement the full numerical solution, generalized analytical forms for the high-frequency response are provided. A special case is also identified--time-constant modulation--for which the response to an arbitrarily strong modulation can be calculated exactly.

  19. Regulation of synaptic nlg-1/neuroligin abundance by the skn-1/Nrf stress response pathway protects against oxidative stress.

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    Trisha A Staab

    2014-01-01

    Full Text Available The Nrf family of transcription factors mediates adaptive responses to stress and longevity, but the identities of the crucial Nrf targets, and the tissues in which they function in multicellular organisms to promote survival, are not known. Here, we use whole transcriptome RNA sequencing to identify 810 genes whose expression is controlled by the SKN-1/Nrf2 negative regulator WDR-23 in the nervous system of Caenorhabditis elegans. Among the genes identified is the synaptic cell adhesion molecule nlg-1/neuroligin. We find that the synaptic abundance of NLG-1 protein increases following pharmacological treatments that generate oxidative stress or by the genetic activation of skn-1. Increasing nlg-1 dosage correlates with increased survival in response to oxidative stress, whereas genetic inactivation of nlg-1 reduces survival and impairs skn-1-mediated stress resistance. We identify a canonical SKN-1 binding site in the nlg-1 promoter that binds to SKN-1 in vitro and is necessary for SKN-1 and toxin-mediated increases in nlg-1 expression in vivo. Together, our results suggest that SKN-1 activation in the nervous system can confer protection to organisms in response to stress by directly regulating nlg-1/neuroligin expression.

  20. UNC-16/JIP3 regulates early events in synaptic vesicle protein trafficking via LRK-1/LRRK2 and AP complexes.

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    Bikash Choudhary

    2017-11-01

    Full Text Available JIP3/UNC-16/dSYD is a MAPK-scaffolding protein with roles in protein trafficking. We show that it is present on the Golgi and is necessary for the polarized distribution of synaptic vesicle proteins (SVPs and dendritic proteins in neurons. UNC-16 excludes Golgi enzymes from SVP transport carriers and facilitates inclusion of specific SVPs into the same transport carrier. The SVP trafficking roles of UNC-16 are mediated through LRK-1, whose localization to the Golgi is reduced in unc-16 animals. UNC-16, through LRK-1, also enables Golgi-localization of the μ-subunit of the AP-1 complex. AP1 regulates the size but not the composition of SVP transport carriers. Additionally, UNC-16 and LRK-1 through the AP-3 complex regulates the composition but not the size of the SVP transport carrier. These early biogenesis steps are essential for dependence on the synaptic vesicle motor, UNC-104 for axonal transport. Our results show that UNC-16 and its downstream effectors, LRK-1 and the AP complexes function at the Golgi and/or post-Golgi compartments to control early steps of SV biogenesis. The UNC-16 dependent steps of exclusion, inclusion and motor recruitment are critical for polarized distribution of neuronal cargo.

  1. Taurine regulation of short term synaptic plasticity in fragile X mice.

    Science.gov (United States)

    El Idrissi, Abdeslem; Neuwirth, Lorenz S; L'Amoreaux, William

    2010-08-24

    Fragile X Syndrome is the most common known genetic cause of autism. The Fmr1-KO mouse, lacks the fragile X mental retardation protein (FMRP), and is used as a model of the syndrome. The core behavioral deficits of autism may be conceptualized either as excessive adherence to patterns as seen in repetitive actions and aberrant language, or as insensitivity to subtle but socially important changes in patterns. The hippocampus receives information from the entorhinal cortex and plays a crucial role in the processing of patterned information. To gain more insight into the physiological function of FMRP and the neuronal mechanisms underlying fragile X syndrome, we examined the electrophysiological response of the hippocampus to pair pulse stimulation as a measure of patterned information processing and how it is affected in the Fmr1-KO mouse. In this study, we used paired-pulse stimulation of the afferent perforant path and recorded from the CA1 region of the hippocampus. Two-month-old FVB/NJ male mice and age-matched Fmr1-KO mice were used in this study. Hippocampal slices were prepared, equilibrated in artificial cerebrospinal fluid (aCSF), and excitatory post synaptic potentials (EPSPs) measured by stimulating the perforant path of the dentate gyrus (DG) while recording from the molecular layer of CA1. Stimulation occurred by setting current and pulse width to evoke a fixed percentage of maximal EPSP amplitude. This stimulation paradigm allowed us to examine the processing capabilities of the hippocampus as a function of increasing interstimulus intervals (ISI) and how taurine, a GABAA receptor agonist, affects such information processing. We found that hippocampal slices from wild type (WT) showed pair-pulse facilitation at ISI of 100-300 ms whereas slices from Fmr1-KO brains showed a consistent pair-pulse depression at a comparable ISI. Addition of 10 muM taurine to WT slices resulted in a drastic decrease of the peak response to the second stimulus, resulting in

  2. Impact of Morphometry, Myelinization and Synaptic Current Strength on Spike Conduction in Human and Cat Spiral Ganglion Neurons

    Science.gov (United States)

    Rattay, Frank; Potrusil, Thomas; Wenger, Cornelia; Wise, Andrew K.; Glueckert, Rudolf; Schrott-Fischer, Anneliese

    2013-01-01

    Background Our knowledge about the neural code in the auditory nerve is based to a large extent on experiments on cats. Several anatomical differences between auditory neurons in human and cat are expected to lead to functional differences in speed and safety of spike conduction. Methodology/Principal Findings Confocal microscopy was used to systematically evaluate peripheral and central process diameters, commonness of myelination and morphology of spiral ganglion neurons (SGNs) along the cochlea of three human and three cats. Based on these morphometric data, model analysis reveales that spike conduction in SGNs is characterized by four phases: a postsynaptic delay, constant velocity in the peripheral process, a presomatic delay and constant velocity in the central process. The majority of SGNs are type I, connecting the inner hair cells with the brainstem. In contrast to those of humans, type I neurons of the cat are entirely myelinated. Biophysical model evaluation showed delayed and weak spikes in the human soma region as a consequence of a lack of myelin. The simulated spike conduction times are in accordance with normal interwave latencies from auditory brainstem response recordings from man and cat. Simulated 400 pA postsynaptic currents from inner hair cell ribbon synapses were 15 times above threshold. They enforced quick and synchronous spiking. Both of these properties were not present in type II cells as they receive fewer and much weaker (∼26 pA) synaptic stimuli. Conclusions/Significance Wasting synaptic energy boosts spike initiation, which guarantees the rapid transmission of temporal fine structure of auditory signals. However, a lack of myelin in the soma regions of human type I neurons causes a large delay in spike conduction in comparison with cat neurons. The absent myelin, in combination with a longer peripheral process, causes quantitative differences of temporal parameters in the electrically stimulated human cochlea compared to the cat

  3. γ1-Containing GABA-A Receptors Cluster at Synapses Where they Mediate Slower Synaptic Currents than γ2-Containing GABA-A Receptors

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    Christine L. Dixon

    2017-06-01

    Full Text Available GABA-A receptors (GABAARs are pentameric ligand-gated ion channels that are assembled mainly from α (α1–6, β (β1–3 and γ (γ1–3 subunits. Although GABAARs containing γ2L subunits mediate most of the inhibitory neurotransmission in the brain, significant expression of γ1 subunits is seen in the amygdala, pallidum and substantia nigra. However, the location and function of γ1-containing GABAARs in these regions remains unclear. In “artificial” synapses, where the subunit composition of postsynaptic receptors is specifically controlled, γ1 incorporation slows the synaptic current decay rate without affecting channel deactivation, suggesting that γ1-containing receptors are not clustered and therefore activated by diffuse neurotransmitter. However, we show that γ1-containing receptors are localized at neuronal synapses and form clusters in both synaptic and extrasynaptic regions. In addition, they exhibit rapid membrane diffusion and a higher frequency of exchange between synaptic and perisynaptic populations compared to γ2L-containing GABAARs. A point mutation in the large intracellular domain and a pharmacological analysis reveal that when a single non-conserved γ2L residue is mutated to its γ1 counterpart (T349L, the synaptic current decay is slowed from γ2L- to γ1-like without changing the clustering or diffusion properties of the receptors. In addition, previous fast perfusion and single channel kinetic experiments revealed no difference in the intrinsic closing rates of γ2L- and γ1-containing receptors when expressed in HEK293 cells. These observations together with Monte Carlo simulations of synaptic function confirm that decreased clustering does not control γ1-containing GABAAR kinetics. Rather, they suggest that γ1- and γ2L-containing receptors exhibit differential synaptic current decay rates due to differential gating dynamics when localized at the synapse.

  4. The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning.

    Science.gov (United States)

    Gao, Jie; Marosi, Mate; Choi, Jinkuk; Achiro, Jennifer M; Kim, Sangmok; Li, Sandy; Otis, Klara; Martin, Kelsey C; Portera-Cailliau, Carlos; Tontonoz, Peter

    2017-09-11

    Neuronal ApoE receptors are linked to learning and memory, but the pathways governing their abundance, and the mechanisms by which they affect the function of neural circuits are incompletely understood. Here we demonstrate that the E3 ubiquitin ligase IDOL determines synaptic ApoER2 protein levels in response to neuronal activation and regulates dendritic spine morphogenesis and plasticity. IDOL-dependent changes in ApoER2 abundance modulate dendritic filopodia initiation and synapse maturation. Loss of IDOL in neurons results in constitutive overexpression of ApoER2 and is associated with impaired activity-dependent structural remodeling of spines and defective LTP in primary neuron cultures and hippocampal slices. IDOL-deficient mice show profound impairment in experience-dependent reorganization of synaptic circuits in the barrel cortex, as well as diminished spatial and associative learning. These results identify control of lipoprotein receptor abundance by IDOL as a post-transcriptional mechanism underlying the structural and functional plasticity of synapses and neural circuits.

  5. Long-lasting alterations in membrane properties, K+ currents and glutamatergic synaptic currents of nucleus accumbens medium spiny neurons in a rat model of alcohol dependence

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    Igor eSpigelman

    2012-06-01

    Full Text Available Chronic alcohol exposure causes marked changes in reinforcement mechanisms and motivational state that are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc is a key structure of the mesolimbic dopaminergic reward system. Although the NAcc plays an important role in mediating alcohol-seeking behaviors, little is known about the molecular mechanisms underlying alcohol-induced neuroadaptive changes in NAcc function. The aim of this study was to investigate the effects of chronic intermittent ethanol (CIE treatment, a rat model of alcohol withdrawal and dependence, on intrinsic electrical membrane properties and glutamatergic synaptic transmission of medium spiny neurons (MSNs in the NAcc core during protracted withdrawal. We show that CIE treatment followed by prolonged withdrawal increased the inward rectification of MSNs observed at hyperpolarized potentials. In addition, MSNs from CIE-treated animals displayed a lower input resistance, faster action potentials (APs and larger fast afterhyperpolarizations (fAHPs than MSNs from vehicle-treated animals, all suggestive of increases in K+-channel conductances. Significant increases in the Cs+-sensitive inwardly-rectifying K+-current accounted for the increased input resistance, while increases in the A-type K+-current accounted for the faster APs and increased fAHPs in MSNs from CIE rats. We also show that the amplitude and the conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR-mediated mEPSCs were enhanced in CIE-treated animals due to an increase in a small fraction of functional postsynaptic GluA2-lacking AMPARs. These long-lasting modifications of excitability and excitatory synaptic receptor function of MSNs in the NAcc core could play a critical role in the neuroadaptive changes underlying alcohol withdrawal and dependence.

  6. Miniature excitatory synaptic ion currents in the earthworm Lumbricus terrestris body wall muscles

    Czech Academy of Sciences Publication Activity Database

    Volkov, E. M.; Nurullin, L. F.; Nikolsky, E.; Vyskočil, František

    2007-01-01

    Roč. 56, č. 5 (2007), s. 655-658 ISSN 0862-8408 R&D Projects: GA AV ČR(CZ) IAA5011411 Grant - others:RFBR(RU) 06-04-48458; Nsh(RU) 4444.2006.4 Institutional research plan: CEZ:AV0Z50110509 Keywords : ion currents * muscle cells * acetylcholine receptor Subject RIV: ED - Physiology Impact factor: 1.505, year: 2007

  7. A tale of two stories: astrocyte regulation of synaptic depression and facilitation.

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    Maurizio De Pittà

    2011-12-01

    Full Text Available Short-term presynaptic plasticity designates variations of the amplitude of synaptic information transfer whereby the amount of neurotransmitter released upon presynaptic stimulation changes over seconds as a function of the neuronal firing activity. While a consensus has emerged that the resulting decrease (depression and/or increase (facilitation of the synapse strength are crucial to neuronal computations, their modes of expression in vivo remain unclear. Recent experimental studies have reported that glial cells, particularly astrocytes in the hippocampus, are able to modulate short-term plasticity but the mechanism of such a modulation is poorly understood. Here, we investigate the characteristics of short-term plasticity modulation by astrocytes using a biophysically realistic computational model. Mean-field analysis of the model, supported by intensive numerical simulations, unravels that astrocytes may mediate counterintuitive effects. Depending on the expressed presynaptic signaling pathways, astrocytes may globally inhibit or potentiate the synapse: the amount of released neurotransmitter in the presence of the astrocyte is transiently smaller or larger than in its absence. But this global effect usually coexists with the opposite local effect on paired pulses: with release-decreasing astrocytes most paired pulses become facilitated, namely the amount of neurotransmitter released upon spike i+1 is larger than that at spike i, while paired-pulse depression becomes prominent under release-increasing astrocytes. Moreover, we show that the frequency of astrocytic intracellular Ca(2+ oscillations controls the effects of the astrocyte on short-term synaptic plasticity. Our model explains several experimental observations yet unsolved, and uncovers astrocytic gliotransmission as a possible transient switch between short-term paired-pulse depression and facilitation. This possibility has deep implications on the processing of neuronal spikes

  8. GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity.

    OpenAIRE

    Duprat, Fabrice; Daw, Michael; Lim, Wonil; Collingridge, Graham; Isaac, John

    2003-01-01

    AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these i...

  9. Synaptic Correlates of Working Memory Capacity.

    Science.gov (United States)

    Mi, Yuanyuan; Katkov, Mikhail; Tsodyks, Misha

    2017-01-18

    Psychological studies indicate that human ability to keep information in readily accessible working memory is limited to four items for most people. This extremely low capacity severely limits execution of many cognitive tasks, but its neuronal underpinnings remain unclear. Here we show that in the framework of synaptic theory of working memory, capacity can be analytically estimated to scale with characteristic time of short-term synaptic depression relative to synaptic current time constant. The number of items in working memory can be regulated by external excitation, enabling the system to be tuned to the desired load and to clear the working memory of currently held items to make room for new ones. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Amine Neurotransmitter Regulation of Long-Term Synaptic Plasticity in Hippocampus.

    Science.gov (United States)

    1986-04-15

    structure and certain active membrane currents ( Hodgkin and Huxley sodium current, Hodgkin and Huxley potassium current, and voltage- dependent calcium...20 CL 50-- I- N-20 25 CONTROL NE PTX NE S i i f i cot I y greotar than contro l. pc. 05 PTX a i gn I F i cont 1 y 9 rmotar thorn PTX. pc. 025 Fig. 2

  11. Spine Calcium Transients Induced by Synaptically-Evoked Action Potentials Can Predict Synapse Location and Establish Synaptic Democracy

    Science.gov (United States)

    Meredith, Rhiannon M.; van Ooyen, Arjen

    2012-01-01

    CA1 pyramidal neurons receive hundreds of synaptic inputs at different distances from the soma. Distance-dependent synaptic scaling enables distal and proximal synapses to influence the somatic membrane equally, a phenomenon called “synaptic democracy”. How this is established is unclear. The backpropagating action potential (BAP) is hypothesised to provide distance-dependent information to synapses, allowing synaptic strengths to scale accordingly. Experimental measurements show that a BAP evoked by current injection at the soma causes calcium currents in the apical shaft whose amplitudes decay with distance from the soma. However, in vivo action potentials are not induced by somatic current injection but by synaptic inputs along the dendrites, which creates a different excitable state of the dendrites. Due to technical limitations, it is not possible to study experimentally whether distance information can also be provided by synaptically-evoked BAPs. Therefore we adapted a realistic morphological and electrophysiological model to measure BAP-induced voltage and calcium signals in spines after Schaffer collateral synapse stimulation. We show that peak calcium concentration is highly correlated with soma-synapse distance under a number of physiologically-realistic suprathreshold stimulation regimes and for a range of dendritic morphologies. Peak calcium levels also predicted the attenuation of the EPSP across the dendritic tree. Furthermore, we show that peak calcium can be used to set up a synaptic democracy in a homeostatic manner, whereby synapses regulate their synaptic strength on the basis of the difference between peak calcium and a uniform target value. We conclude that information derived from synaptically-generated BAPs can indicate synapse location and can subsequently be utilised to implement a synaptic democracy. PMID:22719238

  12. Synapse geometry and receptor dynamics modulate synaptic strength.

    Directory of Open Access Journals (Sweden)

    Dominik Freche

    Full Text Available Synaptic transmission relies on several processes, such as the location of a released vesicle, the number and type of receptors, trafficking between the postsynaptic density (PSD and extrasynaptic compartment, as well as the synapse organization. To study the impact of these parameters on excitatory synaptic transmission, we present a computational model for the fast AMPA-receptor mediated synaptic current. We show that in addition to the vesicular release probability, due to variations in their release locations and the AMPAR distribution, the postsynaptic current amplitude has a large variance, making a synapse an intrinsic unreliable device. We use our model to examine our experimental data recorded from CA1 mice hippocampal slices to study the differences between mEPSC and evoked EPSC variance. The synaptic current but not the coefficient of variation is maximal when the active zone where vesicles are released is apposed to the PSD. Moreover, we find that for certain type of synapses, receptor trafficking can affect the magnitude of synaptic depression. Finally, we demonstrate that perisynaptic microdomains located outside the PSD impacts synaptic transmission by regulating the number of desensitized receptors and their trafficking to the PSD. We conclude that geometrical modifications, reorganization of the PSD or perisynaptic microdomains modulate synaptic strength, as the mechanisms underlying long-term plasticity.

  13. Astrocyte-like glial cells physiologically regulate olfactory processing through the modification of ORN-PN synaptic strength in Drosophila.

    Science.gov (United States)

    Liu, He; Zhou, Bangyu; Yan, Wenjun; Lei, Zhengchang; Zhao, Xiaoliang; Zhang, Ke; Guo, Aike

    2014-09-01

    Astrocyte-like glial cells are abundant in the central nervous system of adult Drosophila and exhibit morphology similar to astrocytes of mammals. Previous evidence has shown that astrocyte-like glial cells are strongly associated with synapses in the antennal lobe (AL), the first relay of the olfactory system, where olfactory receptor neurons (ORNs) transmit information into projection neurons (PNs). However, the function of astrocyte-like glia in the AL remains obscure. In this study, using in vivo calcium imaging, we found that astrocyte-like glial cells exhibited spontaneous microdomain calcium elevations. Using simultaneous manipulation of glial activity and monitoring of neuronal function, we found that the astrocyte-like glial activation, but not ensheathing glial activation, could inhibit odor-evoked responses of PNs. Ensheathing glial cells are another subtype of glia, and are of functional importance in the AL. Electrophysiological experiments indicated that astrocyte-like glial activation decreased the amplitude and slope of excitatory postsynaptic potentials evoked through electrical stimulation of the antennal nerve. These results suggest that astrocyte-like glial cells may regulate olfactory processing through negative regulation of ORN-PN synaptic strength. Beyond the antennal lobe we observed astrocyte-like glial spontaneous calcium activities in the ventromedial protocerebrum, indicating that astrocyte-like glial spontaneous calcium elevations might be general in the adult fly brain. Overall, our study demonstrates a new function for astrocyte-like glial cells in the physiological modulation of olfactory information transmission, possibly through regulating ORN-PN synapse strength. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  14. Regulation of synaptic inhibition by phospho-dependent binding of the AP2 complex to a YECL motif in the GABAA receptor γ2 subunit

    Science.gov (United States)

    Kittler, Josef T.; Chen, Guojun; Kukhtina, Viktoria; Vahedi-Faridi, Ardeschir; Gu, Zhenglin; Tretter, Verena; Smith, Katharine R.; McAinsh, Kristina; Arancibia-Carcamo, I. Lorena; Saenger, Wolfram; Haucke, Volker; Yan, Zhen; Moss, Stephen J.

    2008-01-01

    The regulation of the number of γ2-subunit-containing GABAA receptors (GABAARs) present at synapses is critical for correct synaptic inhibition and animal behavior. This regulation occurs, in part, by the controlled removal of receptors from the membrane in clathrin-coated vesicles, but it remains unclear how clathrin recruitment to surface γ2-subunit-containing GABAARs is regulated. Here, we identify a γ2-subunit-specific Yxxφ-type-binding motif for the clathrin adaptor protein, AP2, which is located within a site for γ2-subunit tyrosine phosphorylation. Blocking GABAAR-AP2 interactions via this motif increases synaptic responses within minutes. Crystallographic and biochemical studies reveal that phosphorylation of the Yxxφ motif inhibits AP2 binding, leading to increased surface receptor number. In addition, the crystal structure provides an explanation for the high affinity of this motif for AP2 and suggests that γ2-subunit-containing heteromeric GABAARs may be internalized as dimers or multimers. These data define a mechanism for tyrosine kinase regulation of GABAAR surface levels and synaptic inhibition. PMID:18305175

  15. Regulation of synaptic inhibition by phospho-dependent binding of the AP2 complex to a YECL motif in the GABAA receptor gamma2 subunit.

    Science.gov (United States)

    Kittler, Josef T; Chen, Guojun; Kukhtina, Viktoria; Vahedi-Faridi, Ardeschir; Gu, Zhenglin; Tretter, Verena; Smith, Katharine R; McAinsh, Kristina; Arancibia-Carcamo, I Lorena; Saenger, Wolfram; Haucke, Volker; Yan, Zhen; Moss, Stephen J

    2008-03-04

    The regulation of the number of gamma2-subunit-containing GABA(A) receptors (GABA(A)Rs) present at synapses is critical for correct synaptic inhibition and animal behavior. This regulation occurs, in part, by the controlled removal of receptors from the membrane in clathrin-coated vesicles, but it remains unclear how clathrin recruitment to surface gamma2-subunit-containing GABA(A)Rs is regulated. Here, we identify a gamma2-subunit-specific Yxxvarphi-type-binding motif for the clathrin adaptor protein, AP2, which is located within a site for gamma2-subunit tyrosine phosphorylation. Blocking GABA(A)R-AP2 interactions via this motif increases synaptic responses within minutes. Crystallographic and biochemical studies reveal that phosphorylation of the Yxxvarphi motif inhibits AP2 binding, leading to increased surface receptor number. In addition, the crystal structure provides an explanation for the high affinity of this motif for AP2 and suggests that gamma2-subunit-containing heteromeric GABA(A)Rs may be internalized as dimers or multimers. These data define a mechanism for tyrosine kinase regulation of GABA(A)R surface levels and synaptic inhibition.

  16. Synaptic Plasticity and Translation Initiation

    Science.gov (United States)

    Klann, Eric; Antion, Marcia D.; Banko, Jessica L.; Hou, Lingfei

    2004-01-01

    It is widely accepted that protein synthesis, including local protein synthesis at synapses, is required for several forms of synaptic plasticity. Local protein synthesis enables synapses to control synaptic strength independent of the cell body via rapid protein production from pre-existing mRNA. Therefore, regulation of translation initiation is…

  17. Munc13 C[subscript 2]B domain is an activity-dependent Ca[superscript 2+] regulator of synaptic exocytosis

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Ok-Ho; Lu, Jun; Rhee, Jeong-Seop; Tomchick, Diana R.; Pang, Zhiping P.; Wojcik, Sonja M.; Camacho-Perez, Marcial; Brose, Nils; Machius, Mischa; Rizo, Josep; Rosenmund, Christian; Südhof, Thomas C. (Baylor); (MXPL-B); (MXPL); (UTSMC)

    2010-04-26

    Munc13 is a multidomain protein present in presynaptic active zones that mediates the priming and plasticity of synaptic vesicle exocytosis, but the mechanisms involved remain unclear. Here we use biophysical, biochemical and electrophysiological approaches to show that the central C{sub 2}B domain of Munc13 functions as a Ca{sup 2+} regulator of short-term synaptic plasticity. The crystal structure of the C{sub 2}B domain revealed an unusual Ca{sup 2+}-binding site with an amphipathic {alpha}-helix. This configuration confers onto the C{sub 2}B domain unique Ca{sup 2+}-dependent phospholipid-binding properties that favor phosphatidylinositolphosphates. A mutation that inactivated Ca{sup 2+}-dependent phospholipid binding to the C{sub 2}B domain did not alter neurotransmitter release evoked by isolated action potentials, but it did depress release evoked by action-potential trains. In contrast, a mutation that increased Ca{sup 2+}-dependent phosphatidylinositolbisphosphate binding to the C{sub 2}B domain enhanced release evoked by isolated action potentials and by action-potential trains. Our data suggest that, during repeated action potentials, Ca{sup 2+} and phosphatidylinositolphosphate binding to the Munc13 C{sub 2}B domain potentiate synaptic vesicle exocytosis, thereby offsetting synaptic depression induced by vesicle depletion.

  18. Phospho-dependent binding of the clathrin AP2 adaptor complex to GABAA receptors regulates the efficacy of inhibitory synaptic transmission

    OpenAIRE

    Kittler, Josef T.; Chen, Guojun; Honing, Stephan; Bogdanov, Yury; McAinsh, Kristina; Arancibia-Carcamo, I. Lorena; Jovanovic, Jasmina N.; Pangalos, Menelas N.; Haucke, Volker; Yan, Zhen; Moss, Stephen J.

    2005-01-01

    The efficacy of synaptic inhibition depends on the number of γ-aminobutyric acid type A receptors (GABAARs) expressed on the cell surface of neurons. The clathrin adaptor protein 2 (AP2) complex is a critical regulator of GABAAR endocytosis and, hence, surface receptor number. Here, we identify a previously uncharacterized atypical AP2 binding motif conserved within the intracellular domains of all GABAAR β subunit isoforms. This AP2 binding motif (KTHLRRRSSQLK in the β3 subunit) incorporates...

  19. Vorinostat positively regulates synaptic plasticity genes expression and spine density in HIV infected neurons: role of nicotine in progression of HIV-associated neurocognitive disorder

    Science.gov (United States)

    2014-01-01

    Background HIV-associated neurocognitive disorder (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occurs in approximately 50% of HIV infected individuals. In the United States, the prevalence of cigarette smoking ranges from 35-70% in HIV-infected individuals compared to 20% in general population. Cognitive impairment in heavy cigarette smokers has been well reported. However, the synergistic effects of nicotine and HIV infection and the underlying mechanisms in the development of HAND are unknown. Results In this study, we explored the role of nicotine in the progression of HAND using SK-N-MC, a neuronal cell line. SK-N-MC cells were infected with HIV-1 in the presence or absence of nicotine for 7 days. We observed significant increase in HIV infectivity in SK-N-MC treated with nicotine compared to untreated HIV-infected neuronal cells. HIV and nicotine synergize to significantly dysregulate the expression of synaptic plasticity genes and spine density; with a concomitant increase of HDAC2 levels in SK-N-MC cells. In addition, inhibition of HDAC2 up-regulation with the use of vorinostat resulted in HIV latency breakdown and recovery of synaptic plasticity genes expression and spine density in nicotine/HIV alone and in co-treated SK-N-MC cells. Furthermore, increased eIF2 alpha phosphorylation, which negatively regulates eukaryotic translational process, was observed in HIV alone and in co-treatment with nicotine compared to untreated control and nicotine alone treated SK-N-MC cells. Conclusions These results suggest that nicotine and HIV synergize to negatively regulate the synaptic plasticity gene expression and spine density and this may contribute to the increased risk of HAND in HIV infected smokers. Apart from disrupting latency, vorinostat may be a useful therapeutic to inhibit the negative regulatory effects on synaptic plasticity in HIV infected nicotine abusers. PMID:24886748

  20. Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment.

    Science.gov (United States)

    Lawrence, James L M; Tong, Mei; Alfulaij, Naghum; Sherrin, Tessi; Contarino, Mark; White, Michael M; Bellinger, Frederick P; Todorovic, Cedomir; Nichols, Robert A

    2014-10-22

    Soluble β-amyloid has been shown to regulate presynaptic Ca(2+) and synaptic plasticity. In particular, picomolar β-amyloid was found to have an agonist-like action on presynaptic nicotinic receptors and to augment long-term potentiation (LTP) in a manner dependent upon nicotinic receptors. Here, we report that a functional N-terminal domain exists within β-amyloid for its agonist-like activity. This sequence corresponds to a N-terminal fragment generated by the combined action of α- and β-secretases, and resident carboxypeptidase. The N-terminal β-amyloid fragment is present in the brains and CSF of healthy adults as well as in Alzheimer's patients. Unlike full-length β-amyloid, the N-terminal β-amyloid fragment is monomeric and nontoxic. In Ca(2+) imaging studies using a model reconstituted rodent neuroblastoma cell line and isolated mouse nerve terminals, the N-terminal β-amyloid fragment proved to be highly potent and more effective than full-length β-amyloid in its agonist-like action on nicotinic receptors. In addition, the N-terminal β-amyloid fragment augmented theta burst-induced post-tetanic potentiation and LTP in mouse hippocampal slices. The N-terminal fragment also rescued LTP inhibited by elevated levels of full-length β-amyloid. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal β-amyloid fragment into the dorsal hippocampi of intact mice. The fragment-induced augmentation of fear conditioning was attenuated by coadministration of nicotinic antagonist. The activity of the N-terminal β-amyloid fragment appears to reside largely in a sequence surrounding a putative metal binding site, YEVHHQ. These findings suggest that the N-terminal β-amyloid fragment may serve as a potent and effective endogenous neuromodulator. Copyright © 2014 the authors 0270-6474/14/3414210-09$15.00/0.

  1. Differential regulation of synaptic and extrasynaptic α4 GABA(A) receptor populations by protein kinase A and protein kinase C in cultured cortical neurons.

    Science.gov (United States)

    Bohnsack, John Peyton; Carlson, Stephen L; Morrow, A Leslie

    2016-06-01

    The GABAA α4 subunit exists in two distinct populations of GABAA receptors. Synaptic GABAA α4 receptors are localized at the synapse and mediate phasic inhibitory neurotransmission, while extrasynaptic GABAA receptors are located outside of the synapse and mediate tonic inhibitory transmission. These receptors have distinct pharmacological and biophysical properties that contribute to interest in how these different subtypes are regulated under physiological and pathological states. We utilized subcellular fractionation procedures to separate these populations of receptors in order to investigate their regulation by protein kinases in cortical cultured neurons. Protein kinase A (PKA) activation decreases synaptic α4 expression while protein kinase C (PKC) activation increases α4 subunit expression, and these effects are associated with increased β3 S408/409 or γ2 S327 phosphorylation respectively. In contrast, PKA activation increases extrasynaptic α4 and δ subunit expression, while PKC activation has no effect. Our findings suggest synaptic and extrasynaptic GABAA α4 subunit expression can be modulated by PKA to inform the development of more specific therapeutics for neurological diseases that involve deficits in GABAergic transmission. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Regulation of synaptic MAPK/ERK phosphorylation in the rat striatum and medial prefrontal cortex by dopamine and muscarinic acetylcholine receptors.

    Science.gov (United States)

    Xue, Bing; Mao, Li-Min; Jin, Dao-Zhong; Wang, John Q

    2015-10-01

    Dopamine and acetylcholine are two principal transmitters in the striatum and are usually balanced to modulate local neural activity and to maintain striatal homeostasis. This study investigates the role of dopamine and muscarinic acetylcholine receptors in the regulation of a central signaling protein, i.e., the mitogen-activated protein kinase (MAPK). We focus on the synaptic pool of MAPKs because of the fact that these kinases reside in peripheral synaptic structures in addition to their somatic locations. We show that a systemic injection of dopamine D1 receptor (D1R) agonist SKF81297 enhances phosphorylation of extracellular signal-regulated kinases (ERKs), a prototypic subclass of MAPKs, in the adult rat striatum. Similar results were observed in another dopamine-responsive region, the medial prefrontal cortex (mPFC). The dopamine D2 receptor agonist quinpirole had no such effects. Pretreatment with a positive allosteric modulator (PAM) of muscarinic acetylcholine M4 receptors (M4Rs), VU0152100, attenuated the D1R agonist-stimulated ERK phosphorylation in the two regions, whereas the PAM itself did not alter basal ERK phosphorylation. All drug treatments had no effect on phosphorylation of c-Jun N-terminal kinases (JNKs), another MAPK subclass, in the striatum and mPFC. These results demonstrate that dopamine and acetylcholine are integrated to control synaptic ERK but not JNK activation in striatal and mPFC neurons in vivo. Activation of M4Rs exerts an inhibitory effect on the D1R-mediated upregulation of synaptic ERK phosphorylation. © 2015 Wiley Periodicals, Inc.

  3. Nuclear regulations: current status and proposed initiatives

    International Nuclear Information System (INIS)

    Domondon, D.B.; Valdezco, E.M.; Mateo, A.J.; Parami, V.K.

    1996-01-01

    The science Act of 1958 created the Philippine Atomic Energy Commission, presently known as the Philippine Nuclear Research Institute (PNRI), under the Department of Science and Technology (DOST). The PNRI is tasked with the dual role of promotion and control of the peaceful applications of atomic energy. To carry its mandate of regulation and control on the use of raioisotopes in various fields, the PNRI had promulgated and issued specific regulations known as the Code of PNRI regulations. This paper summarizes the activities undertaken by PNRI in the continuing process of review and subsequent revisions of the Code of PNRI regulations and related guidance documents. It highlights proposed modifications in the present regulations in an attempt to adopt the new international basic safety standards, the practical problems and related issues attendant to the implementation of these new standards, among others. In line with the overall objective of PNRI to ensure the safe application of nuclear energy and radiation technology in various fields, the institute conducted a series of regulatory information conferences to provide an opportunity for members of the regulatory staff of the PNRI and licenses to discuss safety initiatives and regulatory issues. This paper will also provide an in-depth assessment of the lessons learned from these conferences which were conducted by sector or by specific applications for a more focused approach, e.g. radiopharmaceuticals, industrial radiography, research, among others. Licensees' feedback on the PNRI regulatory process are presented as part of the overall objective of enhancing the operational experiences of the licensing, review and evaluation group as well as that of inspection, enforcement and compliance. Several proposed initiatives for consideration of the PNRI to further strengthen its regulatory functions are also briefly outlined. (author)

  4. UK medicines regulation: responding to current challenges.

    Science.gov (United States)

    Richards, Natalie; Hudson, Ian

    2016-12-01

    The medicines regulatory environment is evolving rapidly in response to the changing environment. Advances in science and technology have led to a vast field of increasingly complicated pharmaceutical and medical device products; increasing globalization of the pharmaceutical industry, advances in digital technology and the internet, changing patient populations, and shifts in society also affect the regulatory environment. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) regulates medicines, medical devices and blood products to protect and improve public health, and supports innovation through scientific research and development. It works closely with other bodies in a single medicines network across Europe and takes forward UK health priorities. This paper discusses the range of initiatives in the UK and across Europe to support innovation in medicines regulation. The MHRA leads a number of initiatives, such as the Innovation Office, which helps innovators to navigate the regulatory processes to progress their products or technologies; and simplification of the Clinical Trials Regulations and the Early Access to Medicines Scheme, to bring innovative medicines to patients faster. The Accelerated Access Review will identify reforms to accelerate access for National Health Service patients to innovative medicines and medical technologies. PRIME and Adaptive Pathways initiatives are joint endeavours within the European regulatory community. The MHRA runs spontaneous reporting schemes and works with INTERPOL to tackle counterfeiting and substandard products sold via the internet. The role of the regulator is changing rapidly, with new risk-proportionate, flexible approaches being introduced. International collaboration is a key element of the work of regulators, and is set to expand. © 2016 The British Pharmacological Society.

  5. Energy-conserving development regulations: current practice

    Energy Technology Data Exchange (ETDEWEB)

    1980-05-01

    Almost every aspect of land development has an effect on energy use, from minute architectural details to broad considerations of urban density. Energy-efficiency depends in part on how development is planned and carried out. Conventional development regulations, such as zoning ordinances and subdivision regulations, can be adapted in many ways to promote energy conservation at the community level. This report is about energy-efficient site and neighborhood design. It examines recent experiences of local governments that have adopted new development regulations or amended existing ones to promote energy conservation, more efficient generation and distribution, or a switch to alternative, renewable sources. Although much has been written in recent years about saving energy through community design, actual experience in applying these new ideas is still limited. To date, most communities have focused their efforts on studying the problem, documenting consumption patterns, and writing reports and plans. Only a handful have amended their land-use controls for the express purpose of saving energy. This study identifies 13 of these pioneering communities, after undertaking a survey of over 1400 local, regional, and state planning agencies. It takes a look at their experiences, to learn what has been done, how well it has worked, and what problems have been encountered.

  6. Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 “Signalosome”

    DEFF Research Database (Denmark)

    Jacobsen, Sylwia Owczarek; Bang, Marie Louise; Berezin, Vladimir

    2015-01-01

    Neurexins (NXs) and neuroligins (NLs) are cell adhesion molecules that are localized at opposite sites of synaptic membranes. They interact with each other to promote the assembly, maintenance, and function of synapses in the central nervous system. Both NX and NL are cleaved from a membrane-atta...

  7. A targeted glycan-related gene screen reveals heparan sulfate proteoglycan sulfation regulates WNT and BMP trans-synaptic signaling.

    Directory of Open Access Journals (Sweden)

    Neil Dani

    Full Text Available A Drosophila transgenic RNAi screen targeting the glycan genome, including all N/O/GAG-glycan biosynthesis/modification enzymes and glycan-binding lectins, was conducted to discover novel glycan functions in synaptogenesis. As proof-of-product, we characterized functionally paired heparan sulfate (HS 6-O-sulfotransferase (hs6st and sulfatase (sulf1, which bidirectionally control HS proteoglycan (HSPG sulfation. RNAi knockdown of hs6st and sulf1 causes opposite effects on functional synapse development, with decreased (hs6st and increased (sulf1 neurotransmission strength confirmed in null mutants. HSPG co-receptors for WNT and BMP intercellular signaling, Dally-like Protein and Syndecan, are differentially misregulated in the synaptomatrix of these mutants. Consistently, hs6st and sulf1 nulls differentially elevate both WNT (Wingless; Wg and BMP (Glass Bottom Boat; Gbb ligand abundance in the synaptomatrix. Anterograde Wg signaling via Wg receptor dFrizzled2 C-terminus nuclear import and retrograde Gbb signaling via synaptic MAD phosphorylation and nuclear import are differentially activated in hs6st and sulf1 mutants. Consequently, transcriptional control of presynaptic glutamate release machinery and postsynaptic glutamate receptors is bidirectionally altered in hs6st and sulf1 mutants, explaining the bidirectional change in synaptic functional strength. Genetic correction of the altered WNT/BMP signaling restores normal synaptic development in both mutant conditions, proving that altered trans-synaptic signaling causes functional differentiation defects.

  8. The brain-tumor related protein podoplanin regulates synaptic plasticity and hippocampus-dependent learning and memory.

    Science.gov (United States)

    Cicvaric, Ana; Yang, Jiaye; Krieger, Sigurd; Khan, Deeba; Kim, Eun-Jung; Dominguez-Rodriguez, Manuel; Cabatic, Maureen; Molz, Barbara; Acevedo Aguilar, Juan Pablo; Milicevic, Radoslav; Smani, Tarik; Breuss, Johannes M; Kerjaschki, Dontscho; Pollak, Daniela D; Uhrin, Pavel; Monje, Francisco J

    2016-12-01

    Podoplanin is a cell-surface glycoprotein constitutively expressed in the brain and implicated in human brain tumorigenesis. The intrinsic function of podoplanin in brain neurons remains however uncharacterized. Using an established podoplanin-knockout mouse model and electrophysiological, biochemical, and behavioral approaches, we investigated the brain neuronal role of podoplanin. Ex-vivo electrophysiology showed that podoplanin deletion impairs dentate gyrus synaptic strengthening. In vivo, podoplanin deletion selectively impaired hippocampus-dependent spatial learning and memory without affecting amygdala-dependent cued fear conditioning. In vitro, neuronal overexpression of podoplanin promoted synaptic activity and neuritic outgrowth whereas podoplanin-deficient neurons exhibited stunted outgrowth and lower levels of p-Ezrin, TrkA, and CREB in response to nerve growth factor (NGF). Surface Plasmon Resonance data further indicated a physical interaction between podoplanin and NGF. This work proposes podoplanin as a novel component of the neuronal machinery underlying neuritogenesis, synaptic plasticity, and hippocampus-dependent memory functions. The existence of a relevant cross-talk between podoplanin and the NGF/TrkA signaling pathway is also for the first time proposed here, thus providing a novel molecular complex as a target for future multidisciplinary studies of the brain function in the physiology and the pathology. Key messages Podoplanin, a protein linked to the promotion of human brain tumors, is required in vivo for proper hippocampus-dependent learning and memory functions. Deletion of podoplanin selectively impairs activity-dependent synaptic strengthening at the neurogenic dentate-gyrus and hampers neuritogenesis and phospho Ezrin, TrkA and CREB protein levels upon NGF stimulation. Surface plasmon resonance data indicates a physical interaction between podoplanin and NGF. On these grounds, a relevant cross-talk between podoplanin and NGF as well

  9. Synaptic Cell Adhesion

    OpenAIRE

    Missler, Markus; Südhof, Thomas C.; Biederer, Thomas

    2012-01-01

    Chemical synapses are asymmetric intercellular junctions that mediate synaptic transmission. Synaptic junctions are organized by trans-synaptic cell adhesion molecules bridging the synaptic cleft. Synaptic cell adhesion molecules not only connect pre- and postsynaptic compartments, but also mediate trans-synaptic recognition and signaling processes that are essential for the establishment, specification, and plasticity of synapses. A growing number of synaptic cell adhesion molecules that inc...

  10. Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine

    Science.gov (United States)

    Huang, Wei; Placzek, Andon N; Viana Di Prisco, Gonzalo; Khatiwada, Sanjeev; Sidrauski, Carmela; Krnjević, Krešimir; Walter, Peter; Dani, John A; Costa-Mattioli, Mauro

    2016-01-01

    Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)—whose disruption is postulated to increase vulnerability to drug addiction—was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction. DOI: http://dx.doi.org/10.7554/eLife.12052.001 PMID:26928234

  11. Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine.

    Science.gov (United States)

    Huang, Wei; Placzek, Andon N; Viana Di Prisco, Gonzalo; Khatiwada, Sanjeev; Sidrauski, Carmela; Krnjević, Krešimir; Walter, Peter; Dani, John A; Costa-Mattioli, Mauro

    2016-03-01

    Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)-whose disruption is postulated to increase vulnerability to drug addiction-was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction.

  12. Diacylglycerol Kinases in the Coordination of Synaptic Plasticity.

    Science.gov (United States)

    Lee, Dongwon; Kim, Eunjoon; Tanaka-Yamamoto, Keiko

    2016-01-01

    Synaptic plasticity is activity-dependent modification of the efficacy of synaptic transmission. Although, detailed mechanisms underlying synaptic plasticity are diverse and vary at different types of synapses, diacylglycerol (DAG)-associated signaling has been considered as an important regulator of many forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Recent evidences indicate that DAG kinases (DGKs), which phosphorylate DAG to phosphatidic acid to terminate DAG signaling, are important regulators of LTP and LTD, as supported by the results from mice lacking specific DGK isoforms. This review will summarize these studies and discuss how specific DGK isoforms distinctly regulate different forms of synaptic plasticity at pre- and postsynaptic sites. In addition, we propose a general role of DGKs as coordinators of synaptic plasticity that make local synaptic environments more permissive for synaptic plasticity by regulating DAG concentration and interacting with other synaptic proteins.

  13. Endocannabinoid signaling and synaptic function

    Science.gov (United States)

    Castillo, Pablo E.; Younts, Thomas J.; Chávez, Andrés E.; Hashimotodani, Yuki

    2012-01-01

    Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a non-retrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. Synaptic endocannabinoid signaling is thus mechanistically more complex and diverse than originally thought. In this review, we focus on new advances in endocannabinoid signaling and highlight their role as potent regulators of synaptic function in the mammalian brain. PMID:23040807

  14. 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.

  15. SynProt: A Database for Proteins of Detergent-Resistant Synaptic Protein Preparations

    Science.gov (United States)

    Pielot, Rainer; Smalla, Karl-Heinz; Müller, Anke; Landgraf, Peter; Lehmann, Anne-Christin; Eisenschmidt, Elke; Haus, Utz-Uwe; Weismantel, Robert; Gundelfinger, Eckart D.; Dieterich, Daniela C.

    2012-01-01

    Chemical synapses are highly specialized cell–cell contacts for communication between neurons in the CNS characterized by complex and dynamic protein networks at both synaptic membranes. The cytomatrix at the active zone (CAZ) organizes the apparatus for the regulated release of transmitters from the presynapse. At the postsynaptic side, the postsynaptic density constitutes the machinery for detection, integration, and transduction of the transmitter signal. Both pre- and postsynaptic protein networks represent the molecular substrates for synaptic plasticity. Their function can be altered both by regulating their composition and by post-translational modification of their components. For a comprehensive understanding of synaptic networks the entire ensemble of synaptic proteins has to be considered. To support this, we established a comprehensive database for synaptic junction proteins (SynProt database) primarily based on proteomics data obtained from biochemical preparations of detergent-resistant synaptic junctions. The database currently contains 2,788 non-redundant entries of rat, mouse, and some human proteins, which mainly have been manually extracted from 12 proteomic studies and annotated for synaptic subcellular localization. Each dataset is completed with manually added information including protein classifiers as well as automatically retrieved and updated information from public databases (UniProt and PubMed). We intend that the database will be used to support modeling of synaptic protein networks and rational experimental design. PMID:22737123

  16. SynProt: A Comprehensive Database for Proteins of the Detergent-Resistant Synaptic Junctions Fraction

    Directory of Open Access Journals (Sweden)

    Rainer ePielot

    2012-06-01

    Full Text Available Chemical synapses are highly specialized cell-cell contacts for communication between neurons in the CNS characterized by complex and dynamic protein networks at both synaptic membranes. The cytomatrix at the active zone (CAZ organizes the apparatus for the regulated release of transmitters from the presynapse. At the postsynaptic side, the postsynaptic density constitutes the machinery for detection, integration and transduction of the transmitter signal. Both pre- and postsynaptic protein networks represent the molecular substrates for synaptic plasticity. Their function can be altered both by regulating their composition and by post-translational modification of their components. For a comprehensive understanding of synaptic networks the entire ensemble of synaptic proteins has to be considered. To support this, we established a comprehensive database for synaptic junction proteins (SynProt database primarily based on proteomics data obtained from biochemical preparations of detergent-resistant synaptic junctions. The database currently contains 2,788 non-redundant entries of rat, mouse and some human proteins, which mainly have been manually extracted from twelve proteomic studies and annotated for synaptic subcellular localization. Each dataset is completed with manually added information including protein classifiers as well as automatically retrieved and updated information from public databases (UniProt and PubMed. We intend that the database will be used to support modeling of synaptic protein networks and rational experimental design.

  17. Modulation of Synaptic Plasticity by Glutamatergic Gliotransmission: A Modeling Study

    Science.gov (United States)

    De Pittà, Maurizio; Brunel, Nicolas

    2016-01-01

    Glutamatergic gliotransmission, that is, the release of glutamate from perisynaptic astrocyte processes in an activity-dependent manner, has emerged as a potentially crucial signaling pathway for regulation of synaptic plasticity, yet its modes of expression and function in vivo remain unclear. Here, we focus on two experimentally well-identified gliotransmitter pathways, (i) modulations of synaptic release and (ii) postsynaptic slow inward currents mediated by glutamate released from astrocytes, and investigate their possible functional relevance on synaptic plasticity in a biophysical model of an astrocyte-regulated synapse. Our model predicts that both pathways could profoundly affect both short- and long-term plasticity. In particular, activity-dependent glutamate release from astrocytes could dramatically change spike-timing-dependent plasticity, turning potentiation into depression (and vice versa) for the same induction protocol. PMID:27195153

  18. Review of the current state of UAV regulations

    NARCIS (Netherlands)

    Stöcker, Elvira Claudia; Bennett, Rohan; Nex, Francesco; Gerke, Markus; Zevenbergen, Jaap

    2017-01-01

    UAVs-unmanned aerial vehicles-facilitate data acquisition at temporal and spatial scales that still remain unachievable for traditional remote sensing platforms. However, current legal frameworks that regulate UAVs present significant barriers to research and development. To highlight the

  19. EDITORIAL: Synaptic electronics Synaptic electronics

    Science.gov (United States)

    Demming, Anna; Gimzewski, James K.; Vuillaume, Dominique

    2013-09-01

    Conventional computers excel in logic and accurate scientific calculations but make hard work of open ended problems that human brains handle easily. Even von Neumann—the mathematician and polymath who first developed the programming architecture that forms the basis of today's computers—was already looking to the brain for future developments before his death in 1957 [1]. Neuromorphic computing uses approaches that better mimic the working of the human brain. Recent developments in nanotechnology are now providing structures with very accommodating properties for neuromorphic approaches. This special issue, with guest editors James K Gimzewski and Dominique Vuillaume, is devoted to research at the serendipitous interface between the two disciplines. 'Synaptic electronics', looks at artificial devices with connections that demonstrate behaviour similar to synapses in the nervous system allowing a new and more powerful approach to computing. Synapses and connecting neurons respond differently to incident signals depending on the history of signals previously experienced, ultimately leading to short term and long term memory behaviour. The basic characteristics of a synapse can be replicated with around ten simple transistors. However with the human brain having around 1011 neurons and 1015 synapses, artificial neurons and synapses from basic transistors are unlikely to accommodate the scalability required. The discovery of nanoscale elements that function as 'memristors' has provided a key tool for the implementation of synaptic connections [2]. Leon Chua first developed the concept of the 'The memristor—the missing circuit element' in 1971 [3]. In this special issue he presents a tutorial describing how memristor research has fed into our understanding of synaptic behaviour and how they can be applied in information processing [4]. He also describes, 'The new principle of local activity, which uncovers a minuscule life-enabling "Goldilocks zone", dubbed the

  20. Synaptic devices based on purely electronic memristors

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Ruobing [Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201 (China); Institute of Materials Science, School of Materials Science and Engineering, Shanghai University, Shanghai 200072 (China); Li, Jun; Zhuge, Fei, E-mail: zhugefei@nimte.ac.cn, E-mail: h-cao@nimte.ac.cn; Zhu, Liqiang; Liang, Lingyan; Zhang, Hongliang; Gao, Junhua; Cao, Hongtao, E-mail: zhugefei@nimte.ac.cn, E-mail: h-cao@nimte.ac.cn; Fu, Bing; Li, Kang [Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201 (China)

    2016-01-04

    Memristive devices have been widely employed to emulate biological synaptic behavior. In these cases, the memristive switching generally originates from electrical field induced ion migration or Joule heating induced phase change. In this letter, the Ti/ZnO/Pt structure was found to show memristive switching ascribed to a carrier trapping/detrapping of the trap sites (e.g., oxygen vacancies or zinc interstitials) in ZnO. The carrier trapping/detrapping level can be controllably adjusted by regulating the current compliance level or voltage amplitude. Multi-level conductance states can, therefore, be realized in such memristive device. The spike-timing-dependent plasticity, an important Hebbian learning rule, has been implemented in this type of synaptic device. Compared with filamentary-type memristive devices, purely electronic memristors have potential to reduce their energy consumption and work more stably and reliably, since no structural distortion occurs.

  1. Comparing development of synaptic proteins in rat visual, somatosensory, and frontal cortex

    Science.gov (United States)

    Pinto, Joshua G. A.; Jones, David G.; Murphy, Kathryn M.

    2013-01-01

    Two theories have influenced our understanding of cortical development: the integrated network theory, where synaptic development is coordinated across areas; and the cascade theory, where the cortex develops in a wave-like manner from sensory to non-sensory areas. These different views on cortical development raise challenges for current studies aimed at comparing detailed maturation of the connectome among cortical areas. We have taken a different approach to compare synaptic development in rat visual, somatosensory, and frontal cortex by measuring expression of pre-synaptic (synapsin and synaptophysin) proteins that regulate vesicle cycling, and post-synaptic density (PSD-95 and Gephyrin) proteins that anchor excitatory or inhibitory (E-I) receptors. We also compared development of the balances between the pairs of pre- or post-synaptic proteins, and the overall pre- to post-synaptic balance, to address functional maturation and emergence of the E-I balance. We found that development of the individual proteins and the post-synaptic index overlapped among the three cortical areas, but the pre-synaptic index matured later in frontal cortex. Finally, we applied a neuroinformatics approach using principal component analysis and found that three components captured development of the synaptic proteins. The first component accounted for 64% of the variance in protein expression and reflected total protein expression, which overlapped among the three cortical areas. The second component was gephyrin and the E-I balance, it emerged as sequential waves starting in somatosensory, then frontal, and finally visual cortex. The third component was the balance between pre- and post-synaptic proteins, and this followed a different developmental trajectory in somatosensory cortex. Together, these results give the most support to an integrated network of synaptic development, but also highlight more complex patterns of development that vary in timing and end point among the

  2. Comparing development of synaptic proteins in rat visual, somatosensory, and frontal cortex.

    Science.gov (United States)

    Pinto, Joshua G A; Jones, David G; Murphy, Kathryn M

    2013-01-01

    Two theories have influenced our understanding of cortical development: the integrated network theory, where synaptic development is coordinated across areas; and the cascade theory, where the cortex develops in a wave-like manner from sensory to non-sensory areas. These different views on cortical development raise challenges for current studies aimed at comparing detailed maturation of the connectome among cortical areas. We have taken a different approach to compare synaptic development in rat visual, somatosensory, and frontal cortex by measuring expression of pre-synaptic (synapsin and synaptophysin) proteins that regulate vesicle cycling, and post-synaptic density (PSD-95 and Gephyrin) proteins that anchor excitatory or inhibitory (E-I) receptors. We also compared development of the balances between the pairs of pre- or post-synaptic proteins, and the overall pre- to post-synaptic balance, to address functional maturation and emergence of the E-I balance. We found that development of the individual proteins and the post-synaptic index overlapped among the three cortical areas, but the pre-synaptic index matured later in frontal cortex. Finally, we applied a neuroinformatics approach using principal component analysis and found that three components captured development of the synaptic proteins. The first component accounted for 64% of the variance in protein expression and reflected total protein expression, which overlapped among the three cortical areas. The second component was gephyrin and the E-I balance, it emerged as sequential waves starting in somatosensory, then frontal, and finally visual cortex. The third component was the balance between pre- and post-synaptic proteins, and this followed a different developmental trajectory in somatosensory cortex. Together, these results give the most support to an integrated network of synaptic development, but also highlight more complex patterns of development that vary in timing and end point among the

  3. Ca2+-permeable AMPA receptors in homeostatic synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Hey-Kyoung eLee

    2012-02-01

    Full Text Available Neurons possess diverse mechanisms of homeostatic adaptation to overall changes in neural and synaptic activity, which are critical for proper brain functions. Homeostatic regulation of excitatory synapses has been studied in the context of synaptic scaling, which allows neurons to adjust their excitatory synaptic gain to maintain their activity within a dynamic range. Recent evidence suggests that one of the main mechanisms underlying synaptic scaling is by altering the function of postsynaptic AMPA receptors (AMPARs, including synaptic expression of Ca2+-permeable (CP- AMPARs. CP-AMPARs endow synapses with unique properties, which may benefit adaptation of neurons to periods of inactivity as would occur when a major input is lost. This review will summarize how synaptic expression of CP-AMPARs is regulated during homeostatic synaptic plasticity in the context of synaptic scaling, and will address the potential functional consequences of altering synaptic CP-AMPAR content.

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

    Science.gov (United States)

    Beckhauser, Thiago Fernando; Francis-Oliveira, José; De Pasquale, Roberto

    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 decline in cognitive functions, as observed in some neurodegenerative disorders and age-dependent decay of neuroplasticity. Nevertheless, controlled ROS production provides the optimal redox state for the activation of transductional pathways involved in synaptic changes. Since ROS may regulate neuronal activity and elicit negative effects at the same time, the distinction between beneficial and deleterious consequences is unclear. In this regard, this review assesses current research and describes the main sources of ROS in neurons, specifying their involvement in synaptic plasticity and distinguishing between physiological and pathological processes implicated. PMID:27625575

  5. Persistent inflammation-induced up-regulation of brain-derived neurotrophic factor (BDNF) promotes synaptic delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunits in descending pain modulatory circuits.

    Science.gov (United States)

    Tao, Wenjuan; Chen, Quan; Zhou, Wenjie; Wang, Yunping; Wang, Lu; Zhang, Zhi

    2014-08-08

    The enhanced AMPA receptor phosphorylation at GluA1 serine 831 sites in the central pain-modulating system plays a pivotal role in descending pain facilitation after inflammation, but the underlying mechanisms remain unclear. We show here that, in the rat brain stem, in the nucleus raphe magnus, which is a critical relay in the descending pain-modulating system of the brain, persistent inflammatory pain induced by complete Freund adjuvant (CFA) can enhance AMPA receptor-mediated excitatory postsynaptic currents and the GluA2-lacking AMPA receptor-mediated rectification index. Western blot analysis showed an increase in GluA1 phosphorylation at Ser-831 but not at Ser-845. This was accompanied by an increase in distribution of the synaptic GluA1 subunit. In parallel, the level of histone H3 acetylation at bdnf gene promoter regions was reduced significantly 3 days after CFA injection, as indicated by ChIP assays. This was correlated with an increase in BDNF mRNA levels and BDNF protein levels. Sequestering endogenous extracellular BDNF with TrkB-IgG in the nucleus raphe magnus decreased AMPA receptor-mediated synaptic transmission and GluA1 phosphorylation at Ser-831 3 days after CFA injection. Under the same conditions, blockade of TrkB receptor functions, phospholipase C, or PKC impaired GluA1 phosphorylation at Ser-831 and decreased excitatory postsynaptic currents mediated by GluA2-lacking AMPA receptors. Taken together, these results suggest that epigenetic up-regulation of BDNF by peripheral inflammation induces GluR1 phosphorylation at Ser-831 sites through activation of the phospholipase C-PKC signaling cascade, leading to the trafficking of GluA1 to pain-modulating neuronal synapses. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus.

    OpenAIRE

    Isaacson, J S; Nicoll, R A

    1991-01-01

    Aniracetam is a nootropic drug that has been shown to selectively enhance quisqualate receptor-mediated responses in Xenopus oocytes injected with brain mRNA and in hippocampal pyramidal cells [Ito, I., Tanabe, S., Kohda, A. & Sugiyama, H. (1990) J. Physiol. (London) 424, 533-544]. We have used patch clamp recording techniques in hippocampal slices to elucidate the mechanism for this selective action. We find that aniracetam enhances glutamate-evoked currents in whole-cell recordings and, in ...

  7. Mitochondria and Synaptic Plasticity in the Mature and Aging Nervous System.

    Science.gov (United States)

    Todorova, Vyara; Blokland, Arjan

    2017-01-01

    Synaptic plasticity in the adult brain is believed to represent the cellular mechanisms of learning and memory. Mitochondria are involved in the regulation of the complex processes of synaptic plasticity. This paper reviews the current knowledge on the regulatory roles of mitochondria in the function and plasticity of synapses and the implications of mitochondrial dysfunctions in synaptic transmission. First, the importance of mitochondrial distribution and motility for maintenance and strengthening of dendritic spines, but also for new spines/synapses formation is presented. Secondly, the major mitochondrial functions as energy supplier and calcium buffer organelles are considered as possible explanation for their essential and regulatory roles in neuronal plasticity processes. Thirdly, the effects of synaptic potentiation on mitochondrial gene expression are discussed. And finally, the relation between age-related alterations in synaptic plasticity and mitochondrial dysfunctions is considered. It appears that memory loss and neurodegeneration during aging are related to mitochondrial (dys)function. Although, it is clear that mitochondria are essential for synaptic plasticity, further studies are indicated to scrutinize the intracellular and molecular processes that regulate the functions of mitochondria in synaptic plasticity.

  8. Differential regulation of polarized synaptic vesicle trafficking and synapse stability in neural circuit rewiring in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Naina Kurup

    2017-06-01

    Full Text Available Neural circuits are dynamic, with activity-dependent changes in synapse density and connectivity peaking during different phases of animal development. In C. elegans, young larvae form mature motor circuits through a dramatic switch in GABAergic neuron connectivity, by concomitant elimination of existing synapses and formation of new synapses that are maintained throughout adulthood. We have previously shown that an increase in microtubule dynamics during motor circuit rewiring facilitates new synapse formation. Here, we further investigate cellular control of circuit rewiring through the analysis of mutants obtained in a forward genetic screen. Using live imaging, we characterize novel mutations that alter cargo binding in the dynein motor complex and enhance anterograde synaptic vesicle movement during remodeling, providing in vivo evidence for the tug-of-war between kinesin and dynein in fast axonal transport. We also find that a casein kinase homolog, TTBK-3, inhibits stabilization of nascent synapses in their new locations, a previously unexplored facet of structural plasticity of synapses. Our study delineates temporally distinct signaling pathways that are required for effective neural circuit refinement.

  9. Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain

    Science.gov (United States)

    Sheffler-Collins, Sean I.; Xia, Nan L.; Henderson, Nathan; Tillu, Dipti V.; Hassler, Shayne; Spellman, Daniel S.; Zhang, Guoan; Neubert, Thomas A.; Price, Theodore J.

    2017-01-01

    Extracellular phosphorylation of proteins was suggested in the late 1800s when it was demonstrated that casein contains phosphate. More recently, extracellular kinases that phosphorylate extracellular serine, threonine, and tyrosine residues of numerous proteins have been identified. However, the functional significance of extracellular phosphorylation of specific residues in the nervous system is poorly understood. Here we show that synaptic accumulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) and pathological pain are controlled by ephrin-B-induced extracellular phosphorylation of a single tyrosine (p*Y504) in a highly conserved region of the fibronectin type III (FN3) domain of the receptor tyrosine kinase EphB2. Ligand-dependent Y504 phosphorylation modulates the EphB-NMDAR interaction in cortical and spinal cord neurons. Furthermore, Y504 phosphorylation enhances NMDAR localization and injury-induced pain behavior. By mediating inducible extracellular interactions that are capable of modulating animal behavior, extracellular tyrosine phosphorylation of EphBs may represent a previously unknown class of mechanism mediating protein interaction and function. PMID:28719605

  10. Current state and trend of radiation regulation system in Japan

    International Nuclear Information System (INIS)

    Yonehara, Hidenori

    2004-01-01

    Japanese regulation system for safety against radiation essentially started from 'Atomic Energy Basic Law' enacted in 1955 and 'Law Concerning Prevention of Radiation Hazards due to Radioisotopes, etc' enacted in 1957, has been regarded as a central rule for radiation protection and safety. Related laws and regulations have been enacted together with their revision. Radiation Council, established in the Science and Technology Agency in 1962 and now belonging to the Ministry of Education, Culture, Sports, Science and Technology, has deliberated basically on International Commission of Radiological Protection (ICRP) statements for legal revision and has set up working groups for current problems. Activities of the groups have concerned ICRP Publication 60 (1990) and later related publications for incorporating the principle into laws as to concepts of dose limits, effective dose, and then of exemption and exclusion. International status of the Japanese regulation, problems and tasks in the regulation are also commented. (N.I.)

  11. The cholinergic agonist carbachol increases the frequency of spontaneous GABAergic synaptic currents in dorsal raphe serotonergic neurons in the mouse.

    Science.gov (United States)

    Yang, C; Brown, R E

    2014-01-31

    Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons play an important role in feeding, mood control and stress responses. One important feature of their activity across the sleep-wake cycle is their reduced firing during rapid-eye-movement (REM) sleep which stands in stark contrast to the wake/REM-on discharge pattern of brainstem cholinergic neurons. A prominent model of REM sleep control posits a reciprocal interaction between these cell groups. 5-HT inhibits cholinergic neurons, and activation of nicotinic receptors can excite DRN 5-HT neurons but the cholinergic effect on inhibitory inputs is incompletely understood. Here, in vitro, in DRN brain slices prepared from GAD67-GFP knock-in mice, a brief (3 min) bath application of carbachol (50 μM) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in GFP-negative, putative 5-HT neurons but did not affect miniature (tetrodotoxin-insensitive) IPSCs. Carbachol had no direct postsynaptic effect. Thus, carbachol likely increases the activity of local GABAergic neurons which synapse on 5-HT neurons. Removal of dorsal regions of the slice including the ventrolateral periaqueductal gray (vlPAG) region where GABAergic neurons projecting to the DRN have been identified, abolished the effect of carbachol on sIPSCs whereas the removal of ventral regions containing the oral region of the pontine reticular nucleus (PnO) did not. In addition, carbachol directly excited GFP-positive, GABAergic vlPAG neurons. Antagonism of both muscarinic and nicotinic receptors completely abolished the effects of carbachol. We suggest cholinergic neurons inhibit DRN 5-HT neurons when acetylcholine levels are lower i.e. during quiet wakefulness and the beginning of REM sleep periods, in part via excitation of muscarinic and nicotinic receptors located on local vlPAG and DRN GABAergic neurons. Higher firing rates or burst firing of cholinergic neurons associated with attentive wakefulness or phasic REM sleep periods

  12. Propofol prevents electroconvulsive-shock-induced memory impairment through regulation of hippocampal synaptic plasticity in a rat model of depression

    Directory of Open Access Journals (Sweden)

    Luo J

    2014-09-01

    Full Text Available Jie Luo, Su Min, Ke Wei, Jun Cao, Bin Wang, Ping Li, Jun Dong, Yuanyuan Liu Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China Background: Although a rapid and efficient psychiatric treatment, electroconvulsive therapy (ECT induces memory impairment. Modified ECT requires anesthesia for safety purposes. Although traditionally found to exert amnesic effects in general anesthesia, which is an inherent part of modified ECT, some anesthetics have been found to protect against ECT-induced cognitive impairment. However, the mechanisms remain unclear. We investigated the effects of propofol (2,6-diisopropylphenol on memory in depressed rats undergoing electroconvulsive shock (ECS, the analog of ECT in animals, under anesthesia as well as its mechanisms.Methods: Chronic unpredictable mild stresses were adopted to reproduce depression in a rodent model. Rats underwent ECS (or sham ECS with anesthesia with propofol or normal saline. Behavior was assessed in sucrose preference, open field and Morris water maze tests. Hippocampal long-term potentiation (LTP was measured using electrophysiological techniques. PSD-95, CREB, and p-CREB protein expression was assayed with western blotting.Results: Depression induced memory damage, and downregulated LTP, PSD-95, CREB, and p-CREB; these effects were exacerbated in depressed rats by ECS; propofol did not reverse the depression-induced changes, but when administered in modified ECS, propofol improved memory and reversed the downregulation of LTP and the proteins. Conclusion: These findings suggest that propofol prevents ECS-induced memory impairment, and modified ECS under anesthesia with propofol improves memory in depressed rats, possibly by reversing the excessive changes in hippocampal synaptic plasticity. These observations provide a novel insight into potential targets for optimizing the clinical use of ECT for psychiatric

  13. Muscle Contraction Regulates BDNF/TrkB Signaling to Modulate Synaptic Function through Presynaptic cPKCα and cPKCβI

    Directory of Open Access Journals (Sweden)

    Erica Hurtado

    2017-05-01

    Full Text Available The neurotrophin brain-derived neurotrophic factor (BDNF acts via tropomyosin-related kinase B receptor (TrkB to regulate synapse maintenance and function in the neuromuscular system. The potentiation of acetylcholine (ACh release by BDNF requires TrkB phosphorylation and Protein Kinase C (PKC activation. BDNF is secreted in an activity-dependent manner but it is not known if pre- and/or postsynaptic activities enhance BDNF expression in vivo at the neuromuscular junction (NMJ. Here, we investigated whether nerve and muscle cell activities regulate presynaptic conventional PKC (cPKCα and βI via BDNF/TrkB signaling to modulate synaptic strength at the NMJ. To differentiate the effects of presynaptic activity from that of muscle contraction, we stimulated the phrenic nerve of rat diaphragms (1 Hz, 30 min with or without contraction (abolished by μ-conotoxin GIIIB. Then, we performed ELISA, Western blotting, qRT-PCR, immunofluorescence and electrophysiological techniques. We found that nerve-induced muscle contraction: (1 increases the levels of mature BDNF protein without affecting pro-BDNF protein or BDNF mRNA levels; (2 downregulates TrkB.T1 without affecting TrkB.FL or p75 neurotrophin receptor (p75 levels; (3 increases presynaptic cPKCα and cPKCβI protein level through TrkB signaling; and (4 enhances phosphorylation of cPKCα and cPKCβI. Furthermore, we demonstrate that cPKCβI, which is exclusively located in the motor nerve terminals, increases activity-induced acetylcholine release. Together, these results show that nerve-induced muscle contraction is a key regulator of BDNF/TrkB signaling pathway, retrogradely activating presynaptic cPKC isoforms (in particular cPKCβI to modulate synaptic function. These results indicate that a decrease in neuromuscular activity, as occurs in several neuromuscular disorders, could affect the BDNF/TrkB/PKC pathway that links pre- and postsynaptic activity to maintain neuromuscular function.

  14. Review of the Current State of UAV Regulations

    Directory of Open Access Journals (Sweden)

    Claudia Stöcker

    2017-05-01

    Full Text Available UAVs—unmanned aerial vehicles—facilitate data acquisition at temporal and spatial scales that still remain unachievable for traditional remote sensing platforms. However, current legal frameworks that regulate UAVs present significant barriers to research and development. To highlight the importance, impact, and diversity of UAV regulations, this paper provides an exploratory investigation of UAV regulations on the global scale. For this, the methodological approach consists of a research synthesis of UAV regulations, including a thorough literature review and a comparative analysis of national regulatory frameworks. Similarities and contrasting elements in the various national UAV regulations are explored including their statuses from the perspectives of past, present, and future trends. Since the early 2000s, countries have gradually established national legal frameworks. Although all UAV regulations have one common goal—minimizing the risks to other airspace users and to both people and property on the ground—the results reveal distinct variations in all the compared variables. Furthermore, besides the clear presence of legal frameworks, market forces such as industry design standards and reliable information about UAVs as public goods are expected to shape future developments.

  15. Radix Puerariae modulates glutamatergic synaptic architecture and potentiates functional synaptic plasticity in primary hippocampal neurons.

    Science.gov (United States)

    Bhuiyan, Mohammad Maqueshudul Haque; Haque, Md Nazmul; Mohibbullah, Md; Kim, Yung Kyu; Moon, Il Soo

    2017-09-14

    reserve vesicle pools at presynaptic terminals; (4) enhanced NMDA receptor-mediated postsynaptic currents, and (5) increased cell viability against naturally occurring cell death. Moreover, upregulation of actin-related protein 2 (ARP2) in RPE and puerarin treated brain neurons suggest that RPE and puerarin induced synaptic plasticity might be associated, at least in part, with ARP2-mediated actin-dependent regulation of spinogenesis. Our findings indicate that RPE and puerarin might play a substantial role in the morphological and functional maturation of brain neurons and suggest that RPE and puerarin are potentially valuable preventative therapeutics for memory-related nervous disorders. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  16. The interaction of mammalian Class C Vps with nSec-1/Munc18-a and syntaxin 1A regulates pre-synaptic release

    International Nuclear Information System (INIS)

    Kim, Bong Yoon; Sahara, Yoshinori; Yamamoto, Akitsugu; Kominami, Eiki; Kohsaka, Shinichi; Akazawa, Chihiro

    2006-01-01

    Membrane docking and fusion in neurons is a highly regulated process requiring the participation of a large number of SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptors) and SNARE-interacting proteins. We found that mammalian Class C Vps protein complex associated specifically with nSec-1/Munc18-a, and syntaxin 1A both in vivo and in vitro. In contrast, VAMP2 and SNAP-25, other neuronal core complex proteins, did not interact. When co-transfected with the human growth hormone (hGH) reporter gene, mammalian Class C Vps proteins enhanced Ca 2+ -dependent exocytosis, which was abolished by the Ca 2+ -channel blocker nifedipine. In hippocampal primary cultures, the lentivirus-mediated overexpression of hVps18 increased asynchronous spontaneous synaptic release without changing mEPSCs. These results indicate that mammalian Class C Vps proteins are involved in the regulation of membrane docking and fusion through an interaction with neuronal specific SNARE molecules, nSec-1/Munc18-a and syntaxin 1A

  17. Modulation of Synaptic Plasticity by Exercise Training as a Basis for Ischemic Stroke Rehabilitation.

    Science.gov (United States)

    Nie, Jingjing; Yang, Xiaosu

    2017-01-01

    In recent years, rehabilitation of ischemic stroke draws more and more attention in the world, and has been linked to changes of synaptic plasticity. Exercise training improves motor function of ischemia as well as cognition which is associated with formation of learning and memory. The molecular basis of learning and memory might be synaptic plasticity. Research has therefore been conducted in an attempt to relate effects of exercise training to neuroprotection and neurogenesis adjacent to the ischemic injury brain. The present paper reviews the current literature addressing this question and discusses the possible mechanisms involved in modulation of synaptic plasticity by exercise training. This review shows the pathological process of synaptic dysfunction in ischemic roughly and then discusses the effects of exercise training on scaffold proteins and regulatory protein expression. The expression of scaffold proteins generally increased after training, but the effects on regulatory proteins were mixed. Moreover, the compositions of postsynaptic receptors were changed and the strength of synaptic transmission was enhanced after training. Finally, the recovery of cognition is critically associated with synaptic remodeling in an injured brain, and the remodeling occurs through a number of local regulations including mRNA translation, remodeling of cytoskeleton, and receptor trafficking into and out of the synapse. We do provide a comprehensive knowledge of synaptic plasticity enhancement obtained by exercise training in this review.

  18. Synaptic Determinants of Rett Syndrome

    Science.gov (United States)

    Boggio, Elena M.; Lonetti, Giuseppina; Pizzorusso, Tommaso; Giustetto, Maurizio

    2010-01-01

    There is mounting evidence showing that the structural and molecular organization of synaptic connections is 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. PMID:21423514

  19. 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.

  20. Activity Dependent Synaptic Plasticity Mimicked on Indium-Tin-Oxide Electric-Double-Layer Transistor.

    Science.gov (United States)

    Wen, Juan; Zhu, Li Qiang; Fu, Yang Ming; Xiao, Hui; Guo, Li Qiang; Wan, Qing

    2017-10-25

    Ion coupling has provided an additional method to modulate electric properties for solid-state materials. Here, phosphorosilicate glass (PSG)-based electrolyte gated protonic/electronic coupled indium-tin-oxide electric-double-layer (EDL) transistors are fabricated. The oxide transistor exhibits good electrical performances due to an extremely strong proton gating behavior for the electrolyte. With interfacial electrochemical doping, channel conductances of the oxide EDL transistor can be regulated to different levels, corresponding to different initial synaptic weights. Thus, activity dependent synaptic responses such as excitatory postsynaptic current, paired-pulse facilitation, and high-pass filtering are discussed in detail. The proposed proton conductor gated oxide EDL synaptic transistors with activity dependent synaptic plasticities may act as fundamental building blocks for neuromorphic system applications.

  1. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord.

    Science.gov (United States)

    Kawasaki, Yasuhiko; Zhang, Ling; Cheng, Jen-Kun; Ji, Ru-Rong

    2008-05-14

    Central sensitization, increased sensitivity in spinal cord dorsal horn neurons after injuries, plays an essential role in the induction and maintenance of chronic pain. However, synaptic mechanisms underlying central sensitization are incompletely known. Growing evidence suggests that proinflammatory cytokines (PICs), such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha), are induced in the spinal cord under various injury conditions and contribute to pain hypersensitivity. Using patch-clamp recordings in lamina II neurons of isolated spinal cord slices, we compared the effects of IL-1beta, IL-6, and TNFalpha on excitatory and inhibitory synaptic transmission. Whereas TNFalpha enhanced the frequency of spontaneous EPSCs (sEPSCs), IL-6 reduced the frequency of spontaneous IPSCs (sIPSCs). Notably, IL-1beta both enhanced the frequency and amplitude of sEPSCs and reduced the frequency and amplitude of sIPSCs. Consistently, TNFalpha and IL-1beta enhanced AMPA- or NMDA-induced currents, and IL-1beta and IL-6 suppressed GABA- and glycine-induced currents. Furthermore, all the PICs increased cAMP response element-binding protein (CREB) phosphorylation in superficial dorsal horn neurons and produced heat hyperalgesia after spinal injection. Surprisingly, soluble IL-6 receptor (sIL-6R) produced initial decrease of sEPSCs, followed by increase of sEPSCs and CREB phosphorylation. Spinal injection of sIL-6R also induced heat hyperalgesia that was potentiated by coadministration with IL-6. Together, our data have demonstrated that PICs induce central sensitization and hyperalgesia via distinct and overlapping synaptic mechanisms in superficial dorsal horn neurons either by increasing excitatory synaptic transmission or by decreasing inhibitory synaptic transmission. PICs may further induce long-term synaptic plasticity through CREB-mediated gene transcription. Blockade of PIC signaling could be an effective way to suppress

  2. The Serine Protease Inhibitor Neuroserpin Is Required for Normal Synaptic Plasticity and Regulates Learning and Social Behavior

    Science.gov (United States)

    Reumann, Rebecca; Vierk, Ricardo; Zhou, Lepu; Gries, Frederice; Kraus, Vanessa; Mienert, Julia; Romswinkel, Eva; Morellini, Fabio; Ferrer, Isidre; Nicolini, Chiara; Fahnestock, Margaret; Rune, Gabriele; Glatzel, Markus; Galliciotti, Giovanna

    2017-01-01

    The serine protease inhibitor neuroserpin regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin expression is particularly prominent at late stages of neuronal development in most regions of the central nervous system (CNS), whereas it is restricted to regions related to learning and memory in the…

  3. How do astrocytes shape synaptic transmission? Insights from electrophysiology

    Directory of Open Access Journals (Sweden)

    Glenn eDallérac

    2013-10-01

    Full Text Available A major breakthrough in neuroscience has been the realization in the last decades that the dogmatic view of astroglial cells as being merely fostering and buffering elements of the nervous system is simplistic. A wealth of investigations now shows that astrocytes actually participate in the control of synaptic transmission in an active manner. This was first hinted by the intimate contacts glial processes make with neurons, particularly at the synaptic level, and evidenced using electrophysiological and calcium imaging techniques. Calcium imaging has provided critical evidence demonstrating that astrocytic regulation of synaptic efficacy is not a passive phenomenon. However, given that cellular activation is not only represented by calcium signaling, it is also crucial to assess concomitant mechanisms. We and others have used electrophysiological techniques to simultaneously record neuronal and astrocytic activity, thus enabling the study of multiple ionic currents and in depth investigation of neuro-glial dialogues. In the current review, we focus on the input such approach has provided in the understanding of astrocyte-neuron interactions underlying control of synaptic efficacy.

  4. Audit Risk Assessment in the Light of Current European Regulations

    Directory of Open Access Journals (Sweden)

    Ciprian-Costel Munteanu

    2015-06-01

    Full Text Available Recent European reforms on audit regulations have been motivated by efforts to increase audit quality, functioning and performance. We believe the adoption of Directive 2014/56 and Regulation 537/2014 strengthened the role of independent audit and risk committees, which will positively contribute towards audit quality. This paper aims to critically assess the status quo of audit risk assessment in current European standards and regulations, by conducting a theoretical analysis of different aspects of audit risk. Our main objective is to stress the importance of detecting inherent and control risk, which lead to material misstatement at the assertion level. They need to be assessed so as to determine the nature, timing and extent of further audit procedures necessary to obtain sufficient appropriate audit evidence. These pieces of evidence enable the auditor to express an opinion on the financial statements at an acceptably low level of audit risk. Therefore, we point to the fact that researchers as well as practitioners and policymakers have to be careful when using audit tools and assessing risk levels, as their conclusions continuously shape the regulations.

  5. Flexible Proton-Gated Oxide Synaptic Transistors on Si Membrane.

    Science.gov (United States)

    Zhu, Li Qiang; Wan, Chang Jin; Gao, Ping Qi; Liu, Yang Hui; Xiao, Hui; Ye, Ji Chun; Wan, Qing

    2016-08-24

    Ion-conducting materials have received considerable attention for their applications in fuel cells, electrochemical devices, and sensors. Here, flexible indium zinc oxide (InZnO) synaptic transistors with multiple presynaptic inputs gated by proton-conducting phosphorosilicate glass-based electrolyte films are fabricated on ultrathin Si membranes. Transient characteristics of the proton gated InZnO synaptic transistors are investigated, indicating stable proton-gating behaviors. Short-term synaptic plasticities are mimicked on the proposed proton-gated synaptic transistors. Furthermore, synaptic integration regulations are mimicked on the proposed synaptic transistor networks. Spiking logic modulations are realized based on the transition between superlinear and sublinear synaptic integration. The multigates coupled flexible proton-gated oxide synaptic transistors may be interesting for neuroinspired platforms with sophisticated spatiotemporal information processing.

  6. EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice.

    Science.gov (United States)

    Xu, Xin; Pozzo-Miller, Lucas

    2017-08-15

    Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Mecp2 deletion in mice results in an imbalance of excitation and inhibition in hippocampal neurons, which affects 'Hebbian' synaptic plasticity. We show that Mecp2-deficient neurons also lack homeostatic synaptic plasticity, likely due to reduced levels of EEA1, a protein involved in AMPA receptor endocytosis. Expression of EEA1 restored homeostatic synaptic plasticity in Mecp2-deficient neurons, providing novel targets of intervention in Rett syndrome. Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects 'Hebbian' long-term synaptic plasticity. Since the excitatory-inhibitory balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling up of the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and of synaptic levels of the GluA1 subunit of AMPA-type glutamate receptors after 48 h silencing with the Na + channel blocker tetrodotoxin. This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale down mEPSC amplitudes and GluA1 synaptic levels after 48 h blockade of type A GABA receptor (GABA A R)-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors in HSP, Mecp2 KO neurons

  7. 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…

  8. Homeostatic scaling of neuronal excitability by synaptic modulation of somatic hyperpolarization-activated Ih channels.

    NARCIS (Netherlands)

    van Welie, I.; van Hooft, J.A.; Wadman, W.J.

    2004-01-01

    The hyperpolarization-activated cation current (Ih) plays an important role in determining membrane potential and firing characteristics of neurons and therefore is a potential target for regulation of intrinsic excitability. Here we show that an increase in AMPA-receptor-dependent synaptic activity

  9. Optogenetic Examination of Prefrontal-Amygdala Synaptic Development.

    Science.gov (United States)

    Arruda-Carvalho, Maithe; Wu, Wan-Chen; Cummings, Kirstie A; Clem, Roger L

    2017-03-15

    A brain network comprising the medial prefrontal cortex (mPFC) and amygdala plays important roles in developmentally regulated cognitive and emotional processes. However, very little is known about the maturation of mPFC-amygdala circuitry. We conducted anatomical tracing of mPFC projections and optogenetic interrogation of their synaptic connections with neurons in the basolateral amygdala (BLA) at neonatal to adult developmental stages in mice. Results indicate that mPFC-BLA projections exhibit delayed emergence relative to other mPFC pathways and establish synaptic transmission with BLA excitatory and inhibitory neurons in late infancy, events that coincide with a massive increase in overall synaptic drive. During subsequent adolescence, mPFC-BLA circuits are further modified by excitatory synaptic strengthening as well as a transient surge in feedforward inhibition. The latter was correlated with increased spontaneous inhibitory currents in excitatory neurons, suggesting that mPFC-BLA circuit maturation culminates in a period of exuberant GABAergic transmission. These findings establish a time course for the onset and refinement of mPFC-BLA transmission and point to potential sensitive periods in the development of this critical network. SIGNIFICANCE STATEMENT Human mPFC-amygdala functional connectivity is developmentally regulated and figures prominently in numerous psychiatric disorders with a high incidence of adolescent onset. However, it remains unclear when synaptic connections between these structures emerge or how their properties change with age. Our work establishes developmental windows and cellular substrates for synapse maturation in this pathway involving both excitatory and inhibitory circuits. The engagement of these substrates by early life experience may support the ontogeny of fundamental behaviors but could also lead to inappropriate circuit refinement and psychopathology in adverse situations. Copyright © 2017 the authors 0270-6474/17/372976-10$15.00/0.

  10. Polymer-electrolyte-gated nanowire synaptic transistors for neuromorphic applications

    Science.gov (United States)

    Zou, Can; Sun, Jia; Gou, Guangyang; Kong, Ling-An; Qian, Chuan; Dai, Guozhang; Yang, Junliang; Guo, Guang-hua

    2017-09-01

    Polymer-electrolytes are formed by dissolving a salt in polymer instead of water, the conducting mechanism involves the segmental motion-assisted diffusion of ion in the polymer matrix. Here, we report on the fabrication of tin oxide (SnO2) nanowire synaptic transistors using polymer-electrolyte gating. A thin layer of poly(ethylene oxide) and lithium perchlorate (PEO/LiClO4) was deposited on top of the devices, which was used to boost device performances. A voltage spike applied on the in-plane gate attracts ions toward the polymer-electrolyte/SnO2 nanowire interface and the ions are gradually returned after the pulse is removed, which can induce a dynamic excitatory postsynaptic current in the nanowire channel. The SnO2 synaptic transistors exhibit the behavior of short-term plasticity like the paired-pulse facilitation and self-adaptation, which is related to the electric double-effect regulation. In addition, the synaptic logic functions and the logical function transformation are also discussed. Such single SnO2 nanowire-based synaptic transistors are of great importance for future neuromorphic devices.

  11. Molecular Recognition within Synaptic Scaffolds

    DEFF Research Database (Denmark)

    Erlendsson, Simon

    -length structural model of the PICK1 dimer in-solution. We found the PICK1 BAR dimer to resemble an elongated crescent-shaped structure, spanning ~160 Å, with the PICK1 PDZ domains loosely attached to the BAR domain. This finding is in contrast to previous findings for other BAR domain proteins, where adjacent......Scaffolding proteins are abundant participants and regulators of the extensive intracellular framework required for maintaining cellular functions such as cellular adhesion and signal transduction cascades. In excitatory neuronal synapses these scaffolding proteins often contain one or more PDZ...... domains, responsible for tethering their respective synaptic protein ligands. Therefore, understanding the specificity and binding mechanisms of PDZ domain proteins is essential to understand regulation of synaptic plasticity. PICK1 is a PDZ domain-containing scaffolding protein predominantly expressed...

  12. The activity of spontaneous action potentials in developing hair cells is regulated by Ca(2+-dependence of a transient K+ current.

    Directory of Open Access Journals (Sweden)

    Snezana Levic

    Full Text Available Spontaneous action potentials have been described in developing sensory systems. These rhythmic activities may have instructional roles for the functional development of synaptic connections. The importance of spontaneous action potentials in the developing auditory system is underpinned by the stark correlation between the time of auditory system functional maturity, and the cessation of spontaneous action potentials. A prominent K(+ current that regulates patterning of action potentials is I(A. This current undergoes marked changes in expression during chicken hair cell development. Although the properties of I(A are not normally classified as Ca(2+-dependent, we demonstrate that throughout the development of chicken hair cells, I(A is greatly reduced by acute alterations of intracellular Ca(2+. As determinants of spike timing and firing frequency, intracellular Ca(2+ buffers shift the activation and inactivation properties of the current to more positive potentials. Our findings provide evidence to demonstrate that the kinetics and functional expression of I(A are tightly regulated by intracellular Ca(2+. Such feedback mechanism between the functional expression of I(A and intracellular Ca(2+ may shape the activity of spontaneous action potentials, thus potentially sculpting synaptic connections in an activity-dependent manner in the developing cochlea.

  13. 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.

  14. TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.

    Science.gov (United States)

    Liu, Yong; Zhou, Li-Jun; Wang, Jun; Li, Dai; Ren, Wen-Jie; Peng, Jiyun; Wei, Xiao; Xu, Ting; Xin, Wen-Jun; Pang, Rui-Ping; Li, Yong-Yong; Qin, Zhi-Hai; Murugan, Madhuvika; Mattson, Mark P; Wu, Long-Jun; Liu, Xian-Guo

    2017-01-25

    Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippocampal volume. Experimental studies show that spared nerve injury (SNI) of the sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, but impairs LTP in the hippocampus. The opposite changes may contribute to neuropathic pain and memory deficits, respectively. However, the cellular and molecular mechanisms underlying the functional synaptic changes are unclear. Here, we show that the dendrite lengths and spine densities are reduced significantly in hippocampal CA1 pyramidal neurons, but increased in spinal neurokinin-1-positive neurons in mice after SNI, indicating that the excitatory synaptic connectivity is reduced in hippocampus but enhanced in spinal dorsal horn in this neuropathic pain model. Mechanistically, tumor necrosis factor-alpha (TNF-α) is upregulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, whereas brain-derived neurotrophic factor (BDNF) is decreased in the hippocampus but increased in the ipsilateral spinal dorsal horn after SNI. Importantly, the SNI-induced opposite changes in synaptic connectivity and BDNF expression are prevented by genetic deletion of TNF receptor 1 in vivo and are mimicked by TNF-α in cultured slices. Furthermore, SNI activated microglia in both spinal dorsal horn and hippocampus; pharmacological inhibition or genetic ablation of microglia prevented the region-dependent synaptic changes, neuropathic pain, and memory deficits induced by SNI. The data suggest that neuropathic pain involves different structural synaptic alterations in spinal and hippocampal neurons that are mediated by overproduction of TNF-α and microglial activation and may underlie chronic pain and memory deficits. Chronic pain is often accompanied by memory deficits. Previous studies have shown that peripheral nerve injury produces both neuropathic pain and memory deficits and induces long

  15. Carbon Nanotube Synaptic Transistor Network for Pattern Recognition.

    Science.gov (United States)

    Kim, Sungho; Yoon, Jinsu; Kim, Hee-Dong; Choi, Sung-Jin

    2015-11-18

    Inspired by the human brain, a neuromorphic system combining complementary metal-oxide semiconductor (CMOS) and adjustable synaptic devices may offer new computing paradigms by enabling massive neural-network parallelism. In particular, synaptic devices, which are capable of emulating the functions of biological synapses, are used as the essential building blocks for an information storage and processing system. However, previous synaptic devices based on two-terminal resistive devices remain challenging because of their variability and specific physical mechanisms of resistance change, which lead to a bottleneck in the implementation of a high-density synaptic device network. Here we report that a three-terminal synaptic transistor based on carbon nanotubes can provide reliable synaptic functions that encode relative timing and regulate weight change. In addition, using system-level simulations, the developed synaptic transistor network associated with CMOS circuits can perform unsupervised learning for pattern recognition using a simplified spike-timing-dependent plasticity scheme.

  16. Tripartite synapses: astrocytes process and control synaptic information.

    Science.gov (United States)

    Perea, Gertrudis; Navarrete, Marta; Araque, Alfonso

    2009-08-01

    The term 'tripartite synapse' refers to a concept in synaptic physiology based on the demonstration of the existence of bidirectional communication between astrocytes and neurons. Consistent with this concept, in addition to the classic 'bipartite' information flow between the pre- and postsynaptic neurons, astrocytes exchange information with the synaptic neuronal elements, responding to synaptic activity and, in turn, regulating synaptic transmission. Because recent evidence has demonstrated that astrocytes integrate and process synaptic information and control synaptic transmission and plasticity, astrocytes, being active partners in synaptic function, are cellular elements involved in the processing, transfer and storage of information by the nervous system. Consequently, in contrast to the classically accepted paradigm that brain function results exclusively from neuronal activity, there is an emerging view, which we review herein, in which brain function actually arises from the coordinated activity of a network comprising both neurons and glia.

  17. L-DOPA Oppositely Regulates Synaptic Strength and Spine Morphology in D1 and D2 Striatal Projection Neurons in Dyskinesia

    Science.gov (United States)

    Suarez, Luz M; Solis, Oscar; Aguado, Carolina; Lujan, Rafael; Moratalla, Rosario

    2016-01-01

    Dopamine depletion in Parkinson's disease (PD) produces dendritic spine loss in striatal medium spiny neurons (MSNs) and increases their excitability. However, the synaptic changes that occur in MSNs in PD, in particular those induced by chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, are still poorly understood. We exposed BAC-transgenic D1-tomato and D2-eGFP mice to PD and dyskinesia model paradigms, enabling cell type-specific assessment of changes in synaptic physiology and morphology. The distinct fluorescence markers allowed us to identify D1 and D2 MSNs for analysis using intracellular sharp electrode recordings, electron microscopy, and 3D reconstructions with single-cell Lucifer Yellow injections. Dopamine depletion induced spine pruning in both types of MSNs, affecting mushroom and thin spines equally. Dopamine depletion also increased firing rate in both D1- and D2-MSNs, but reduced evoked-EPSP amplitude selectively in D2-MSNs. L-DOPA treatment that produced dyskinesia differentially affected synaptic properties in D1- and D2-MSNs. In D1-MSNs, spine density remained reduced but the remaining spines were enlarged, with bigger heads and larger postsynaptic densities. These morphological changes were accompanied by facilitation of action potential firing triggered by synaptic inputs. In contrast, although L-DOPA restored the number of spines in D2-MSNs, it resulted in shortened postsynaptic densities. These changes in D2-MSNs correlated with a decrease in synaptic transmission. Our findings indicate that L-DOPA-induced dyskinesia is associated with abnormal spine morphology, modified synaptic transmission, and altered EPSP-spike coupling, with distinct effects in D1- and D2-MSNs. PMID:27613437

  18. Neural ECM molecules in axonal and synaptic homeostatic plasticity.

    Science.gov (United States)

    Frischknecht, Renato; Chang, Kae-Jiun; Rasband, Matthew N; Seidenbecher, Constanze I

    2014-01-01

    Neural circuits can express different forms of plasticity. So far, Hebbian synaptic plasticity was considered the most important plastic phenomenon, but over the last decade, homeostatic mechanisms gained more interest because they can explain how a neuronal network maintains stable baseline function despite multiple plastic challenges, like developmental plasticity, learning, or lesion. Such destabilizing influences can be counterbalanced by the mechanisms of homeostatic plasticity, which restore the stability of neuronal circuits. Synaptic scaling is a mechanism in which neurons can detect changes in their own firing rates through a set of molecular sensors that then regulate receptor trafficking to scale the accumulation of glutamate receptors at synaptic sites. Additional homeostatic mechanisms allow local changes in synaptic activation to generate local synaptic adaptations and network-wide changes in activity, which lead to adjustments in the balance between excitation and inhibition. The molecular pathways underlying these forms of homeostatic plasticity are currently under intense investigation, and it becomes clear that the extracellular matrix (ECM) of the brain, which surrounds individual neurons and integrates them into the tissue, is an important element in these processes. As a highly dynamic structure, which can be remodeled and degraded in an activity-dependent manner and in concerted action of neurons and glial cells, it can on one hand promote structural and functional plasticity and on the other hand stabilize neural microcircuits. This chapter highlights the composition of brain ECM with particular emphasis on perisynaptic and axonal matrix formations and its involvement in plastic and adaptive processes of the central nervous system.

  19. Molecular mechanisms of synaptic remodeling in alcoholism.

    Science.gov (United States)

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-05

    Alcohol use and alcohol addiction represent dysfunctional brain circuits resulting from neuroadaptive changes during protracted alcohol exposure and its withdrawal. Alcohol exerts a potent effect on synaptic plasticity and dendritic spine formation in specific brain regions, providing a neuroanatomical substrate for the pathophysiology of alcoholism. Epigenetics has recently emerged as a critical regulator of gene expression and synaptic plasticity-related events in the brain. Alcohol exposure and withdrawal induce changes in crucial epigenetic processes in the emotional brain circuitry (amygdala) that may be relevant to the negative affective state defined as the "dark side" of addiction. Here, we review the literature concerning synaptic plasticity and epigenetics, with a particular focus on molecular events related to dendritic remodeling during alcohol abuse and alcoholism. Targeting epigenetic processes that modulate synaptic plasticity may yield novel treatments for alcoholism. Published by Elsevier Ireland Ltd.

  20. Factors affecting the regulation of pacing: current perspectives

    Directory of Open Access Journals (Sweden)

    Mauger AR

    2014-09-01

    Full Text Available Alexis R Mauger Endurance Research Group, School of Sport and Exercise Sciences, Faculty of Science, University of Kent, Chatham, UK Abstract: During prolonged dynamic and rhythmic exercise, muscular pain and discomfort arises as a result of an increased concentration of deleterious metabolites. Sensed by peripheral nociceptors and transmitted via afferent feedback to the brain, this provides important information regarding the physiological state of the muscle. These sensations ultimately contribute to what is termed "exercise-induced pain". Despite being well recognized by athletes and coaches, and suggested to be integral to exercise performance, this construct has largely escaped attention in experimental work. This perspective article highlights the current understanding of pacing in endurance performance, and the causes of exercise-induced pain. A new perspective is described, which proposes how exercise-induced pain may be a contributing factor in helping individuals to regulate their work rate during exercise and thus provides an important construct in pacing. Keywords: pain, exercise-induced pain, discomfort, exercise performance, self-paced

  1. 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.

  2. Spontaneous Glutamatergic Synaptic Activity Regulates Constitutive COX-2 Expression in Neurons: OPPOSING ROLES FOR THE TRANSCRIPTION FACTORS CREB (cAMP RESPONSE ELEMENT BINDING) PROTEIN AND Sp1 (STIMULATORY PROTEIN-1).

    Science.gov (United States)

    Hewett, Sandra J; Shi, Jingxue; Gong, Yifan; Dhandapani, Krishnan; Pilbeam, Carol; Hewett, James A

    2016-12-30

    Burgeoning evidence supports a role for cyclooxygenase metabolites in regulating membrane excitability in various forms of synaptic plasticity. Two cyclooxygenases, COX-1 and COX-2, catalyze the initial step in the metabolism of arachidonic acid to prostaglandins. COX-2 is generally considered inducible, but in glutamatergic neurons in some brain regions, including the cerebral cortex, it is constitutively expressed. However, the transcriptional mechanisms by which this occurs have not been elucidated. Here, we used quantitative PCR and also analyzed reporter gene expression in a mouse line carrying a construct consisting of a portion of the proximal promoter region of the mouse COX-2 gene upstream of luciferase cDNA to characterize COX-2 basal transcriptional regulation in cortical neurons. Extracts from the whole brain and from the cerebral cortex, hippocampus, and olfactory bulbs exhibited high luciferase activity. Moreover, constitutive COX-2 expression and luciferase activity were detected in cortical neurons, but not in cortical astrocytes, cultured from wild-type and transgenic mice, respectively. Constitutive COX-2 expression depended on spontaneous but not evoked excitatory synaptic activity and was shown to be N-methyl-d-aspartate receptor-dependent. Constitutive promoter activity was reduced in neurons transfected with a dominant-negative cAMP response element binding protein (CREB) and was eliminated by mutating the CRE-binding site on the COX-2 promoter. However, mutation of the stimulatory protein-1 (Sp1)-binding site resulted in an N-methyl-d-aspartate receptor-dependent enhancement of COX-2 promoter activity. Basal binding of the transcription factors CREB and Sp1 to the native neuronal COX-2 promoter was confirmed. In toto, our data suggest that spontaneous glutamatergic synaptic activity regulates constitutive neuronal COX-2 expression via Sp1 and CREB protein-dependent transcriptional mechanisms. © 2016 by The American Society for Biochemistry

  3. Orchestrated Regulation of Nogo Receptors, Lotus, AMPA Receptors and BDNF in an ECT Model Suggests Opening and Closure of a Window of Synaptic Plasticity

    OpenAIRE

    Nordgren, Max; Karlsson, Tobias; Svensson, Maria; Koczy, Josefin; Josephson, Anna; Olson, Lars; Tingstroem, Anders; Brene, Stefan

    2013-01-01

    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, ...

  4. Presynaptic inhibition of GABAergic synaptic transmission by adenosine in mouse hypothalamic hypocretin neurons.

    Science.gov (United States)

    Xia, J X; Xiong, J X; Wang, H K; Duan, S M; Ye, J N; Hu, Z A

    2012-01-10

    Hypocretin neurons in the lateral hypothalamus, a new wakefulness-promoting center, have been recently regarded as an important target involved in endogenous adenosine-regulating sleep homeostasis. The GABAergic synaptic transmissions are the main inhibitory afferents to hypocretin neurons, which play an important role in the regulation of excitability of these neurons. The inhibitory effect of adenosine, a homeostatic sleep-promoting factor, on the excitatory glutamatergic synaptic transmissions in hypocretin neurons has been well documented, whether adenosine also modulates these inhibitory GABAergic synaptic transmissions in these neurons has not been investigated. In this study, the effect of adenosine on inhibitory postsynaptic currents (IPSCs) in hypocretin neurons was examined by using perforated patch-clamp recordings in the acute hypothalamic slices. The findings demonstrated that adenosine suppressed the amplitude of evoked IPSCs in a dose-dependent manner, which was completely abolished by 8-cyclopentyltheophylline (CPT), a selective antagonist of adenosine A1 receptor but not adenosine A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl) xanthine. A presynaptic origin was suggested as following: adenosine increased paired-pulse ratio as well as reduced GABAergic miniature IPSC frequency without affecting the miniature IPSC amplitude. Further findings demonstrated that when the frequency of electrical stimulation was raised to 10 Hz, but not 1 Hz, a time-dependent depression of evoked IPSC amplitude was detected in hypocretin neurons, which could be partially blocked by CPT. However, under a higher frequency at 100 Hz stimulation, CPT had no action on the depressed GABAergic synaptic transmission induced by such tetanic stimulation in these hypocretin neurons. These results suggest that endogenous adenosine generated under certain stronger activities of synaptic transmissions exerts an inhibitory effect on GABAergic synaptic transmission in hypocretin

  5. Synaptic Homeostasis and Its Immunological Disturbance in Neuromuscular Junction Disorders

    Directory of Open Access Journals (Sweden)

    Masaharu Takamori

    2017-04-01

    Full Text Available In the neuromuscular junction, postsynaptic nicotinic acetylcholine receptor (nAChR clustering, trans-synaptic communication and synaptic stabilization are modulated by the molecular mechanisms underlying synaptic plasticity. The synaptic functions are based presynaptically on the active zone architecture, synaptic vesicle proteins, Ca2+ channels and synaptic vesicle recycling. Postsynaptically, they are based on rapsyn-anchored nAChR clusters, localized sensitivity to ACh, and synaptic stabilization via linkage to the extracellular matrix so as to be precisely opposed to the nerve terminal. Focusing on neural agrin, Wnts, muscle-specific tyrosine kinase (a mediator of agrin and Wnts signalings and regulator of trans-synaptic communication, low-density lipoprotein receptor-related protein 4 (the receptor of agrin and Wnts and participant in retrograde signaling, laminin-network (including muscle-derived agrin, extracellular matrix proteins (participating in the synaptic stabilization and presynaptic receptors (including muscarinic and adenosine receptors, we review the functional structures of the synapse by making reference to immunological pathogenecities in postsynaptic disease, myasthenia gravis. The synapse-related proteins including cortactin, coronin-6, caveolin-3, doublecortin, R-spondin 2, amyloid precursor family proteins, glia cell-derived neurotrophic factor and neurexins are also discussed in terms of their possible contribution to efficient synaptic transmission at the neuromuscular junction.

  6. [Involvement of aquaporin-4 in synaptic plasticity, learning and memory].

    Science.gov (United States)

    Wu, Xin; Gao, Jian-Feng

    2017-06-25

    Aquaporin-4 (AQP-4) is the predominant water channel in the central nervous system (CNS) and primarily expressed in astrocytes. Astrocytes have been generally believed to play important roles in regulating synaptic plasticity and information processing. However, the role of AQP-4 in regulating synaptic plasticity, learning and memory, cognitive function is only beginning to be investigated. It is well known that synaptic plasticity is the prime candidate for mediating of learning and memory. Long term potentiation (LTP) and long term depression (LTD) are two forms of synaptic plasticity, and they share some but not all the properties and mechanisms. Hippocampus is a part of limbic system that is particularly important in regulation of learning and memory. This article is to review some research progresses of the function of AQP-4 in synaptic plasticity, learning and memory, and propose the possible role of AQP-4 as a new target in the treatment of cognitive dysfunction.

  7. Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance

    Science.gov (United States)

    Cohen, Laurie D.; Zuchman, Rina; Sorokina, Oksana; Müller, Anke; Dieterich, Daniela C.; Armstrong, J. Douglas; Ziv, Tamar; Ziv, Noam E.

    2013-01-01

    Chemical synapses contain multitudes of proteins, which in common with all proteins, have finite lifetimes and therefore need to be continuously replaced. Given the huge numbers of synaptic connections typical neurons form, the demand to maintain the protein contents of these connections might be expected to place considerable metabolic demands on each neuron. Moreover, synaptic proteostasis might differ according to distance from global protein synthesis sites, the availability of distributed protein synthesis facilities, trafficking rates and synaptic protein dynamics. To date, the turnover kinetics of synaptic proteins have not been studied or analyzed systematically, and thus metabolic demands or the aforementioned relationships remain largely unknown. In the current study we used dynamic Stable Isotope Labeling with Amino acids in Cell culture (SILAC), mass spectrometry (MS), Fluorescent Non–Canonical Amino acid Tagging (FUNCAT), quantitative immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. We found that nearly all synaptic proteins identified here exhibited half-lifetimes in the range of 2–5 days. Unexpectedly, metabolic turnover rates were not significantly different for presynaptic and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. Some functionally or structurally related proteins exhibited very similar turnover rates, indicating that their biogenesis and degradation might be coupled, a possibility further supported by bioinformatics-based analyses. The relatively low turnover rates measured here (∼0.7% of synaptic protein content per hour) are in good agreement with imaging-based studies of synaptic protein trafficking, yet indicate that the metabolic load

  8. Potentiation of electrical and chemical synaptic transmission mediated by endocannabinoids

    Science.gov (United States)

    Cachope, Roger; Mackie, Ken; Triller, Antoine; O’Brien, John; Pereda, Alberto E.

    2009-01-01

    SUMMARY Endocannabinoids are well established as inhibitors of chemical synaptic transmission via presynaptic activation of the cannabinoid type 1 receptor (CB1R). Contrasting this notion, we show that dendritic release of endocannabinoids mediates potentiation of synaptic transmission at mixed (electrical and chemical) synaptic contacts on the goldfish Mauthner cell. Remarkably, the observed enhancement was not restricted to the glutamatergic component of the synaptic response but also included a parallel increase in electrical transmission. This novel effect involved the activation of CB1 receptors and was indirectly mediated via the release of dopamine from nearby varicosities, which in turn led to potentiation of the synaptic response via a cAMP-dependent protein kinase-mediated postsynaptic mechanism. Thus, endocannabinoid release can potentiate synaptic transmission and its functional roles include the regulation of gap junction-mediated electrical synapses. Similar interactions between endocannabinoid and dopaminergic systems may be widespread and potentially relevant for the motor and rewarding effects of cannabis derivatives. PMID:18093525

  9. Astrocytes and synaptic plasticity in health and disease.

    Science.gov (United States)

    Singh, A; Abraham, Wickliffe C

    2017-06-01

    Activity-dependent synaptic plasticity phenomena such as long-term potentiation and long-term depression are candidate mechanisms for storing information in the brain. Regulation of synaptic plasticity is critical for healthy cognition and learning and this is provided in part by metaplasticity, which can act to maintain synaptic transmission within a dynamic range and potentially prevent excitotoxicity. Metaplasticity mechanisms also allow neurons to integrate plasticity-associated signals over time. Interestingly, astrocytes appear to be critical for certain forms of synaptic plasticity and metaplasticity mechanisms. Synaptic dysfunction is increasingly viewed as an early feature of AD that is correlated with the severity of cognitive decline, and the development of these pathologies is correlated with a rise in reactive astrocytes. This review focuses on the contributions of astrocytes to synaptic plasticity and metaplasticity in normal tissue, and addresses whether astroglial pathology may lead to aberrant engagement of these mechanisms in neurological diseases such as Alzheimer's disease.

  10. Transcriptional coupling of synaptic transmission and energy metabolism: role of nuclear respiratory factor 1 in co-regulating neuronal nitric oxide synthase and cytochrome c oxidase genes in neurons.

    Science.gov (United States)

    Dhar, Shilpa S; Liang, Huan Ling; Wong-Riley, Margaret T T

    2009-10-01

    Neuronal activity is highly dependent on energy metabolism; yet, the two processes have traditionally been regarded as independently regulated at the transcriptional level. Recently, we found that the same transcription factor, nuclear respiratory factor 1 (NRF-1) co-regulates an important energy-generating enzyme, cytochrome c oxidase, as well as critical subunits of glutamatergic receptors. The present study tests our hypothesis that the co-regulation extends to the next level of glutamatergic synapses, namely, neuronal nitric oxide synthase, which generates nitric oxide as a downstream signaling molecule. Using in silico analysis, electrophoretic mobility shift assay, chromatin immunoprecipitation, promoter mutations, and NRF-1 silencing, we documented that NRF-1 functionally bound to Nos1, but not Nos2 (inducible) and Nos3 (endothelial) gene promoters. Both COX and Nos1 transcripts were up-regulated by depolarizing KCl treatment and down-regulated by TTX-mediated impulse blockade in neurons. However, NRF-1 silencing blocked the up-regulation of both Nos1 and COX induced by KCl depolarization, and over-expression of NRF-1 rescued both Nos1 and COX transcripts down-regulated by TTX. These findings are consistent with our hypothesis that synaptic neuronal transmission and energy metabolism are tightly coupled at the molecular level.

  11. 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

  12. Synaptic plasticity at the interface of health and disease: New insights on the role of endoplasmic reticulum intracellular calcium stores.

    Science.gov (United States)

    Maggio, N; Vlachos, A

    2014-12-05

    Work from the past 40years has unraveled a wealth of information on the cellular and molecular mechanisms underlying synaptic plasticity and their relevance in physiological brain function. At the same time, it has been recognized that a broad range of neurological diseases may be accompanied by severe alterations in synaptic plasticity, i.e., 'maladaptive synaptic plasticity', which could initiate and sustain the remodeling of neuronal networks under pathological conditions. Nonetheless, our current knowledge on the specific contribution and interaction of distinct forms of synaptic plasticity (including metaplasticity and homeostatic plasticity) in the context of pathological brain states remains limited. This review focuses on recent experimental evidence, which highlights the fundamental role of endoplasmic reticulum-mediated Ca(2+) signals in modulating the duration, direction, extent and type of synaptic plasticity. We discuss the possibility that intracellular Ca(2+) stores may regulate synaptic plasticity and hence behavioral and cognitive functions at the interface between physiology and pathology. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. Current insights into hormonal regulation of microspore embryogenesis

    Directory of Open Access Journals (Sweden)

    Iwona eŻur

    2015-06-01

    Full Text Available Plant growth regulator (PGR crosstalk and interaction with the plant’s genotype and environmental factors play a crucial role in microspore embryogenesis (ME, controlling microspore-derived embryo differentiation and development as well as haploid/doubled haploid plant regeneration. The complexity of the PGR network which could exist at the level of biosynthesis, distribution, gene expression or signaling pathways, renders the creation of an integrated model of ME-control crosstalk impossible at present. However, the analysis of the published data together with the results received recently with the use of modern analytical techniques brings new insights into hormonal regulation of this process. This review presents a short historical overview of the most important milestones in the recognition of hormonal requirements for effective ME in the most important crop plant species and complements it with new concepts that evolved over the last decade of ME studies.

  14. A pivotal role of GSK-3 in synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Clarrisa A Bradley

    2012-02-01

    Full Text Available Glycogen synthase kinase-3 (GSK-3 has many cellular functions. Recent evidence suggests that it plays a key role in certain types of synaptic plasticity, in particular a form of long-term depression (LTD that is induced by the synaptic activation of N-methyl-D-aspartate (NMDA receptors. In the present article we summarise what is currently known concerning the roles of GSK-3 in synaptic plasticity at both glutamatergic and GABAergic synapses. We summarise its role in cognition and speculate on how alterations in the synaptic functioning of GSK-3 may be a major factor in certain neurodegenerative disorders.

  15. A pivotal role of GSK-3 in synaptic plasticity

    Science.gov (United States)

    Bradley, Clarrisa A.; Peineau, Stéphane; Taghibiglou, Changiz; Nicolas, Celine S.; Whitcomb, Daniel J.; Bortolotto, Zuner A.; Kaang, Bong-Kiun; Cho, Kwangwook; Wang, Yu Tian; Collingridge, Graham L.

    2012-01-01

    Glycogen synthase kinase-3 (GSK-3) has many cellular functions. Recent evidence suggests that it plays a key role in certain types of synaptic plasticity, in particular a form of long-term depression (LTD) that is induced by the synaptic activation of N-methyl-D-aspartate receptors (NMDARs). In the present article we summarize what is currently known concerning the roles of GSK-3 in synaptic plasticity at both glutamatergic and GABAergic synapses. We summarize its role in cognition and speculate on how alterations in the synaptic functioning of GSK-3 may be a major factor in certain neurodegenerative disorders. PMID:22363262

  16. 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

  17. International Legal Regulation of Seamen Work: Current State

    Directory of Open Access Journals (Sweden)

    Alexandra V. Aleshina

    2016-03-01

    Full Text Available In article questions of international legal regulation of work of seamen are considered, activities of the International Labour Organization for preparation of standards in the field of protection of the rights of workers are lit. This organization made an essential contribution to development of standards in the sphere of a labor activity of the seamen on questions concerning special working conditions, and also protection of the rights of this employee category. The author analysed provisions of the Convention on work in sea navigation of 2006 which replaced with itself the existing sea conventions of the ILO and the related recommendations. She establishes the minimum international requirements concerning almost all aspects of working conditions and accommodation of seamen on the vessel: the minimum age, suitability for health reasons, professional training, terms of employment, including the rights concerning compensation, a paid annual leave, repatriation, duration of operating time and rest. In the course of scientific research the author comes to a conclusion that the Convention on work accepted in 2006 in sea navigation considerably simplifies the procedure of regulation of employment relationships on ocean ships owing to high extent of standardization of its precepts of law having comprehensive character and also their consolidation in the single document.

  18. Astrocytes optimize the synaptic transmission of information.

    Directory of Open Access Journals (Sweden)

    Suhita Nadkarni

    2008-05-01

    Full Text Available Chemical synapses transmit information via the release of neurotransmitter-filled vesicles from the presynaptic terminal. Using computational modeling, we predict that the limited availability of neurotransmitter resources in combination with the spontaneous release of vesicles limits the maximum degree of enhancement of synaptic transmission. This gives rise to an optimal tuning that depends on the number of active zones. There is strong experimental evidence that astrocytes that enwrap synapses can modulate the probabilities of vesicle release through bidirectional signaling and hence regulate synaptic transmission. For low-fidelity hippocampal synapses, which typically have only one or two active zones, the predicted optimal values lie close to those determined by experimentally measured astrocytic feedback, suggesting that astrocytes optimize synaptic transmission of information.

  19. Reflections on Competition, Competition Regulation and the Current Crises

    DEFF Research Database (Denmark)

    Buch-Hansen, Hubert; Wigger, Angela

    2013-01-01

    Economists, politicians, business leaders and opinion makers are convinced that competition enhances efficiency and maximises social welfare. As a result conditions conducive to the maximisation of competition have been created throughout developed capitalist societies. This article explains how...... crises currently facing humanity. The implication of the argument is that these crises can only be solved if prevailing notions of competition and its role in society are reconsidered....

  20. A presynaptic role for PKA in synaptic tagging and memory.

    Science.gov (United States)

    Park, Alan Jung; Havekes, Robbert; Choi, Jennifer Hk; Luczak, Vince; Nie, Ting; Huang, Ted; Abel, Ted

    2014-10-01

    Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and memory because PKA also regulates presynaptic transmitter release. Here, we examine this issue using genetic and pharmacological application of Ht31, a PKA anchoring disrupting peptide. At the hippocampal Schaffer collateral CA3-CA1 synapse, Ht31 treatment elicits a rapid decay of synaptic responses to repetitive stimuli, indicating a fast depletion of the readily releasable pool of synaptic vesicles. The interaction between PKA and proteins involved in producing this pool of synaptic vesicles is supported by biochemical assays showing that synaptic vesicle protein 2 (SV2), Rim1, and SNAP25 are components of a complex that interacts with cAMP. Moreover, acute treatment with Ht31 reduces the levels of SV2. Finally, experiments with transgenic mouse lines, which express Ht31 in excitatory neurons at the Schaffer collateral CA3-CA1 synapse, highlight a requirement for presynaptically anchored PKA in pathway-specific synaptic tagging and long-term contextual fear memory. These results suggest that a presynaptically compartmentalized PKA is critical for synaptic plasticity and memory by regulating the readily releasable pool of synaptic vesicles. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Role of MicroRNA in Governing Synaptic Plasticity.

    Science.gov (United States)

    Ye, Yuqin; Xu, Hongyu; Su, Xinhong; He, Xiaosheng

    2016-01-01

    Although synaptic plasticity in neural circuits is orchestrated by an ocean of genes, molecules, and proteins, the underlying mechanisms remain poorly understood. Recently, it is well acknowledged that miRNA exerts widespread regulation over the translation and degradation of target gene in nervous system. Increasing evidence suggests that quite a few specific miRNAs play important roles in various respects of synaptic plasticity including synaptogenesis, synaptic morphology alteration, and synaptic function modification. More importantly, the miRNA-mediated regulation of synaptic plasticity is not only responsible for synapse development and function but also involved in the pathophysiology of plasticity-related diseases. A review is made here on the function of miRNAs in governing synaptic plasticity, emphasizing the emerging regulatory role of individual miRNAs in synaptic morphological and functional plasticity, as well as their implications in neurological disorders. Understanding of the way in which miRNAs contribute to synaptic plasticity provides rational clues in establishing the novel therapeutic strategy for plasticity-related diseases.

  2. ERβ and ApoE isoforms interact to regulate BDNF-5-HT2Asignaling and synaptic function in the female brain.

    Science.gov (United States)

    Chhibber, Anindit; Zhao, Liqin

    2017-09-21

    Depression has been reported to be commonly manifested in patients with Alzheimer's disease (AD) and is considered a risk factor for AD. The human apolipoprotein E (ApoE) gene exists in three major isoforms (coded by ε2, ε3, and ε4), and the ε4 allele has been associated with a greater incidence of both depression and AD. Although mounting evidence points to the potentially complex interaction between these two brain disorders in which ApoE might play a role, the underlying mechanisms are largely unknown. Using human ApoE2, ApoE3, and ApoE4 gene-targeted replacement (hApoE-TR) mouse models, we investigated the role of ApoE isoforms and their potential interactions with estrogen receptor β (ERβ) signaling in modulating the brain mechanisms involved in depression. Our initial analyses in 6-month-old female hApoE-TR mice demonstrated that ApoE influenced the expression of brain-derived neurotrophic factor (BDNF) and the 5-hydroxytryptamine 2A (5-HT 2A ) serotonin receptor in an isoform-dependent manner, with the ApoE4 brain exhibiting the lowest level of BDNF and the highest level of 5-HT 2A . In addition, both presynaptic and postsynaptic proteins were downregulated, indicating a synaptic deficit in ApoE4 brains. Our subsequent analyses revealed that a 3-month chronic treatment with an ERβ-targeted (83-fold selectivity over ERα) phytoestrogenic diet induced several changes in ApoE2 and ApoE3 brains, including a significant decrease in the expression of 5-HT 2A receptors and an increase in BDNF/tropomyosin receptor kinase B and synaptic proteins. In contrast, ApoE4 brains were largely unresponsive to the treatment, with an increase only in select synaptic proteins in the treated group. Taken together, these results indicate that ApoE4 negatively impacts BDNF-5-HT 2A signaling in the female brain, which could in part underlie the ApoE4-mediated increased risk for depression. In a larger context, this mechanism could serve as a molecular link between depression

  3. 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.

  4. Current regulator for the stabilization of an electrostatic Van de Graaff generator

    International Nuclear Information System (INIS)

    Gabet, A.; Taieb, J.

    1953-01-01

    In a previous report (CEA report number 46) we described a current regulator destined to enslave the current of charge of the strap of a model of Van de Graaff. We will now describe the regulator destined to the 5 MeV Van de Graaff built in the Nuclear center of Saclay. (author) [fr

  5. Structure and function of the amygdaloid NPY system: NPY Y2 receptors regulate excitatory and inhibitory synaptic transmission in the centromedial amygdala.

    Science.gov (United States)

    Wood, J; Verma, D; Lach, G; Bonaventure, P; Herzog, H; Sperk, G; Tasan, R O

    2016-09-01

    The amygdala is essential for generating emotional-affective behaviors. It consists of several nuclei with highly selective, elaborate functions. In particular, the central extended amygdala, consisting of the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST) is an essential component actively controlling efferent connections to downstream effectors like hypothalamus and brain stem. Both, CEA and BNST contain high amounts of different neuropeptides that significantly contribute to synaptic transmission. Among these, neuropeptide Y (NPY) has emerged as an important anxiolytic and fear-reducing neuromodulator. Here, we characterized the expression, connectivity and electrophysiological function of NPY and Y2 receptors within the CEA. We identified several NPY-expressing neuronal populations, including somatostatin- and calretinin-expressing neurons. Furthermore, in the main intercalated nucleus, NPY is expressed primarily in dopamine D1 receptor-expressing neurons but also in interspersed somatostatin-expressing neurons. Interestingly, NPY neurons did not co-localize with the Y2 receptor. Retrograde tract tracing experiments revealed that NPY neurons reciprocally connect the CEA and BNST. Functionally, the Y2 receptor agonist PYY3-36, reduced both, inhibitory as well as excitatory synaptic transmission in the centromedial amygdala (CEm). However, we also provide evidence that lack of NPY or Y2 receptors results in increased GABA release specifically at inhibitory synapses in the CEm. Taken together, our findings suggest that NPY expressed by distinct populations of neurons can modulate afferent and efferent projections of the CEA via presynaptic Y2 receptors located at inhibitory and excitatory synapses.

  6. Medicines Regulation in Africa: Current State and Opportunities.

    Science.gov (United States)

    Ndomondo-Sigonda, Margareth; Miot, Jacqueline; Naidoo, Shan; Dodoo, Alexander; Kaale, Eliangiringa

    2017-01-01

    Sound regulatory systems are critical for protecting public health against use of medical products which do not meet international standards of quality, safety and efficacy. This review provides a summary of the current status of National Medicines Regulatory Authorities (NMRAs) in Africa, and various initiatives that have been established to improve their performance. All countries in Africa (except Sahrawi Republic), have NMRAs but their organizational set-up and functionality is variable. Some are located within Ministries of Health and others are semi-autonomous. There is progressive improvement in regulatory capacity, particularly in quality control and post-marketing surveillance, pharmacovigilance and clinical trials oversight. The African Vaccines Regulatory Forum, African Medicines Regulatory Harmonization Initiative, Network of Official Medicines Control Laboratories and WHO Prequalification Scheme have helped countries strengthen their regulatory capacities. The potential establishment of the African Medicines Agency (AMA) in 2018 is an opportunity to improve NMRAs' capacity in Africa.

  7. Youth perceptions of alcohol advertising: are current advertising regulations working?

    Science.gov (United States)

    Aiken, Alexandra; Lam, Tina; Gilmore, William; Burns, Lucy; Chikritzhs, Tanya; Lenton, Simon; Lloyd, Belinda; Lubman, Dan; Ogeil, Rowan; Allsop, Steve

    2018-04-26

    We investigated young people's exposure to alcohol advertising, their intentions to consume and purchase alcohol products following the viewing of advertisements, and whether they perceived the actors in the advertisements as being under the age of 25 years. Face-to-face interviews were completed with 351 risky drinking 16-19-year-old Australians, with a sub-sample (n=68) responding to a range of alcohol advertisements in an in-depth interview. Participants were exposed to alcohol advertisements from an average of seven specific contexts in the past 12 months, with younger adolescents more likely to recall TV and outdoor billboards (n=351). Positive perception of advertisements was associated with increased intention to use and to purchase advertised products (n=68). A liqueur advertisement actor was perceived by 94% as being under 25 years-old, and almost 30% thought the advertisement was marketed at people younger than 18 years of age. Young people's perceptions of alcohol advertising are not necessarily in line with expert/industry assessment; products are sometimes marketed in a way that is highly appealing to young people. Greater appeal was associated with increased intention to consume and to purchase products. Implications for public health: These results indicate deficiencies in the effectiveness of current advertising codes in regard to protecting the health and wellbeing of adolescents. © 2018 The Authors.

  8. Mechanisms of glycine release, which build up synaptic and extrasynaptic glycine levels: the role of synaptic and non-synaptic glycine transporters.

    Science.gov (United States)

    Harsing, Laszlo G; Matyus, Peter

    2013-04-01

    Glycine is an amino acid neurotransmitter that is involved in both inhibitory and excitatory neurochemical transmission in the central nervous system. The role of glycine in excitatory neurotransmission is related to its coagonist action at glutamatergic N-methyl-D-aspartate receptors. The glycine levels in the synaptic cleft rise many times higher during synaptic activation assuring that glycine spills over into the extrasynaptic space. Another possible origin of extrasynaptic glycine is the efflux of glycine occurring from astrocytes associated with glutamatergic synapses. The release of glycine from neuronal or glial origins exhibits several differences compared to that of biogenic amines or other amino acid neurotransmitters. These differences appear in an external Ca(2+)- and temperature-dependent manner, conferring unique characteristics on glycine as a neurotransmitter. Glycine transporter type-1 at synapses may exhibit neural and glial forms and plays a role in controlling synaptic glycine levels and the spill over rate of glycine from the synaptic cleft into the extrasynaptic biophase. Non-synaptic glycine transporter type-1 regulates extrasynaptic glycine concentrations, either increasing or decreasing them depending on the reverse or normal mode operation of the carrier molecule. While we can, at best, only estimate synaptic glycine levels at rest and during synaptic activation, glycine concentrations are readily measurable via brain microdialysis technique applied in the extrasynaptic space. The non-synaptic N-methyl-D-aspartate receptor may obtain glycine for activation following its spill over from highly active synapses or from its release mediated by the reverse operation of non-synaptic glycine transporter-1. The sensitivity of non-synaptic N-methyl-D-aspartate receptors to glutamate and glycine is many times higher than that of synaptic N-methyl-D-aspartate receptors making the former type of receptor the primary target for drug action. Synaptic

  9. Synaptic Plasticity onto Dopamine Neurons Shapes Fear Learning.

    Science.gov (United States)

    Pignatelli, Marco; Umanah, George Kwabena Essien; Ribeiro, Sissi Palma; Chen, Rong; Karuppagounder, Senthilkumar Senthil; Yau, Hau-Jie; Eacker, Stephen; Dawson, Valina Lynn; Dawson, Ted Murray; Bonci, Antonello

    2017-01-18

    Fear learning is a fundamental behavioral process that requires dopamine (DA) release. Experience-dependent synaptic plasticity occurs on DA neurons while an organism is engaged in aversive experiences. However, whether synaptic plasticity onto DA neurons is causally involved in aversion learning is unknown. Here, we show that a stress priming procedure enhances fear learning by engaging VTA synaptic plasticity. Moreover, we took advantage of the ability of the ATPase Thorase to regulate the internalization of AMPA receptors (AMPARs) in order to selectively manipulate glutamatergic synaptic plasticity on DA neurons. Genetic ablation of Thorase in DAT + neurons produced increased AMPAR surface expression and function that lead to impaired induction of both long-term depression (LTD) and long-term potentiation (LTP). Strikingly, animals lacking Thorase in DAT + neurons expressed greater associative learning in a fear conditioning paradigm. In conclusion, our data provide a novel, causal link between synaptic plasticity onto DA neurons and fear learning. Published by Elsevier Inc.

  10. Synaptic Scaling in Combination with Many Generic Plasticity Mechanisms Stabilizes Circuit Connectivity

    Science.gov (United States)

    Tetzlaff, Christian; Kolodziejski, Christoph; Timme, Marc; Wörgötter, Florentin

    2011-01-01

    Synaptic scaling is a slow process that modifies synapses, keeping the firing rate of neural circuits in specific regimes. Together with other processes, such as conventional synaptic plasticity in the form of long term depression and potentiation, synaptic scaling changes the synaptic patterns in a network, ensuring diverse, functionally relevant, stable, and input-dependent connectivity. How synaptic patterns are generated and stabilized, however, is largely unknown. Here we formally describe and analyze synaptic scaling based on results from experimental studies and demonstrate that the combination of different conventional plasticity mechanisms and synaptic scaling provides a powerful general framework for regulating network connectivity. In addition, we design several simple models that reproduce experimentally observed synaptic distributions as well as the observed synaptic modifications during sustained activity changes. These models predict that the combination of plasticity with scaling generates globally stable, input-controlled synaptic patterns, also in recurrent networks. Thus, in combination with other forms of plasticity, synaptic scaling can robustly yield neuronal circuits with high synaptic diversity, which potentially enables robust dynamic storage of complex activation patterns. This mechanism is even more pronounced when considering networks with a realistic degree of inhibition. Synaptic scaling combined with plasticity could thus be the basis for learning structured behavior even in initially random networks. PMID:22203799

  11. Neuronal cytoskeleton in synaptic plasticity and regeneration.

    Science.gov (United States)

    Gordon-Weeks, Phillip R; Fournier, Alyson E

    2014-04-01

    During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo-dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre- and post-synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system. © 2013 International Society for Neurochemistry.

  12. The Role of Proteases in Hippocampal Synaptic Plasticity: Putting Together Small Pieces of a Complex Puzzle.

    Science.gov (United States)

    Salazar, Ivan L; Caldeira, Margarida V; Curcio, Michele; Duarte, Carlos B

    2016-02-01

    Long-term synaptic plasticity in the hippocampus is thought to underlie the formation of certain forms of memory, including spatial memory. The early phase of long-term synaptic potentiation and synaptic depression depends on post-translational modifications of synaptic proteins, while protein synthesis is also required for the late-phase of both forms of synaptic plasticity (L-LTP and L-LTD). Numerous pieces of evidence show a role for different types of proteases in synaptic plasticity, further increasing the diversity of mechanisms involved in the regulation of the intracellular and extracellular protein content. The cleavage of extracellular proteins is coupled to changes in postsynaptic intracellular mechanisms, and additional alterations in this compartment result from the protease-mediated targeting of intracellular proteins. Both mechanisms contribute to initiate signaling cascades that drive downstream pathways coupled to synaptic plasticity. In this review we summarize the evidence pointing to a role for extracellular and intracellular proteases, with distinct specificities, in synaptic plasticity. Where in the cells the proteases are located, and how they are regulated is also discussed. The combined actions of proteases and translation mechanisms contribute to a tight control of the synaptic proteome relevant for long-term synaptic potentiation and synaptic depression in the hippocampus. Additional studies are required to elucidate the mechanisms whereby these changes in the synaptic proteome are related with plasticity phenomena.

  13. BDNF-induced local protein synthesis and synaptic plasticity.

    Science.gov (United States)

    Leal, Graciano; Comprido, Diogo; Duarte, Carlos B

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and long-term potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-γ (PLC-γ) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre- and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short- and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. The induction of cytochrome P450 2E1 by ethanol leads to the loss of synaptic proteins via PPARα down-regulation.

    Science.gov (United States)

    Na, Shufang; Li, Jie; Zhang, Huibo; Li, Yueran; Yang, Zheqiong; Zhong, Yanjun; Dong, Guicheng; Yang, Jing; Yue, Jiang

    2017-06-15

    Ethanol, one of the most commonly abused substances throughout history, is a substrate and potent inducer of cytochrome P450 2E1 (CYP2E1). Our previous study showed that brain CYP2E1 was induced by chronic ethanol treatment and was associated with ethanol-induced neurotoxicity in rats. We therefore investigated the possible mechanism of brain CYP2E1 involvement in ethanol-induced neurodegeneration. Compared with the controls, chronic ethanol treatment (3.0g/kg, i.g., 160days) significantly increased CYP2E1 mRNA levels in the rat cortex, but the mRNA levels of peroxisome proliferator-activated receptor α (PPARα) and the pre- and post-synaptic proteins (synaptophysin, SYP, and drebrin1, DBN1) were decreased. Ethanol treatment dose-dependently induced CYP2E1 mRNA expression, and CYP2E1 overexpression exacerbated the ethanol-induced neurotoxicity. Pretreatment with p38 inhibitor (SB202190) and ERK1/2 inhibitor (U0126) attenuated the induction of CYP2E1 mRNA and protein levels by ethanol; however, no change was observed with JNK inhibitor pretreatment. Ethanol exposure or CYP2E1 overexpression significantly decreased PPARα, SYP, and DBN1 expression as indicated by the data from real-time RT-PCR, Western blotting and immunocytochemistry. The activation of PPARα by WY14643 increased the activity of the SYP and DBN1 promoters and attenuated the inhibition of these genes by ethanol. The specific siRNA for CYP2E1 significantly attenuated the ethanol-induced inhibition of PPARα, SYP and DBN1 mRNA levels. These results suggest that the induction of CYP2E1 by ethanol may be mediated via the p38 and ERK1/2 signaling pathways in neurons but not via the JNK pathway. The CYP2E1-PPARα axis may play a role in ethanol-induced neurotoxicity via the alteration of the genes related with synaptic function. Copyright © 2017. Published by Elsevier B.V.

  15. A novel p38α MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model

    Directory of Open Access Journals (Sweden)

    McNamara Laurie K

    2007-09-01

    Full Text Available Abstract Background An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in proinflammatory cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD. This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38α MAPK, a well-established drug discovery molecular target for altering proinflammatory cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (Aβ and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the blood-brain barrier to allow their use as in vivo research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38α MAPK is a potential in vivo target for orally bioavailable, small molecules capable of suppressing excessive cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes. Methods A novel synthetic small molecule based on a molecular scaffold used previously was designed, synthesized, and subjected to analyses to demonstrate its potential in vivo bioavailability, metabolic stability, safety and brain uptake. Testing for in vivo efficacy used an AD-relevant mouse model. Results A novel, CNS-penetrant, non-toxic, orally bioavailable, small molecule inhibitor of p38α MAPK (MW01-2-069A-SRM was developed. Oral administration of the compound at a low dose (2.5 mg/kg resulted in attenuation of

  16. Modulation of synaptic plasticity by stress hormone associates with plastic alteration of synaptic NMDA receptor in the adult hippocampus.

    Directory of Open Access Journals (Sweden)

    Yiu Chung Tse

    Full Text Available Stress exerts a profound impact on learning and memory, in part, through the actions of adrenal corticosterone (CORT on synaptic plasticity, a cellular model of learning and memory. Increasing findings suggest that CORT exerts its impact on synaptic plasticity by altering the functional properties of glutamate receptors, which include changes in the motility and function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR that are responsible for the expression of synaptic plasticity. Here we provide evidence that CORT could also regulate synaptic plasticity by modulating the function of synaptic N-methyl-D-aspartate receptors (NMDARs, which mediate the induction of synaptic plasticity. We found that stress level CORT applied to adult rat hippocampal slices potentiated evoked NMDAR-mediated synaptic responses within 30 min. Surprisingly, following this fast-onset change, we observed a slow-onset (>1 hour after termination of CORT exposure increase in synaptic expression of GluN2A-containing NMDARs. To investigate the consequences of the distinct fast- and slow-onset modulation of NMDARs for synaptic plasticity, we examined the formation of long-term potentiation (LTP and long-term depression (LTD within relevant time windows. Paralleling the increased NMDAR function, both LTP and LTD were facilitated during CORT treatment. However, 1-2 hours after CORT treatment when synaptic expression of GluN2A-containing NMDARs is increased, bidirectional plasticity was no longer facilitated. Our findings reveal the remarkable plasticity of NMDARs in the adult hippocampus in response to CORT. CORT-mediated slow-onset increase in GluN2A in hippocampal synapses could be a homeostatic mechanism to normalize synaptic plasticity following fast-onset stress-induced facilitation.

  17. High-voltage integrated linear regulator with current sinking capabilities for portable ultrasound scanners

    DEFF Research Database (Denmark)

    Pausas, Guifre Vendrell; Llimos Muntal, Pere; Jørgensen, Ivan Harald Holger

    2017-01-01

    This paper presents a high-voltage integrated regulator capable of sinking current for driving pulse-triggered level shifters in drivers for ultrasound applications. The regulator utilizes a new topology with a feedback loop and a current sinking circuit to satisfy the requirements of the portable...... ultrasound scanner: a great driving strength in the scanner's transducer and a low undershoot voltage in the output node. The design regulates an output voltage of 45 V from an input voltage of 50 V, and it can sink currents up to 100 mA using no external components with only 340 mV of undershoot voltage...

  18. Olfactory receptor signaling is regulated by the post-synaptic density 95, Drosophila discs large, zona-occludens 1 (PDZ) scaffold multi-PDZ domain protein 1.

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2009-12-01

    The unique ability of mammals to detect and discriminate between thousands of different odorant molecules is governed by the diverse array of olfactory receptors expressed by olfactory sensory neurons in the nasal epithelium. Olfactory receptors consist of seven transmembrane domain G protein-coupled receptors and comprise the largest gene superfamily in the mammalian genome. We found that approximately 30% of olfactory receptors possess a classical post-synaptic density 95, Drosophila discs large, zona-occludens 1 (PDZ) domain binding motif in their C-termini. PDZ domains have been established as sites for protein-protein interaction and play a central role in organizing diverse cell signaling assemblies. In the present study, we show that multi-PDZ domain protein 1 (MUPP1) is expressed in the apical compartment of olfactory sensory neurons. Furthermore, on heterologous co-expression with olfactory sensory neurons, MUPP1 was shown to translocate to the plasma membrane. We found direct interaction of PDZ domains 1 + 2 of MUPP1 with the C-terminus of olfactory receptors in vitro. Moreover, the odorant-elicited calcium response of OR2AG1 showed a prolonged decay in MUPP1 small interfering RNA-treated cells. We have therefore elucidated the first building blocks of the putative \\'olfactosome\\

  19. Arc protein: a flexible hub for synaptic plasticity and cognition.

    Science.gov (United States)

    Nikolaienko, Oleksii; Patil, Sudarshan; Eriksen, Maria Steene; Bramham, Clive R

    2017-09-07

    Mammalian excitatory synapses express diverse types of synaptic plasticity. A major challenge in neuroscience is to understand how a neuron utilizes different types of plasticity to sculpt brain development, function, and behavior. Neuronal activity-induced expression of the immediate early protein, Arc, is critical for long-term potentiation and depression of synaptic transmission, homeostatic synaptic scaling, and adaptive functions such as long-term memory formation. However, the molecular basis of Arc protein function as a regulator of synaptic plasticity and cognition remains a puzzle. Recent work on the biophysical and structural properties of Arc, its protein-protein interactions and post-translational modifications have shed light on the issue. Here, we present Arc protein as a flexible, multifunctional and interactive hub. Arc interacts with specific effector proteins in neuronal compartments (dendritic spines, nuclear domains) to bidirectionally regulate synaptic strength by distinct molecular mechanisms. Arc stability, subcellular localization, and interactions are dictated by synaptic activity and post-translational modification of Arc. This functional versatility and context-dependent signaling supports a view of Arc as a highly specialized master organizer of long-term synaptic plasticity, critical for information storage and cognition. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Oxide-based synaptic transistors gated by solution-processed gelatin electrolytes

    Science.gov (United States)

    He, Yinke; Sun, Jia; Qian, Chuan; Kong, Ling-An; Gou, Guangyang; Li, Hongjian

    2017-04-01

    In human brain, a large number of neurons are connected via synapses. Simulation of the synaptic behaviors using electronic devices is the most important step for neuromorphic systems. In this paper, proton conducting gelatin electrolyte-gated oxide field-effect transistors (FETs) were used for emulating synaptic functions, in which the gate electrode is regarded as pre-synaptic neuron and the channel layer as the post-synaptic neuron. In analogy to the biological synapse, a potential spike can be applied at the gate electrode and trigger ionic motion in the gelatin electrolyte, which in turn generates excitatory post-synaptic current (EPSC) in the channel layer. Basic synaptic behaviors including spike time-dependent EPSC, paired-pulse facilitation (PPF), self-adaptation, and frequency-dependent synaptic transmission were successfully mimicked. Such ionic/electronic hybrid devices are beneficial for synaptic electronics and brain-inspired neuromorphic systems.

  1. β-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity.

    Science.gov (United States)

    Gilbert, James; Shu, Shu; Yang, Xin; Lu, Youming; Zhu, Ling-Qiang; Man, Heng-Ye

    2016-12-13

    The over-production of β-amyloid (Aβ) has been strongly correlated to neuronal dysfunction and altered synaptic plasticity in Alzheimer's disease (AD). Accordingly, it has been proposed that disrupted synaptic transmission and neuronal network instability underlie memory failure that is evident in the early phases of AD. Homeostatic synaptic plasticity (HSP) serves to restrain neuronal activity within a physiological range. Therefore a disruption of this mechanism may lead to destabilization in synaptic and neural circuit function. Here, we report that during HSP by neuronal activity deprivation, application of Aβ results in an aberrant over-response of the up-regulation of AMPA receptor (AMPAR)-mediated synaptic currents and cell-surface AMPAR expression. In the visual cortex, in vivo HSP induced by visual deprivation shows a similar over-response following an Aβ local injection. Aβ increases the expression of GluA2-lacking, calcium permeable AMPARs (CP-AMPARs), which are required for the initiation, but not maintenance of HSP. Both GluA2-lacking and GluA2-containing AMPARs contribute to the Aβ-mediated over-scaling of HSP. We also find that Aβ induces the dissociation of HDAC1 from the miR124 transcription factor EVI1, leading to an up-regulation of miR124 expression and increased amount of CP-AMPARs. Thus, via aberrant stimulation of miR124 expression and biogenesis of CP-AMPARs, Aβ is able to induce an over response in HSP. This Aβ-mediated dysregulation in homeostatic plasticity may play an important role in the pathogenesis of altered neural function and memory deficits in the early stages of AD.

  2. 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.

  3. AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging

    Science.gov (United States)

    Henley, Jeremy M.; Wilkinson, Kevin A.

    2013-01-01

    Even in healthy individuals there is an inexorable agerelated decline in cognitive function. This is due, in large part, to reduced synaptic plasticity caused by changes in the molecular composition of the postsynaptic membrane. AMPA receptors (AMPARs) are glutamate-gated cation channels that mediate the overwhelming majority of fast excitatory transmission in the brain. Changes in AMPAR number and/or function are a core feature of synaptic plasticity and age-related cognitive decline, AMPARs are highly dynamic proteins that are subject to highly controlled trafficking, recycling, and/or degradation and replacement. This active regulation of AMPAR synthesis, targeting, synaptic dwell time, and degradation is fundamentally important for memory formation and storage. Further, aberrant AMPAR trafficking and consequent detrimental changes in synapses are strongly implicated in many brain diseases, which represent a vast social and economic burden. The purpose of this article is to provide an overview of the molecular and cellular AMPA receptor trafficking events that control synaptic responsiveness and plasticity, and highlight what is known currently known about how these processes change with age and disease. PMID:23576886

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

    Energy Technology Data Exchange (ETDEWEB)

    Rudenko, Gabby (Texas-MED)

    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.

  5. 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.

  6. Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala.

    Science.gov (United States)

    Di, Shi; Itoga, Christy A; Fisher, Marc O; Solomonow, Jonathan; Roltsch, Emily A; Gilpin, Nicholas W; Tasker, Jeffrey G

    2016-08-10

    Stress and glucocorticoids stimulate the rapid mobilization of endocannabinoids in the basolateral amygdala (BLA). Cannabinoid receptors in the BLA contribute to anxiogenesis and fear-memory formation. We tested for rapid glucocorticoid-induced endocannabinoid regulation of synaptic inhibition in the rat BLA. Glucocorticoid application to amygdala slices elicited a rapid, nonreversible suppression of spontaneous, but not evoked, GABAergic synaptic currents in BLA principal neurons; the effect was also seen with a membrane-impermeant glucocorticoid, but not with intracellular glucocorticoid application, implicating a membrane-associated glucocorticoid receptor. The glucocorticoid suppression of GABA currents was not blocked by antagonists of nuclear corticosteroid receptors, or by inhibitors of gene transcription or protein synthesis, but was blocked by inhibiting postsynaptic G-protein activity, suggesting a postsynaptic nongenomic steroid signaling mechanism that stimulates the release of a retrograde messenger. The rapid glucocorticoid-induced suppression of inhibition was prevented by blocking CB1 receptors and 2-arachidonoylglycerol (2-AG) synthesis, and it was mimicked and occluded by CB1 receptor agonists, indicating it was mediated by the retrograde release of the endocannabinoid 2-AG. The rapid glucocorticoid effect in BLA neurons in vitro was occluded by prior in vivo acute stress-induced, or prior in vitro glucocorticoid-induced, release of endocannabinoid. Acute stress also caused an increase in anxiety-like behavior that was attenuated by blocking CB1 receptor activation and inhibiting 2-AG synthesis in the BLA. Together, these findings suggest that acute stress causes a long-lasting suppression of synaptic inhibition in BLA neurons via a membrane glucocorticoid receptor-induced release of 2-AG at GABA synapses, which contributes to stress-induced anxiogenesis. We provide a cellular mechanism in the basolateral amygdala (BLA) for the rapid stress

  7. Inhibitory Control of Synaptic and Behavioral Plasticity by Octopaminergic Signaling

    Science.gov (United States)

    Koon, Alex C.; Budnik, Vivian

    2012-01-01

    Adrenergic receptors and their ligands are important regulators of synaptic plasticity and metaplasticity, but the exact mechanisms underlying their action are still poorly understood. Octopamine, the invertebrate homolog of mammalian adrenaline or noradrenaline, plays important roles in modulating behavior and synaptic functions. We previously uncovered an octopaminergic positive feedback mechanism to regulate structural synaptic plasticity during development and in response to starvation. Under this mechanism, activation of Octß2R autoreceptors by octopamine at octopaminergic neurons initiated a cAMP-dependent cascade that stimulated the development of new synaptic boutons at the Drosophila larval neuromuscular junction (NMJ). However, the regulatory mechanisms that served to brake such positive feedback were not known. Here, we report the presence of an alternative octopamine autoreceptor, Octß1R, with antagonistic functions on synaptic growth. Mutations in octß1r result in the overgrowth of both glutamatergic and octopaminergic NMJs suggesting that Octß1R is a negative regulator of synaptic expansion. As Octß2R, Octß1R functioned in a cell autonomous manner at presynaptic motorneurons. However, unlike Octß2R, which activated a cAMP pathway, Octß1R likely inhibited cAMP production through inhibitory Goα. Despite its inhibitory role, Octß1R was required for acute changes in synaptic structure in response to octopamine and for starvation-induced increase in locomotor speed. These results demonstrate the dual action of octopamine on synaptic growth and behavioral plasticity, and highlight the important role of inhibitory influences for normal responses to physiological stimuli. PMID:22553037

  8. Molecular Signatures Underlying Synaptic Vesicle Cargo Retrieval

    Science.gov (United States)

    Mori, Yasunori; Takamori, Shigeo

    2018-01-01

    Efficient retrieval of the synaptic vesicle (SV) membrane from the presynaptic plasma membrane, a process called endocytosis, is crucial for the fidelity of neurotransmission, particularly during sustained neural activity. Although multiple modes of endocytosis have been identified, it is clear that the efficient retrieval of the major SV cargos into newly formed SVs during any of these modes is fundamental for synaptic transmission. It is currently believed that SVs are eventually reformed via a clathrin-dependent pathway. Various adaptor proteins recognize SV cargos and link them to clathrin, ensuring the efficient retrieval of the cargos into newly formed SVs. Here, we summarize our current knowledge of the molecular signatures within individual SV cargos that underlie efficient retrieval into SV membranes, as well as discuss possible contributions of the mechanisms under physiological conditions. PMID:29379416

  9. Synaptic Mechanisms of Memory Consolidation during Sleep Slow Oscillations.

    Science.gov (United States)

    Wei, Yina; Krishnan, Giri P; Bazhenov, Maxim

    2016-04-13

    Sleep is critical for regulation of synaptic efficacy, memories, and learning. However, the underlying mechanisms of how sleep rhythms contribute to consolidating memories acquired during wakefulness remain unclear. Here we studied the role of slow oscillations, 0.2-1 Hz rhythmic transitions between Up and Down states during stage 3/4 sleep, on dynamics of synaptic connectivity in the thalamocortical network model implementing spike-timing-dependent synaptic plasticity. We found that the spatiotemporal pattern of Up-state propagation determines the changes of synaptic strengths between neurons. Furthermore, an external input, mimicking hippocampal ripples, delivered to the cortical network results in input-specific changes of synaptic weights, which persisted after stimulation was removed. These synaptic changes promoted replay of specific firing sequences of the cortical neurons. Our study proposes a neuronal mechanism on how an interaction between hippocampal input, such as mediated by sharp wave-ripple events, cortical slow oscillations, and synaptic plasticity, may lead to consolidation of memories through preferential replay of cortical cell spike sequences during slow-wave sleep. Sleep is critical for memory and learning. Replay during sleep of temporally ordered spike sequences related to a recent experience was proposed to be a neuronal substrate of memory consolidation. However, specific mechanisms of replay or how spike sequence replay leads to synaptic changes that underlie memory consolidation are still poorly understood. Here we used a detailed computational model of the thalamocortical system to report that interaction between slow cortical oscillations and synaptic plasticity during deep sleep can underlie mapping hippocampal memory traces to persistent cortical representation. This study provided, for the first time, a mechanistic explanation of how slow-wave sleep may promote consolidation of recent memory events. Copyright © 2016 the authors 0270-6474/16/364231-17$15.00/0.

  10. Agrin and synaptic laminin are required to maintain adult neuromuscular junctions.

    Directory of Open Access Journals (Sweden)

    Melanie A Samuel

    Full Text Available As synapses form and mature the synaptic partners produce organizing molecules that regulate each other's differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ, these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Here, we used mutant mice to ask whether these organizers are also required for synaptic maintenance. Deletion of agrin from a subset of adult motor neurons resulted in the loss of acetylcholine receptors and other components of the postsynaptic apparatus and synaptic cleft. Nerve terminals also atrophied and eventually withdrew from muscle fibers. On the other hand, mice lacking the presynaptic organizer laminin-α4 retained most of the synaptic cleft components but exhibited synaptic alterations reminiscent of those observed in aged animals. Although we detected no marked decrease in laminin or agrin levels at aged NMJs, we observed alterations in the distribution and organization of these synaptic cleft components suggesting that such changes could contribute to age-related synaptic disassembly. Together, these results demonstrate that pre- and post-synaptic organizers actively function to maintain the structure and function of adult NMJs.

  11. 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.

  12. Improved current-regulated delta modulator for reducing switching frequency and low-frequency current error in permanent magnet brushless AC drives \\ud

    OpenAIRE

    Wipasuramonton, P.; Zhu, Z.Q.; Howe, D.

    2005-01-01

    The conventional current-regulated delta modulator (CRDM) results in a high current ripple and a high switching frequency at low rotational speeds, and in low-frequency current harmonics, including a fundamental current error, at high rotational speeds. An improved current controller based on CRDM is proposed which introduces a zero-vector zone and a current error correction technique. It reduces the current ripple and switching frequency at low speeds, without the need to detect the back-emf...

  13. Current control loop design and analysis based on resonant regulators for microgrid applications

    DEFF Research Database (Denmark)

    Federico, de Bosio; Pastorelli, Michelle; de Sousa Ribeiro, Luiz Antonio

    2015-01-01

    Voltage and current control loops play an important role in the performance of microgrids employing power electronics voltage source inverters. Correct design of feedback loops is essential for the proper operation of these systems. This paper analyzes the influence of state feedback cross......-coupling in the design of resonant regulators for inner current loops in power converters operating in standalone microgrids. It is also demonstrated that the effect of state feedback cross-coupling degrades the performance of the control loops by increasing the steady-state error. Different resonant regulators...

  14. [Analysis on current laws and regulations of medical device clinical trial in China].

    Science.gov (United States)

    Wang, Yue; Li, Tianping; Liang, Ningxia

    2014-01-01

    A series of laws and regulations are the essential legal requirement in the field of clinical trial of medical device currently in China, especially the Provision for Clinical Trial of Medical Device. On the basis of current situation of medical device clinical trial, systemic analysis on the hot spot topics in the regulations was conducted to explore the way of improving the control system of clinical trial of medical device in China, which will provide the reference for medical device industry and the investigators of the clinical trial of medical device.

  15. Voltage and Current Regulators Design of Power Converters in Islanded Microgrids based on State Feedback Decoupling

    DEFF Research Database (Denmark)

    Federico, de Bosio; de Sousa Ribeiro, Luiz Antonio; Freijedo Fernandez, Francisco Daniel

    2016-01-01

    In stand-alone microgrids based on voltage source inverters state feedback coupling between the capacitor voltage and inductor current degrades significantly the dynamics performance of voltage and current regulators. The decoupling of the controlled states is proposed, considering the limitation...... introduced by system delays. Moreover, a proportional resonant voltage controller is designed according to Nyquist criterion taking into account application requirements. Experimental tests performed in compliance with the UPS standards verify the theoretical analysis.......In stand-alone microgrids based on voltage source inverters state feedback coupling between the capacitor voltage and inductor current degrades significantly the dynamics performance of voltage and current regulators. The decoupling of the controlled states is proposed, considering the limitations...

  16. Current knowledge of microRNA-mediated regulation of drug metabolism in humans.

    Science.gov (United States)

    Nakano, Masataka; Nakajima, Miki

    2018-05-02

    Understanding the factors causing inter- and intra-individual differences in drug metabolism potencies is required for the practice of personalized or precision medicine, as well as for the promotion of efficient drug development. The expression of drug-metabolizing enzymes is controlled by transcriptional regulation by nuclear receptors and transcriptional factors, epigenetic regulation, such as DNA methylation and histone acetylation, and post-translational modification. In addition to such regulation mechanisms, recent studies revealed that microRNAs (miRNAs), endogenous ~22-nucleotide non-coding RNAs that regulate gene expression through the translational repression and degradation of mRNAs, significantly contribute to post-transcriptional regulation of drug-metabolizing enzymes. Areas covered: This review summarizes the current knowledge regarding miRNAs-dependent regulation of drug-metabolizing enzymes and transcriptional factors and its physiological and clinical significance. We also describe recent advances in miRNA-dependent regulation research, showing that the presence of pseudogenes, single-nucleotide polymorphisms, and RNA editing affects miRNA targeting. Expert opinion: It is unwavering fact that miRNAs are critical factors causing inter- and intra-individual differences in the expression of drug-metabolizing enzymes. Consideration of miRNA-dependent regulation would be a helpful tool for optimizing personalized and precision medicine.

  17. Providing current radiation safety according to new version of 'Ukrytie' object regulation

    International Nuclear Information System (INIS)

    Borovoj, A.A.; Vysotskij, E.D.; Krinitsyn, A.P.; Bogatov, S.A.

    1999-01-01

    Main provisions are given of the 'Ukryttia' object's Regulation related to provision of radiation safety during the object's operation. The safety is provided due to the realization by the object's personnel of functions of global monitoring of current radiation conditions, as well as of the measures of operative or preventive suppression of radiation abnormalities sources

  18. Exploring Faraday's Law of Electrolysis Using Zinc-Air Batteries with Current Regulative Diodes

    Science.gov (United States)

    Kamata, Masahiro; Paku, Miei

    2007-01-01

    Current regulative diodes (CRDs) are applied to develop new educational experiments on Faraday's law by using a zinc-air battery (PR2330) and a resistor to discharge it. The results concluded that the combination of zinc-air batteries and the CRD array is simpler, less expensive, and quantitative and gives accurate data.

  19. The effect of plant growth regulators and their interaction with electric current on winter wheat development

    Czech Academy of Sciences Publication Activity Database

    Biesaga-Koscielniak, J.; Koscielniak, J.; Filek, M.; Marcinska, I.; Krekule, Jan; Macháčková, Ivana; Kubon, M.

    2010-01-01

    Roč. 32, č. 5 (2010), s. 987-995 ISSN 0137-5881 Institutional research plan: CEZ:AV0Z50380511 Keywords : In vitro culture * Plant growth regulators * Electric current Subject RIV: EF - Botanics Impact factor: 1.344, year: 2010

  20. An Improved Test for Detecting Multiplicative Homeostatic Synaptic Scaling

    Science.gov (United States)

    Kim, Jimok; Tsien, Richard W.; Alger, Bradley E.

    2012-01-01

    Homeostatic scaling of synaptic strengths is essential for maintenance of network “gain”, but also poses a risk of losing the distinctions among relative synaptic weights, which are possibly cellular correlates of memory storage. Multiplicative scaling of all synapses has been proposed as a mechanism that would preserve the relative weights among them, because they would all be proportionately adjusted. It is crucial for this hypothesis that all synapses be affected identically, but whether or not this actually occurs is difficult to determine directly. Mathematical tests for multiplicative synaptic scaling are presently carried out on distributions of miniature synaptic current amplitudes, but the accuracy of the test procedure has not been fully validated. We now show that the existence of an amplitude threshold for empirical detection of miniature synaptic currents limits the use of the most common method for detecting multiplicative changes. Our new method circumvents the problem by discarding the potentially distorting subthreshold values after computational scaling. This new method should be useful in assessing the underlying neurophysiological nature of a homeostatic synaptic scaling transformation, and therefore in evaluating its functional significance. PMID:22615990

  1. Isolation of Synaptosomes, Synaptic Plasma Membranes, and Synaptic Junctional Complexes.

    Science.gov (United States)

    Michaelis, Mary L; Jiang, Lei; Michaelis, Elias K

    2017-01-01

    Isolation of synaptic nerve terminals or synaptosomes provides an opportunity to study the process of neurotransmission at many levels and with a variety of approaches. For example, structural features of the synaptic terminals and the organelles within them, such as synaptic vesicles and mitochondria, have been elucidated with electron microscopy. The postsynaptic membranes are joined to the presynaptic "active zone" of transmitter release through cell adhesion molecules and remain attached throughout the isolation of synaptosomes. These "post synaptic densities" or "PSDs" contain the receptors for the transmitters released from the nerve terminals and can easily be seen with electron microscopy. Biochemical and cell biological studies with synaptosomes have revealed which proteins and lipids are most actively involved in synaptic release of neurotransmitters. The functional properties of the nerve terminals, such as responses to depolarization and the uptake or release of signaling molecules, have also been characterized through the use of fluorescent dyes, tagged transmitters, and transporter substrates. In addition, isolated synaptosomes can serve as the starting material for the isolation of relatively pure synaptic plasma membranes (SPMs) that are devoid of organelles from the internal environment of the nerve terminal, such as mitochondria and synaptic vesicles. The isolated SPMs can reseal and form vesicular structures in which transport of ions such as sodium and calcium, as well as solutes such as neurotransmitters can be studied. The PSDs also remain associated with the presynaptic membranes during isolation of SPM fractions, making it possible to isolate the synaptic junctional complexes (SJCs) devoid of the rest of the plasma membranes of the nerve terminals and postsynaptic membrane components. Isolated SJCs can be used to identify the proteins that constitute this highly specialized region of neurons. In this chapter, we describe the steps involved

  2. PSD-95 and PSD-93 Play Critical but Distinct Roles in Synaptic Scaling Up and Down

    Science.gov (United States)

    Sun, Qian; Turrigiano, Gina G.

    2011-01-01

    Synaptic scaling stabilizes neuronal firing through the homeostatic regulation of postsynaptic strength, but the mechanisms by which chronic changes in activity lead to bidirectional adjustments in synaptic AMPAR abundance are incompletely understood. Further, it remains unclear to what extent scaling up and scaling down utilize distinct molecular machinery. PSD-95 is a scaffold protein proposed to serve as a binding “slot” that determines synaptic AMPAR content, and synaptic PSD-95 abundance is regulated by activity, raising the possibility that activity-dependent changes in the synaptic abundance of PSD-95 or other MAGUKs drives the bidirectional changes in AMPAR accumulation during synaptic scaling. We found that synaptic PSD-95 and SAP102 (but not PSD-93) abundance were bidirectionally regulated by activity, but these changes were not sufficient to drive homeostatic changes in synaptic strength. Although not sufficient, the PSD-95-MAGUKs were necessary for synaptic scaling, but scaling up and down were differentially dependent on PSD-95 and PSD-93. Scaling down was completely blocked by reduced or enhanced PSD-95, through a mechanism that depended on the PDZ1/2 domains. In contrast scaling up could be supported by either PSD-95 or PSD-93 in a manner that depended on neuronal age, and was unaffected by a superabundance of PSD-95. Taken together, our data suggest that scaling up and down of quantal amplitude is not driven by changes in synaptic abundance of PSD-95-MAGUKs, but rather that the PSD-95 MAGUKs serve as critical synaptic organizers that utilize distinct protein-protein interactions to mediate homeostatic accumulation and loss of synaptic AMPAR. PMID:21543610

  3. CCL2-ethanol interactions and hippocampal synaptic protein expression in a transgenic mouse model

    Directory of Open Access Journals (Sweden)

    Donna eGruol

    2014-04-01

    Full Text Available Chronic exposure to ethanol produces a number of detrimental effects on behavior. Neuroadaptive changes in brain structure or function underlie these behavioral changes and may be transient or persistent in nature. Central to the functional changes are alterations in the biology of neuronal and glial cells of the brain. Recent data show that ethanol induces glial cells of the brain to produce elevated levels of neuroimmune factors including CCL2, a key innate immune chemokine. Depending on the conditions of ethanol exposure, the upregulated levels of CCL2 can be transient or persistent and outlast the period of ethanol exposure. Importantly, results indicate that the upregulated levels of CCL2 may lead to CCL2-ethanol interactions that mediate or regulate the effects of ethanol on the brain. Glial cells are in close association with neurons and regulate many neuronal functions. Therefore, effects of ethanol on glial cells may underlie some of the effects of ethanol on neurons. To investigate this possibility, we are studying the effects of chronic ethanol on hippocampal synaptic function in a transgenic mouse model that expresses elevated levels of CCL2 in the brain through enhanced glial expression, a situation know to occur in alcoholics. Both CCL2 and ethanol have been reported to alter synaptic function in the hippocampus. In the current study, we determined if interactions are evident between CCL2 and ethanol at level of hippocampal synaptic proteins. Two ethanol exposure paradigms were used; the first involved ethanol exposure by drinking and the second involved ethanol exposure in a paradigm that combines drinking plus ethanol vapor. The first paradigm does not produce dependence on ethanol, whereas the second paradigm is commonly used to produce ethanol dependence. Results show modest effects of both ethanol exposure paradigms on the level of synaptic proteins in the hippocampus of CCL2 transgenic mice compared with their non

  4. Pacemaker neuron and network oscillations depend on a neuromodulator-regulated linear current

    Directory of Open Access Journals (Sweden)

    Shunbing Zhao

    2010-05-01

    Full Text Available Linear leak currents have been implicated in the regulation of neuronal excitability, generation of neuronal and network oscillations, and network state transitions. Yet, few studies have directly tested the dependence of network oscillations on leak currents or explored the role of leak currents on network activity. In the oscillatory pyloric network of decapod crustaceans neuromodulatory inputs are necessary for pacemaker activity. A large subset of neuromodulators is known to activate a single voltage-gated inward current IMI, which has been shown to regulate the rhythmic activity of the network and its pacemaker neurons. Using the dynamic clamp technique, we show that the crucial component of IMI for the generation of oscillatory activity is only a close-to-linear portion of the current-voltage relationship. The nature of this conductance is such that the presence or the absence of neuromodulators effectively regulates the amount of leak current and the input resistance in the pacemaker neurons. When deprived of neuromodulatory inputs, pyloric oscillations are disrupted; yet, a linear reduction of the total conductance in a single neuron within the pacemaker group recovers not only the pacemaker activity in that neuron, but also leads to a recovery of oscillations in the entire pyloric network. The recovered activity produces proper frequency and phasing that is similar to that induced by neuromodulators. These results show that the passive properties of pacemaker neurons can significantly affect their capacity to generate and regulate the oscillatory activity of an entire network, and that this feature is exploited by neuromodulatory inputs.

  5. Synaptic plasticity model of therapeutic sleep deprivation in major depression.

    Science.gov (United States)

    Wolf, Elias; Kuhn, Marion; Normann, Claus; Mainberger, Florian; Maier, Jonathan G; Maywald, Sarah; Bredl, Aliza; Klöppel, Stefan; Biber, Knut; van Calker, Dietrich; Riemann, Dieter; Sterr, Annette; Nissen, Christoph

    2016-12-01

    Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50-60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today's first-line treatments, is not sufficiently understood. This article puts the idea forward that sleep/wake-dependent shifts in synaptic plasticity, i.e., the neural basis of adaptive network function and behavior, represent a critical mechanism of therapeutic SD in MDD. Particularly, this article centers on two major hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, and on how they can be integrated into a novel synaptic plasticity model of therapeutic SD in MDD. As a major component, the model proposes that therapeutic SD, by homeostatically enhancing cortical synaptic strength, shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP) in patients with MDD in a more favorable window of associative plasticity. Research on the molecular effects of SD in animals and humans, including observations in the neurotrophic, adenosinergic, monoaminergic, and glutamatergic system, provides some support for the hypothesis of associative synaptic plasticity facilitation after therapeutic SD in MDD. The model proposes a novel framework for a mechanism of action of therapeutic SD that can be further tested in humans based on non-invasive indices and in animals based on direct studies of synaptic plasticity. Further determining the mechanisms of action of SD might contribute to the development of novel fast acting treatments for MDD, one of the major health problems worldwide. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Anti-cyclic regulation of the Ukrainian economy under current conditions of the international markets volatility

    Directory of Open Access Journals (Sweden)

    Volodymyr Satsyk

    2009-04-01

    Full Text Available In the article there are considered the theoretical and methodological basis of anti-cyclic regulation of the countries’ economy under conditions of the world economy globalization. It suggests the analysis of practices of implementing of anti-cyclic policy in highly developed states, its defining features and directions under current global financial and economic crisis. There has been researched a practical toolkit of economic cycles diagnostics and cyclic fluctuations of total business activity in Ukraine based on this study. There are suggested recommendations concerning the formation of the effective mechanism of anti-cyclic regulation of the Ukrainian economy.

  7. LED Current Balance Using a Variable Voltage Regulator with Low Dropout vDS Control

    Directory of Open Access Journals (Sweden)

    Hung-I Hsieh

    2017-02-01

    Full Text Available A cost-effective light-emitting diode (LED current balance strategy using a variable voltage regulator (VVR with low dropout vDS control is proposed. This can regulate the multiple metal-oxide-semiconductor field-effect transistors (MOSFETs of the linear current regulators (LCR, maintaining low dropout vDS on the flat vGS-characteristic curves and making all drain currents almost the same. Simple group LCRs respectively loaded with a string LED are employed to implement the theme. The voltage VVdc from a VVR is synthesized by a string LED voltage NvD, source voltage vR, and a specified low dropout vDS = VQ. The VVdc updates instantly, through the control loop of the master LCR, which means that all slave MOSFETs have almost the same biases on their flat vGS-characteristic curves. This leads to all of the string LED currents being equal to each other, producing an almost even luminance. An experimental setup with microchip control is built to verify the estimations. Experimental results show that the luminance of all of the string LEDs are almost equal to one another, with a maximum deviation below 1% during a wide dimming range, while keeping all vDS of the MOSFETs at a low dropout voltage, as expected.

  8. Glutamate released spontaneously from astrocytes sets the threshold for synaptic plasticity.

    Science.gov (United States)

    Bonansco, Christian; Couve, Alejandro; Perea, Gertrudis; Ferradas, Carla Á; Roncagliolo, Manuel; Fuenzalida, Marco

    2011-04-01

    Astrocytes exhibit spontaneous calcium oscillations that could induce the release of glutamate as gliotransmitter in rat hippocampal slices. However, it is unknown whether this spontaneous release of astrocytic glutamate may contribute to determining the basal neurotransmitter release probability in central synapses. Using whole-cell recordings and Ca(2+) imaging, we investigated the effects of the spontaneous astrocytic activity on neurotransmission and synaptic plasticity at CA3-CA1 hippocampal synapses. We show here that the metabolic gliotoxin fluorocitrate (FC) reduces the amplitude of evoked excitatory postsynaptic currents and increases the paired-pulse facilitation, mainly due to the reduction of the neurotransmitter release probability and the synaptic potency. FC also decreased intracellular Ca(2+) signalling and Ca(2+) -dependent glutamate release from astrocytes. The addition of glutamine rescued the effects of FC over the synaptic potency; however, the probability of neurotransmitter release remained diminished. The blockage of group I metabotropic glutamate receptors mimicked the effects of FC on the frequency of miniature synaptic responses. In the presence of FC, the Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N ',N '-tetra-acetate or group I metabotropic glutamate receptor antagonists, the excitatory postsynaptic current potentiation induced by the spike-timing-dependent plasticity protocol was blocked, and it was rescued by delivering a stronger spike-timing-dependent plasticity protocol. Taken together, these results suggest that spontaneous glutamate release from astrocytes contributes to setting the basal probability of neurotransmitter release via metabotropic glutamate receptor activation, which could be operating as a gain control mechanism that regulates the threshold of long-term potentiation. Therefore, endogenous astrocyte activity provides a novel non-neuronal mechanism that could be critical for transferring information in

  9. Synaptic vesicle dynamic changes in a model of fragile X.

    Science.gov (United States)

    Broek, Jantine A C; Lin, Zhanmin; de Gruiter, H Martijn; van 't Spijker, Heleen; Haasdijk, Elize D; Cox, David; Ozcan, Sureyya; van Cappellen, Gert W A; Houtsmuller, Adriaan B; Willemsen, Rob; de Zeeuw, Chris I; Bahn, Sabine

    2016-01-01

    Fragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs). The extent of expression level alterations of synaptic proteins affected by FMRP loss and their consequences on synaptic dynamics in FXS has not been fully investigated. Here, we used an Fmr1 knockout (KO) mouse model to investigate the molecular mechanisms underlying FXS by monitoring protein expression changes using shotgun label-free liquid-chromatography mass spectrometry (LC-MS(E)) in brain tissue and synaptosome fractions. FXS-associated candidate proteins were validated using selected reaction monitoring (SRM) in synaptosome fractions for targeted protein quantification. Furthermore, functional alterations in synaptic release and dynamics were evaluated using live-cell imaging, and interpretation of synaptic dynamics differences was investigated using electron microscopy. Key findings relate to altered levels of proteins involved in GABA-signalling, especially in the cerebellum. Further exploration using microscopy studies found reduced synaptic vesicle unloading of hippocampal neurons and increased vesicle unloading in cerebellar neurons, which suggests a general decrease of synaptic transmission. Our findings suggest that FMRP is a regulator of synaptic vesicle dynamics, which supports the role of FMRP in presynaptic functions. Taken together, these studies provide novel insights into the molecular changes associated with FXS.

  10. A high accuracy 22 bit sigma-delta converter for digital regulation of superconducting magnet currents

    CERN Document Server

    Pett, John G

    1999-01-01

    The design of the latest CERN particle accelerator for high energy particle physics research, the Large Hadron Collider (LHC), has been underway for some years. The new machine requires stronger magnetic fields which necessitates $9 the use of super-conducting magnets around most of the 27km ring tunnel. The powering of these magnets, with currents up to 13 kA, presents new challenges in precision, which can be summarised as an improvement in setting and $9 regulation of certain currents to the part per million (ppm) level. This represents approximately a factor of ten improvement over present analogue methods. This paper will concentrate on the design and performance of the analogue to $9 digital converter (ADC), which is the key element in the digital regulation loops employed in each magnet power converter. (1 refs).

  11. SOME CONSIDERATIONS OVER THE INTERNAL CONTROL IN THE CONTEXT OF CURRENT ACCOUNTANCY REGULATIONS

    Directory of Open Access Journals (Sweden)

    Lenghel Dorin Radu

    2012-12-01

    Full Text Available Through the hereby study we set ourselves on an analysis over the internal control and the ways of implementation of it. The final purpose of our research is represented by the characteristics of the internal control system in the context of current accountancy regulations. The accomplishment of such goal has forced us to research the current literature in the area and also the legal regulations over internal control. Of course, the accomplishment of such a research was possible only after a pertinent analysis over the opinions expressed in specialty literature regarding this area. Our research wants to be with a theoretical and applicative character. It is based on analysing the internal control system, the methodology of internal control and the steps of internal control. We express our belief that the implementation of the internal control in a very exact manner comes as an aid to the company management and lead to the accomplishment of managerial objectives and policies. In what it regards the result of our research there can be drawn the following conclusions: from the legal regulations (OMFP nr. 3055/2009, there is no clear conclusion over the procedures and policies of implementation of internal control applicable to an economical entity; also there are not presented in a detailed way the types (forms of internal control, being presented in the legal regulations only a classification of them after the time in which they are exercised (before, during or after the finishing of the operations; also in the legal regulations there is developed a certain way of internal control, represented by the financial and accounting internal control, as if the other forms of internal control do not exist; in what regards the components of internal control, these are presented in another way, but similar to already known models of internal control (Coso and Coco; also in the legal regulations there are presented the general objectives of internal control

  12. On-line monitoring of base current and forward emitter current gain of the voltage regulator's serial pnp transistor in a radiation environment

    Directory of Open Access Journals (Sweden)

    Vukić Vladimir Đ.

    2012-01-01

    Full Text Available A method of on-line monitoring of the low-dropout voltage regulator's operation in a radiation environment is developed in this paper. The method had to enable detection of the circuit's degradation during exploitation, without terminating its operation in an ionizing radiation field. Moreover, it had to enable automatic measurement and data collection, as well as the detection of any considerable degradation, well before the monitored voltage regulator's malfunction. The principal parameters of the voltage regulator's operation that were monitored were the serial pnp transistor's base current and the forward emitter current gain. These parameters were procured indirectly, from the data on the voltage regulator's load and quiescent currents. Since the internal consumption current in moderately and heavily loaded devices was used, the quiescent current of a negligibly loaded voltage regulator of the same type served as a reference. Results acquired by on-line monitoring demonstrated marked agreement with the results acquired from examinations of the voltage regulator's maximum output current and minimum dropout voltage in a radiation environment. The results were particularly consistent in tests with heavily loaded devices. Results obtained for moderately loaded voltage regulators and the risks accompanying the application of the presented method, were also analyzed.

  13. Carbohydrate metabolism in Archaea: current insights into unusual enzymes and pathways and their regulation.

    Science.gov (United States)

    Bräsen, Christopher; Esser, Dominik; Rauch, Bernadette; Siebers, Bettina

    2014-03-01

    The metabolism of Archaea, the third domain of life, resembles in its complexity those of Bacteria and lower Eukarya. However, this metabolic complexity in Archaea is accompanied by the absence of many "classical" pathways, particularly in central carbohydrate metabolism. Instead, Archaea are characterized by the presence of unique, modified variants of classical pathways such as the Embden-Meyerhof-Parnas (EMP) pathway and the Entner-Doudoroff (ED) pathway. The pentose phosphate pathway is only partly present (if at all), and pentose degradation also significantly differs from that known for bacterial model organisms. These modifications are accompanied by the invention of "new," unusual enzymes which cause fundamental consequences for the underlying regulatory principles, and classical allosteric regulation sites well established in Bacteria and Eukarya are lost. The aim of this review is to present the current understanding of central carbohydrate metabolic pathways and their regulation in Archaea. In order to give an overview of their complexity, pathway modifications are discussed with respect to unusual archaeal biocatalysts, their structural and mechanistic characteristics, and their regulatory properties in comparison to their classic counterparts from Bacteria and Eukarya. Furthermore, an overview focusing on hexose metabolic, i.e., glycolytic as well as gluconeogenic, pathways identified in archaeal model organisms is given. Their energy gain is discussed, and new insights into different levels of regulation that have been observed so far, including the transcript and protein levels (e.g., gene regulation, known transcription regulators, and posttranslational modification via reversible protein phosphorylation), are presented.

  14. Microglia actively regulate the number of functional synapses.

    Directory of Open Access Journals (Sweden)

    Kyungmin Ji

    Full Text Available Microglia are the immunocompetent cells of the central nervous system. In the physiological setting, their highly motile processes continually survey the local brain parenchyma and transiently contact synaptic elements. Although recent work has shown that the interaction of microglia with synapses contributes to synaptic remodeling during development, the role of microglia in synaptic physiology is just starting to get explored. To assess this question, we employed an electrophysiological approach using two methods to manipulate microglia in culture: organotypic hippocampal brain slices in which microglia were depleted using clodronate liposomes, and cultured hippocampal neurons to which microglia were added. We show here that the frequency of excitatory postsynaptic current increases in microglia-depleted brain slices, consistent with a higher synaptic density, and that this enhancement ensures from the loss of microglia since it is reversed when the microglia are replenished. Conversely, the addition of microglia to neuronal cultures decreases synaptic activity and reduces the density of synapses, spine numbers, surface expression of AMPA receptor (GluA1, and levels of synaptic adhesion molecules. Taken together, our findings demonstrate that non-activated microglia acutely modulate synaptic activity by regulating the number of functional synapses in the central nervous system.

  15. Leucine-rich repeat-containing synaptic adhesion molecules as organizers of synaptic specificity and diversity.

    Science.gov (United States)

    Schroeder, Anna; de Wit, Joris

    2018-04-09

    The brain harbors billions of neurons that form distinct neural circuits with exquisite specificity. Specific patterns of connectivity between distinct neuronal cell types permit the transfer and computation of information. The molecular correlates that give rise to synaptic specificity are incompletely understood. Recent studies indicate that cell-surface molecules are important determinants of cell type identity and suggest that these are essential players in the specification of synaptic connectivity. Leucine-rich repeat (LRR)-containing adhesion molecules in particular have emerged as key organizers of excitatory and inhibitory synapses. Here, we discuss emerging evidence that LRR proteins regulate the assembly of specific connectivity patterns across neural circuits, and contribute to the diverse structural and functional properties of synapses, two key features that are critical for the proper formation and function of neural circuits.

  16. Cooperative stochastic binding and unbinding explain synaptic size dynamics and statistics.

    Science.gov (United States)

    Shomar, Aseel; Geyrhofer, Lukas; Ziv, Noam E; Brenner, Naama

    2017-07-01

    Synapses are dynamic molecular assemblies whose sizes fluctuate significantly over time-scales of hours and days. In the current study, we examined the possibility that the spontaneous microscopic dynamics exhibited by synaptic molecules can explain the macroscopic size fluctuations of individual synapses and the statistical properties of synaptic populations. We present a mesoscopic model, which ties the two levels. Its basic premise is that synaptic size fluctuations reflect cooperative assimilation and removal of molecules at a patch of postsynaptic membrane. The introduction of cooperativity to both assimilation and removal in a stochastic biophysical model of these processes, gives rise to features qualitatively similar to those measured experimentally: nanoclusters of synaptic scaffolds, fluctuations in synaptic sizes, skewed, stable size distributions and their scaling in response to perturbations. Our model thus points to the potentially fundamental role of cooperativity in dictating synaptic remodeling dynamics and offers a conceptual understanding of these dynamics in terms of central microscopic features and processes.

  17. Cooperative stochastic binding and unbinding explain synaptic size dynamics and statistics.

    Directory of Open Access Journals (Sweden)

    Aseel Shomar

    2017-07-01

    Full Text Available Synapses are dynamic molecular assemblies whose sizes fluctuate significantly over time-scales of hours and days. In the current study, we examined the possibility that the spontaneous microscopic dynamics exhibited by synaptic molecules can explain the macroscopic size fluctuations of individual synapses and the statistical properties of synaptic populations. We present a mesoscopic model, which ties the two levels. Its basic premise is that synaptic size fluctuations reflect cooperative assimilation and removal of molecules at a patch of postsynaptic membrane. The introduction of cooperativity to both assimilation and removal in a stochastic biophysical model of these processes, gives rise to features qualitatively similar to those measured experimentally: nanoclusters of synaptic scaffolds, fluctuations in synaptic sizes, skewed, stable size distributions and their scaling in response to perturbations. Our model thus points to the potentially fundamental role of cooperativity in dictating synaptic remodeling dynamics and offers a conceptual understanding of these dynamics in terms of central microscopic features and processes.

  18. Rapid regulation of tonic GABA currents in cultured rat hippocampal neurons.

    Science.gov (United States)

    Ransom, Christopher B; Tao, Wucheng; Wu, Yuanming; Spain, William J; Richerson, George B

    2013-02-01

    Subacute and chronic changes in tonic GABAergic inhibition occur in human and experimental epilepsy. Less is known about how tonic inhibition is modulated over shorter time frames (seconds). We measured endogenous tonic GABA currents from cultured rat hippocampal neurons to evaluate how they are affected by 1) transient increases in extracellular GABA concentration ([GABA]), 2) transient postsynaptic depolarization, and 3) depolarization of presynaptic cells. Transient increases in [GABA] (1 μM) reduced tonic currents; this reduction resulted from GABA-induced shifts in the reversal potential for GABA currents (E(GABA)). Transient depolarization of postsynaptic neurons reversed the effects of exogenous GABA and potentiated tonic currents. The voltage-dependent potentiation of tonic GABA currents was independent of E(GABA) shifts and represented postdepolarization potentiation (PDP), an intrinsic GABA(A) receptor property (Ransom CB, Wu Y, Richerson GB. J Neurosci 30: 7672-7684, 2010). Inhibition of vesicular GABA release with concanamycin A (ConA) did not affect tonic currents. In ConA-treated cells, transient application of 12 mM K(+) to depolarize presynaptic neurons and glia produced a persistent increase in tonic current amplitude. The K(+)-induced increase in tonic current was reversibly inhibited by SKF89976a (40 μM), indicating that this was caused by nonvesicular GABA release from GABA transporter type 1 (GAT1). Nonvesicular GABA release due to GAT1 reversal also occurred in acute hippocampal brain slices. Our results indicate that tonic GABA currents are rapidly regulated by GABA-induced changes in intracellular Cl(-) concentration, PDP of extrasynaptic GABA(A) receptors, and nonvesicular GABA release. These mechanisms may influence tonic inhibition during seizures when neurons are robustly depolarized and extracellular GABA and K(+) concentrations are elevated.

  19. Glutamate transporter GLAST controls synaptic wrapping by Bergmann glia and ensures proper wiring of Purkinje cells.

    Science.gov (United States)

    Miyazaki, Taisuke; Yamasaki, Miwako; Hashimoto, Kouichi; Kohda, Kazuhisa; Yuzaki, Michisuke; Shimamoto, Keiko; Tanaka, Kohichi; Kano, Masanobu; Watanabe, Masahiko

    2017-07-11

    Astrocytes regulate synaptic transmission through controlling neurotransmitter concentrations around synapses. Little is known, however, about their roles in neural circuit development. Here we report that Bergmann glia (BG), specialized cerebellar astrocytes that thoroughly enwrap Purkinje cells (PCs), are essential for synaptic organization in PCs through the action of the l-glutamate/l-aspartate transporter (GLAST). In GLAST-knockout mice, dendritic innervation by the main ascending climbing fiber (CF) branch was significantly weakened, whereas the transverse branch, which is thin and nonsynaptogenic in control mice, was transformed into thick and synaptogenic branches. Both types of CF branches frequently produced aberrant wiring to proximal and distal dendrites, causing multiple CF-PC innervation. Our electrophysiological analysis revealed that slow and small CF-evoked excitatory postsynaptic currents (EPSCs) were recorded from almost all PCs in GLAST-knockout mice. These atypical CF-EPSCs were far more numerous and had significantly faster 10-90% rise time than those elicited by glutamate spillover under pharmacological blockade of glial glutamate transporters. Innervation by parallel fibers (PFs) was also affected. PF synapses were robustly increased in the entire dendritic trees, leading to impaired segregation of CF and PF territories. Furthermore, lamellate BG processes were retracted from PC dendrites and synapses, leading to the exposure of these neuronal elements to the extracellular milieus. These synaptic and glial phenotypes were reproduced in wild-type mice after functional blockade of glial glutamate transporters. These findings highlight that glutamate transporter function by GLAST on BG plays important roles in development and maintenance of proper synaptic wiring and wrapping in PCs.

  20. Current Regulations for the Production of Multipotent Mesenchymal Stromal Cells for Clinical Application.

    Science.gov (United States)

    Slaper-Cortenbach, Ineke C M

    2008-01-01

    SUMMARY: In this review, the appropriate legislation on the expansion of multipotent mesenchymal stromal cells (MSCs) in Europe is described. The collection of cells and the manufacturing of MSCs are being regulated by European Directives (EUDs). Recently, the Regulation on Advanced Therapies Medicinal Products (ATMPs) is being published, which is of importance for the production of MSCs in Europe, and this legislation is not yet ready, but it is in its final stage. MSCs are currently being used in clinical trials, mostly in academic hospitals, for patients suffering from a wide variety of diseases. Companies (small and medium-sized enterprises) are becoming more and more involved in the production of MSCs for human use, and since marketing authorisation is the scope of the Regulation it was decided to install a Committee on Advanced Therapies (CAT) within European Medicines Agency (EMEA). This CAT will formulate a draft opinion on quality, safety and efficacy of ATMPs and will have an advisory and scientific role for the Committee for Medicinal Products for human use. The aim of this review is to outline the current legislation which is important for the manufacturing of MSCs.

  1. Periodic Safety Review in Interim Storage Facilities - Current Regulation and Experiences in Germany

    International Nuclear Information System (INIS)

    Neles, Julia Mareike; Schmidt, Gerhard

    2014-01-01

    Periodic safety reviews in nuclear power plants in Germany have been performed since the end of the 1980's as an indirect follow-up of the accident in Chernobyl and, in the meantime, are formally required by law. During this process the guidelines governing this review were developed in stages and reached their final form in 1996. Interim storage facilities and other nuclear facilities at that time were not included, so the guidelines were solely focused on the specific safety issues of nuclear power plants. Following IAEA's recommendations, the Western European Nuclear Regulator Association (WENRA) introduced PSRs in its safety reference levels for storage facilities (current version in WGWD report 2.1 as of Feb 2011: SRLs 59 - 61). Based on these formulations, Germany improved its regulation in 2010 with a recommendation of the Nuclear Waste Management Commission (Entsorgungskommission, ESK), an expert advisory commission for the federal regulatory body BMU. The ESK formulated these detailed requirements in the 'ESK recommendation for guides to the performance of periodic safety reviews for interim storage facilities for irradiated fuel elements and heat-generating radioactive waste'. Before finalization of the guideline a test phase was introduced, aimed to test the new regulation in practice and to later include the lessons learned in the final formulation of the guideline. The two-year test phase started in October 2011 in which the performance of a PSR will be tested at two selected interim storage facilities. Currently these recommendations are discussed with interested/concerned institutions. The results of the test phase shall be considered for improvements of the draft and during the final preparation of guidelines. Currently the PSR for the first ISF is in an advanced stage, the second facility just started the process. Preliminary conclusions from the test phase show that the implementation of the draft guideline requires interpretation. The aim of a

  2. Synaptically Driven Phosphorylation of Ribosomal Protein S6 Is Differentially Regulated at Active Synapses versus Dendrites and Cell Bodies by MAPK and PI3K/mTOR Signaling Pathways

    Science.gov (United States)

    Pirbhoy, Patricia Salgado; Farris, Shannon; Steward, Oswald

    2017-01-01

    High-frequency stimulation of the medial perforant path triggers robust phosphorylation of ribosomal protein S6 (rpS6) in activated dendritic domains and granule cell bodies. Here we dissect the signaling pathways responsible for synaptically driven rpS6 phosphorylation in the dentate gyrus using pharmacological agents to inhibit PI3-kinase/mTOR…

  3. Sulforhodamine 101 induces long-term potentiation of intrinsic excitability and synaptic efficacy in hippocampal CA1 pyramidal neurons

    DEFF Research Database (Denmark)

    Kang, J.; Kang, N.; Yu, Y.

    2010-01-01

    Sulforhodamine 101 (SR101) has been extensively used for investigation as a specific marker for astroglia in vivo and activity-dependent dye for monitoring regulated exocytosis. Here, we report that SR101 has bioactive effects on neuronal activity. Perfusion of slices with SR101 (1 microM) for 10...... min induced long-term potentiation of intrinsic neuronal excitability (LTP-IE) and a long-lasting increase in evoked EPSCs (eEPSCs) in CA1 pyramidal neurons in hippocampal slices. The increase in intrinsic neuronal excitability was a result of negative shifts in the action potential (AP) threshold...... NMDAR currents, suggesting that SR101 enhances activation of synaptic NMDARs. SR101-induced LTP-IE and potentiation of synaptic transmission triggered spontaneous neuronal firing in slices and in vivo epileptic seizures. Our results suggest that SR101 is an epileptogenic agent that long-lastingly lowers...

  4. Epigenetic mechanisms in memory and synaptic function

    Science.gov (United States)

    Sultan, Faraz A; Day, Jeremy J

    2011-01-01

    Although the term ‘epigenetics’ was coined nearly seventy years ago, its critical function in memory processing by the adult CNS has only recently been appreciated. The hypothesis that epigenetic mechanisms regulate memory and behavior was motivated by the need for stable molecular processes that evade turnover of the neuronal proteome. In this article, we discuss evidence that supports a role for neural epigenetic modifications in the formation, consolidation and storage of memory. In addition, we will review the evidence that epigenetic mechanisms regulate synaptic plasticity, a cellular correlate of memory. We will also examine how the concerted action of multiple epigenetic mechanisms with varying spatiotemporal profiles influence selective gene expression in response to behavioral experience. Finally, we will suggest key areas for future research that will help elucidate the complex, vital and still mysterious, role of epigenetic mechanisms in neural function and behavior. PMID:22122279

  5. Carbohydrate Metabolism in Archaea: Current Insights into Unusual Enzymes and Pathways and Their Regulation

    Science.gov (United States)

    Esser, Dominik; Rauch, Bernadette

    2014-01-01

    SUMMARY The metabolism of Archaea, the third domain of life, resembles in its complexity those of Bacteria and lower Eukarya. However, this metabolic complexity in Archaea is accompanied by the absence of many “classical” pathways, particularly in central carbohydrate metabolism. Instead, Archaea are characterized by the presence of unique, modified variants of classical pathways such as the Embden-Meyerhof-Parnas (EMP) pathway and the Entner-Doudoroff (ED) pathway. The pentose phosphate pathway is only partly present (if at all), and pentose degradation also significantly differs from that known for bacterial model organisms. These modifications are accompanied by the invention of “new,” unusual enzymes which cause fundamental consequences for the underlying regulatory principles, and classical allosteric regulation sites well established in Bacteria and Eukarya are lost. The aim of this review is to present the current understanding of central carbohydrate metabolic pathways and their regulation in Archaea. In order to give an overview of their complexity, pathway modifications are discussed with respect to unusual archaeal biocatalysts, their structural and mechanistic characteristics, and their regulatory properties in comparison to their classic counterparts from Bacteria and Eukarya. Furthermore, an overview focusing on hexose metabolic, i.e., glycolytic as well as gluconeogenic, pathways identified in archaeal model organisms is given. Their energy gain is discussed, and new insights into different levels of regulation that have been observed so far, including the transcript and protein levels (e.g., gene regulation, known transcription regulators, and posttranslational modification via reversible protein phosphorylation), are presented. PMID:24600042

  6. 17β-Estradiol-Induced Synaptic Rearrangements Are Accompanied by Altered Ectonucleotidase Activities in Male Rat Hippocampal Synaptosomes.

    Science.gov (United States)

    Mitrović, Nataša; Zarić, Marina; Drakulić, Dunja; Martinović, Jelena; Sévigny, Jean; Stanojlović, Miloš; Nedeljković, Nadežda; Grković, Ivana

    2017-03-01

    17β-Estradiol (E2) rapidly, by binding to membrane estrogen receptors, activates cell signaling cascades which induce formation of new dendritic spines in the hippocampus of males as in females, but the interaction with other metabolic processes, such as extracellular adenine nucleotides metabolism, are currently unknown. Extracellular adenine nucleotides play significant roles, controlling excitatory glutamatergic synapses and development of neural circuits and synaptic plasticity. Their precise regulation in the synaptic cleft is tightly controlled by ecto-nucleoside triphosphate diphosphohydrolase (NTPDase)/ecto-5'-nucleotidase (eN) enzyme chain. Therefore, we sought to clarify whether a single systemic injection of E2 in male rats is accompanied by changes in the expression of the pre- and postsynaptic proteins and downstream kinases linked to E2-induced synaptic rearrangement as well as alterations in NTPDase/eN pathway in the hippocampal synaptosomes. Obtained data showed activation of mammalian target of rapamycin and upregulation of key synaptic proteins necessary for spine formation, 24 h after systemic E2 administration. In E2-mediated conditions, we found downregulation of NTPDase1 and NTPDase2 and attenuation of adenine nucleotide hydrolysis by NTPDase/eN enzyme chain, without changes in NTPDase3 properties and augmentation of synaptic tissue-nonspecific alkaline phosphatase (TNAP) activity. Despite reduced NTPDase activities, increased TNAP activity probably prevents toxic accumulation of ATP in the extracellular milieu and also hydrolyzes accumulated ADP due to unchanged NTPDase3 activity. Thus, our initial evaluation supports idea of specific roles of different ectonucleotidases and their coordinated actions in E2-mediated spine remodeling and maintenance.

  7. Neurobeachin regulates neurotransmitter receptor trafficking to synapses

    NARCIS (Netherlands)

    Nair, R.; Lauks, J.; Jung, S; Cooke, N.E.; de Wit, H.; Brose, N.; Kilimann, M.W.; Verhage, M.; Rhee, J.

    2013-01-01

    The surface density of neurotransmitter receptors at synapses is a key determinant of synaptic efficacy. Synaptic receptor accumulation is regulated by the transport, postsynaptic anchoring, and turnover of receptors, involving multiple trafficking, sorting, motor, and scaffold proteins. We found

  8. Is There an Opportunity for Current Chemotherapeutics to Up-regulate MIC-A/B Ligands?

    Directory of Open Access Journals (Sweden)

    Kendel Quirk

    2017-10-01

    Full Text Available Natural killer (NK cells are critical effectors of the immune system. NK cells recognize unhealthy cells by specific ligands [e.g., MHC- class I chain related protein A or B (MIC-A/B] for further elimination by cytotoxicity. Paradoxically, cancer cells down-regulate MIC-A/B and evade NK cell’s anticancer activity. Recent data indicate that cellular-stress induces MIC-A/B, leading to enhanced sensitivity of cancer cells to NK cell-mediated cytotoxicity. In this Perspective article, we hypothesize that current chemotherapeutics at sub-lethal, non-toxic dose may promote cellular-stress and up-regulate the expression of MIC-A/B ligands to augment cancer’s sensitivity to NK cell-mediated cytotoxicity. Preliminary data from two human breast cancer cell lines, MDA-MB-231 and T47D treated with clinically relevant therapeutics such as doxorubicin, paclitaxel and methotrexate support the hypothesis. The goal of this Perspective is to underscore the prospects of current chemotherapeutics in NK cell immunotherapy, and discuss potential challenges and opportunities to improve cancer therapy.

  9. A Small Potassium Current in AgRP/NPY Neurons Regulates Feeding Behavior and Energy Metabolism

    Directory of Open Access Journals (Sweden)

    Yanlin He

    2016-11-01

    Full Text Available Neurons that co-express agouti-related peptide (AgRP and neuropeptide Y (NPY are indispensable for normal feeding behavior. Firing activities of AgRP/NPY neurons are dynamically regulated by energy status and coordinate appropriate feeding behavior to meet nutritional demands. However, intrinsic mechanisms that regulate AgRP/NPY neural activities during the fed-to-fasted transition are not fully understood. We found that AgRP/NPY neurons in satiated mice express high levels of the small-conductance calcium-activated potassium channel 3 (SK3 and are inhibited by SK3-mediated potassium currents; on the other hand, food deprivation suppresses SK3 expression in AgRP/NPY neurons, and the decreased SK3-mediated currents contribute to fasting-induced activation of these neurons. Genetic mutation of SK3 specifically in AgRP/NPY neurons leads to increased sensitivity to diet-induced obesity, associated with chronic hyperphagia and decreased energy expenditure. Our results identify SK3 as a key intrinsic mediator that coordinates nutritional status with AgRP/NPY neural activities and animals’ feeding behavior and energy metabolism.

  10. Optogenetic analysis of synaptic function

    NARCIS (Netherlands)

    Liewald, Jana F.; Brauner, Martin; Stephens, Greg J.; Bouhours, Magali; Schultheis, Christian; Zhen, Mei; Gottschalk, Alexander

    2008-01-01

    We introduce optogenetic investigation of neurotransmission (OptIoN) for time-resolved and quantitative assessment of synaptic function via behavioral and electrophysiological analyses. We photo-triggered release of acetylcholine or γ-aminobutyric acid at Caenorhabditis elegans neuromuscular

  11. Synaptic AMPA receptor plasticity and behavior

    NARCIS (Netherlands)

    Kessels, Helmut W.; Malinow, Roberto

    2009-01-01

    The ability to change behavior likely depends on the selective strengthening and weakening of brain synapses. The cellular models of synaptic plasticity, long-term potentiation (LTP) and depression (LTD) of synaptic strength, can be expressed by the synaptic insertion or removal of AMPA receptors

  12. Exercise-Induced Fatigue Impairs Bidirectional Corticostriatal Synaptic Plasticity.

    Science.gov (United States)

    Ma, Jing; Chen, Huimin; Liu, Xiaoli; Zhang, Lingtao; Qiao, Decai

    2018-01-01

    Exercise-induced fatigue (EF) is a ubiquitous phenomenon in sports competition and training. It can impair athletes' motor skill execution and cognition. Corticostriatal synaptic plasticity is considered to be the cellular mechanism of movement control and motor learning. However, the effect of EF on corticostriatal synaptic plasticity remains elusive. In the present study, using field excitatory postsynaptic potential recording, we found that the corticostriatal long-term potentiation (LTP) and long-term depression (LTD) were both impaired in EF mice. To further investigate the cellular mechanisms underlying the impaired synaptic plasticity in corticostriatal pathway, whole-cell patch clamp recordings were carried out on striatal medium spiny neurons (MSNs). MSNs in EF mice exhibited increased spontaneous excitatory postsynaptic current (sEPSC) frequency and decreased paired-pulse ratio (PPR), while with normal basic electrophysiological properties and normal sEPSC amplitude. Furthermore, the N-methyl-D-aspartate (NMDA)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) ratio of MSNs was reduced in EF mice. These results suggest that the enhanced presynaptic glutamate (Glu) release and downregulated postsynaptic NMDA receptor function lead to the impaired corticostriatal plasticity in EF mice. Taken together, our findings for the first time show that the bidirectional corticostriatal synaptic plasticity is impaired after EF, and suggest that the aberrant corticostriatal synaptic plasticity may be involved in the production and/or maintenance of EF.

  13. Cell-specific synaptic plasticity induced by network oscillations.

    Science.gov (United States)

    Zarnadze, Shota; Bäuerle, Peter; Santos-Torres, Julio; Böhm, Claudia; Schmitz, Dietmar; Geiger, Jörg Rp; Dugladze, Tamar; Gloveli, Tengis

    2016-05-24

    Gamma rhythms are known to contribute to the process of memory encoding. However, little is known about the underlying mechanisms at the molecular, cellular and network levels. Using local field potential recording in awake behaving mice and concomitant field potential and whole-cell recordings in slice preparations we found that gamma rhythms lead to activity-dependent modification of hippocampal networks, including alterations in sharp wave-ripple complexes. Network plasticity, expressed as long-lasting increases in sharp wave-associated synaptic currents, exhibits enhanced excitatory synaptic strength in pyramidal cells that is induced postsynaptically and depends on metabotropic glutamate receptor-5 activation. In sharp contrast, alteration of inhibitory synaptic strength is independent of postsynaptic activation and less pronounced. Further, we found a cell type-specific, directionally biased synaptic plasticity of two major types of GABAergic cells, parvalbumin- and cholecystokinin-expressing interneurons. Thus, we propose that gamma frequency oscillations represent a network state that introduces long-lasting synaptic plasticity in a cell-specific manner.

  14. Interlink Converter with Linear Quadratic Regulator Based Current Control for Hybrid AC/DC Microgrid

    Directory of Open Access Journals (Sweden)

    Dwi Riana Aryani

    2017-11-01

    Full Text Available A hybrid alternate current/direct current (AC/DC microgrid consists of an AC subgrid and a DC subgrid, and the subgrids are connected through the interlink bidirectional AC/DC converter. In the stand-alone operation mode, it is desirable that the interlink bidirectional AC/DC converter manages proportional power sharing between the subgrids by transferring power from the under-loaded subgrid to the over-loaded one. In terms of system security, the interlink bidirectional AC/DC converter takes an important role, so proper control strategies need to be established. In addition, it is assumed that a battery energy storage system is installed in one subgrid, and the coordinated control of interlink bidirectional AC/DC converter and battery energy storage system converter is required so that the power sharing scheme between subgrids becomes more efficient. For the purpose of designing a tracking controller for the power sharing by interlink bidirectional AC/DC converter in a hybrid AC/DC microgrid, a droop control method generates a power reference for interlink bidirectional AC/DC converter based on the deviation of the system frequency and voltages first and then interlink bidirectional AC/DC converter needs to transfer the power reference to the over-loaded subgrid. For efficiency of this power transferring, a linear quadratic regulator with exponential weighting for the current regulation of interlink bidirectional AC/DC converter is designed in such a way that the resulting microgrid can operate robustly against various uncertainties and the power sharing is carried out quickly. Simulation results show that the proposed interlink bidirectional AC/DC converter control strategy provides robust and efficient power sharing scheme between the subgrids without deteriorating the secure system operation.

  15. Factors Influencing Short-term Synaptic Plasticity in the Avian Cochlear Nucleus Magnocellularis

    Directory of Open Access Journals (Sweden)

    Jason Tait Sanchez Quinones

    2015-01-01

    Full Text Available Defined as reduced neural responses during high rates of activity, synaptic depression is a form of short-term plasticity important for the temporal filtering of sound. In the avian cochlear nucleus magnocellularis (NM, an auditory brainstem structure, mechanisms regulating short-term synaptic depression include pre-, post-, and extrasynaptic factors. Using varied paired-pulse stimulus intervals, we found that the time course of synaptic depression lasts up to four seconds at late-developing NM synapses. Synaptic depression was largely reliant on exogenous Ca 2+ -dependent probability of presynaptic neurotransmitter release, and to a lesser extent, on the desensitization of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPA-R. Interestingly, although extrasynaptic glutamate clearance did not play a significant role in regulating synaptic depression, blocking glutamate clearance at early-developing synapses altered synaptic dynamics, changing responses from depression to facilitation. These results suggest a developmental shift in the relative reliance on pre-, post-, and extrasynaptic factors in regulating short-term synaptic plasticity in NM.

  16. Role of DHA in aging-related changes in mouse brain synaptic plasma membrane proteome.

    Science.gov (United States)

    Sidhu, Vishaldeep K; Huang, Bill X; Desai, Abhishek; Kevala, Karl; Kim, Hee-Yong

    2016-05-01

    Aging has been related to diminished cognitive function, which could be a result of ineffective synaptic function. We have previously shown that synaptic plasma membrane proteins supporting synaptic integrity and neurotransmission were downregulated in docosahexaenoic acid (DHA)-deprived brains, suggesting an important role of DHA in synaptic function. In this study, we demonstrate aging-induced synaptic proteome changes and DHA-dependent mitigation of such changes using mass spectrometry-based protein quantitation combined with western blot or messenger RNA analysis. We found significant reduction of 15 synaptic plasma membrane proteins in aging brains including fodrin-α, synaptopodin, postsynaptic density protein 95, synaptic vesicle glycoprotein 2B, synaptosomal-associated protein 25, synaptosomal-associated protein-α, N-methyl-D-aspartate receptor subunit epsilon-2 precursor, AMPA2, AP2, VGluT1, munc18-1, dynamin-1, vesicle-associated membrane protein 2, rab3A, and EAAT1, most of which are involved in synaptic transmission. Notably, the first 9 proteins were further reduced when brain DHA was depleted by diet, indicating that DHA plays an important role in sustaining these synaptic proteins downregulated during aging. Reduction of 2 of these proteins was reversed by raising the brain DHA level by supplementing aged animals with an omega-3 fatty acid sufficient diet for 2 months. The recognition memory compromised in DHA-depleted animals was also improved. Our results suggest a potential role of DHA in alleviating aging-associated cognitive decline by offsetting the loss of neurotransmission-regulating synaptic proteins involved in synaptic function. Published by Elsevier Inc.

  17. Novel Three-Phase Current-Regulated Digital PWM and its Behavioral Analysis

    Science.gov (United States)

    Ohshima, Masaaki; Masada, Eisuke

    With respect to PWM algorithm for a three-phase voltage-source ac/dc power converter various studies have been executed and their results have been published since the analog modulation scheme based on triangular carrier wave was proposed in 1960's. PWM algorithm can be considered the heart of the electronic power conversion. Along with progress and evolution of digital technology gate signals are increasingly requested to be generated directly by digital IC, e.g. MPU, DSP or FPGA/CPLD. The paper analyzes quantitatively the precision of the current controllability of digital PWM taking into account of both the sampling period and the delay time the latter of which is inevitably accompanied by digital procedure. The delay time is pointed out to affect the current error double. In addition the paper derives theoretically the condition for digital PWM to accomplish PPCR (Pulse Polarity Consistency Rule, i.e. the next gate command moves only to the adjacent ones). In so far as the authors know no paper offers the mathematical requirements to execute PPCR taking account of the effect by the delay time with digital PWM. The derived theoretical results are summarized as the digital PWM design criteria for a three-phase PWM converter in order to facilitate practical implementation of the theory, which guarantee the PPCR behavior as well as the quantitative preciseness of the current regulation.

  18. Frequency of Synaptic Autoantibody Accompaniments and Neurological Manifestations of Thymoma.

    Science.gov (United States)

    Zekeridou, Anastasia; McKeon, Andrew; Lennon, Vanda A

    2016-07-01

    with neurological autoimmunity than in those without and were most frequent in patients with neurological manifestations other than or in addition to MG. Synaptic autoantibodies, particularly those reactive with ion channels of the ligand-gated nicotinic acetylcholine receptor superfamily (namely α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, glycine, and γ-aminobutyric acid-A receptors), were prevalent in patients with thymoma. Autoantibodies of this extended spectrum may enhance autoimmune serological testing as an aid to preoperative thymoma diagnosis. Detection of currently known synaptic autoantibody specificities absent from this profile have potential algorithmic usefulness as negative predictors for thymoma (as recognized for neuronal voltage-gated calcium channel autoantibodies).

  19. Current issues of international law in regulating counter-insurgency and counter-terrorism

    Directory of Open Access Journals (Sweden)

    Mária Bordás

    2014-10-01

    Full Text Available The study sheds light on the current tendencies if the international law on warfare can successfully be applied in the practical reality in the progress of counterinsurgency and counterterrorism efforts. There have been two phenomena identified recently in the warfare which are endangering public security and public safety of the democratic states of the world: terrorism and insurgency. Both of them mean a threat and violation to the population and the government authorities. It has been queried in the military literature whether these new forms of warfare should be handled by military engagements or law enforcement. This is, nevertheless, not just a dilemma of the strategy how to combat against it, but should be, at the same time, in accordance with the international legal regulations, too.

  20. Former Soviet Regulations for seismic design of NPPs and comparison with current international practice

    Energy Technology Data Exchange (ETDEWEB)

    Kostarev, V.; Schukin, A.; Berkovski, A. [CKTI-Vibroseism Co. Ltd. (Cape Verde)

    1997-03-01

    This paper presents a summary of current earthquake design criteria used in former Soviet Regulations for equipment and piping systems of nuclear power plants in light of those used in United States and Japan. The detailed comparative seismic analysis of PWR (WWER) Primary Coolant Loop System (PCLS) according to Former Soviet (Russian) PNAE Code and ASME BPV Code with some comments regarding to Japan Code JEAG - 4601 was undertaken for better understanding of the differences and coincidences of seismic design criteria and requirements. The selection of these three guides for the study has very simple explanation: according to ASME BVPC, JEAG and PNAE the huge majority of existing NPPs has been designed. (J.P.N.)

  1. Current products and future plan of regulatory research for risk-informed regulation in Korea

    International Nuclear Information System (INIS)

    Sung, Key Yong; Lee, Chang Ju; Kim, Woong Sik; Kim, Hho Jung

    2003-01-01

    The first phase of a regulatory research project for risk-informed regulation (RIR) and applications (RIA) was finished in March of 2002. Various results that could be useful for preparing Korean RIR system have been developed. One of the remarkable outputs is development of reactor safety goals and acceptance criteria for RIR and RIA in Korea. The Safety Goal has a 4-tier hierarchical structure and each tier has specified goals classified for their usage. Regulatory review guides for probabilistic safety assessment (PSA) including level-1, level-2 and low power and shutdown PSA have been updated by reflecting new information obtained from not only the overseas documents but also experience and insights from regulatory review in Korea. In addition, draft regulatory guides for risk-informed in-service inspection, in-service testing, importance ranking of motor-operated valves, and AOT/STI change of Technical Specifications have been developed for preparing ongoing and future licensing work. Risk-based inspection guides with inspection items selected from a viewpoint of risk importance have been suggested for Korean standard NPPs as well. In the second phase of a research project (April of 2002 to March of 2005), two regulatory research projects on RIR were initiated. One is a study on institutionalization of risk-informed and performance-based regulation. Main topics of this project are evaluation of benefit and characteristics of RIR, development of optimized Korean RIR model, impact analysis for the change of current regulation framework, and suggestion of RIR-related laws and rules. The other is focusing on the development in the areas of a regulatory audit PSA model and regulatory guides for risk monitoring, and application techniques of risk information to the significance determination of plant performance indicators and inspection findings. It is expected that a concrete scheme and detailed regulatory techniques for embodiment of RIR system in Korea will be

  2. [100 years of drinking water regulation. Retrospective review, current situation and prospects].

    Science.gov (United States)

    Rakhmanin, Yu A; Krasovsky, G N; Egorova, N A; Mikhailova, R I

    2014-01-01

    There is considered the history of the development of legislative requirements to the regulation of the quality of drinking water in different countries and international organizations during the period from 1912 to the present time. In terms of comparative analysis there is analyzed the current state of regulatory frameworks of the Russian Federation, WHO, EU, Finland, the UK, Singapore, Australia, Japan, China, Nigeria, the United States and Canada in the field of providing favorable conditions of population drinking water use. There has been noted the significant progress in standardization of the content of the biogenic elements and chemical pollution of drinking water in the absence of uniform requirements to the composition and properties of drinking water globally, that is bound to the need to take into account the national peculiarities of drinking water supply within the separate countries. As promising directions for improving regulation of drinking water quality there are noted: the development of new standards for prioritized water pollution, periodic review ofstandards after appearance of the new scientific data on the biological action of substances, the use of the concept of risk, the harmonization of the normative values and the assessment of the possibility of introduction into the practice the one more criterion of profitableness of population water use--the bioenergetic state of the water.

  3. Does the current regulation of assisted reproductive techniques in the UK safeguard animal welfare?

    Science.gov (United States)

    Campbell, Madeleine L H

    2014-02-01

    Reproductive medicine is one of the fastest-developing fields of veterinary medicine, Regulation of veterinary assisted reproductive technologies (ARTs) is currently divided between the Animals (Scientific Procedures) Act (1986); the Veterinary Surgeons Act 1966, and the Animal Welfare Act (2006). None of those pieces of legislation was purpose designed to protect the welfare of animals undergoing ARTs, either directly or by determining which veterinary ART procedures may or may not be performed. Consequently, due to the lack of reference to such procedures, the welfare protection aims of the legislation are sometimes ambiguous. It is therefore difficult to ascertain whether the aims of the legislation are being fulfilled, but, in the opinion of this author, the legislation is anyway inadequate in scope, most particularly because it fails to provide a reporting function. It is unclear whether all or any veterinary ART procedures being undertaken on post-natal animals are associated with suffering. Some ARTs may cause discomfort, stress or pain: study or review of the welfare effects of these would be valuable. Any future review of the legislation regulating veterinary ARTs, be that an overall review or a review of one of the relevant statutes (for example the VSA), should take into account the interface between research and clinical medicine; the potentially welfare-compromising gaps between the Acts; the need to introduce reporting functions in order to build an evidence base, and the issue of veterinary specialisation and whether specialised techniques should be carried out only by those with specialist post-graduate qualifications.

  4. The methodologies and instruments of vehicle particulate emission measurement for current and future legislative regulations

    Science.gov (United States)

    Otsuki, Yoshinori; Nakamura, Hiroshi; Arai, Masataka; Xu, Min

    2015-09-01

    Since the health risks associated with fine particles whose aerodynamic diameters are smaller than 2.5 μm was first proven, regulations restricting particulate matter (PM) mass emissions from internal combustion engines have become increasingly severe. Accordingly, the gravimetric method of PM mass measurement is facing its lower limit of detection as the emissions from vehicles are further reduced. For example, the variation in the adsorption of gaseous components such as hydrocarbons from unburned fuel and lubricant oil and the presence of agglomerated particles, which are not directly generated in engine combustion but re-entrainment particulates from walls of sampling pipes, can cause uncertainty in measurement. The PM mass measurement systems and methodologies have been continuously refined in order to improve measurement accuracy. As an alternative metric, the particle measurement programme (PMP) within the United Nations Economic Commission for Europe (UNECE) developed a solid particle number measurement method in order to improve the sensitivity of particulate emission measurement from vehicles. Consequently, particle number (PN) limits were implemented into the regulations in Europe from 2011. Recently, portable emission measurement systems (PEMS) for in-use vehicle emission measurements are also attracting attention, currently in North America and Europe, and real-time PM mass and PN instruments are under evaluation.

  5. The methodologies and instruments of vehicle particulate emission measurement for current and future legislative regulations

    International Nuclear Information System (INIS)

    Otsuki, Yoshinori; Nakamura, Hiroshi; Arai, Masataka; Xu, Min

    2015-01-01

    Since the health risks associated with fine particles whose aerodynamic diameters are smaller than 2.5 μm was first proven, regulations restricting particulate matter (PM) mass emissions from internal combustion engines have become increasingly severe. Accordingly, the gravimetric method of PM mass measurement is facing its lower limit of detection as the emissions from vehicles are further reduced. For example, the variation in the adsorption of gaseous components such as hydrocarbons from unburned fuel and lubricant oil and the presence of agglomerated particles, which are not directly generated in engine combustion but re-entrainment particulates from walls of sampling pipes, can cause uncertainty in measurement. The PM mass measurement systems and methodologies have been continuously refined in order to improve measurement accuracy. As an alternative metric, the particle measurement programme (PMP) within the United Nations Economic Commission for Europe (UNECE) developed a solid particle number measurement method in order to improve the sensitivity of particulate emission measurement from vehicles. Consequently, particle number (PN) limits were implemented into the regulations in Europe from 2011. Recently, portable emission measurement systems (PEMS) for in-use vehicle emission measurements are also attracting attention, currently in North America and Europe, and real-time PM mass and PN instruments are under evaluation. (topical review)

  6. Optimal autaptic and synaptic delays enhanced synchronization transitions induced by each other in Newman–Watts neuronal networks

    International Nuclear Information System (INIS)

    Wang, Baoying; Gong, Yubing; Xie, Huijuan; Wang, Qi

    2016-01-01

    Highlights: • Optimal autaptic delay enhanced synchronization transitions induced by synaptic delay in neuronal networks. • Optimal synaptic delay enhanced synchronization transitions induced by autaptic delay. • Optimal coupling strength enhanced synchronization transitions induced by autaptic or synaptic delay. - Abstract: In this paper, we numerically study the effect of electrical autaptic and synaptic delays on synchronization transitions induced by each other in Newman–Watts Hodgkin–Huxley neuronal networks. It is found that the synchronization transitions induced by synaptic delay vary with varying autaptic delay and become strongest when autaptic delay is optimal. Similarly, the synchronization transitions induced by autaptic delay vary with varying synaptic delay and become strongest at optimal synaptic delay. Also, there is optimal coupling strength by which the synchronization transitions induced by either synaptic or autaptic delay become strongest. These results show that electrical autaptic and synaptic delays can enhance synchronization transitions induced by each other in the neuronal networks. This implies that electrical autaptic and synaptic delays can cooperate with each other and more efficiently regulate the synchrony state of the neuronal networks. These findings could find potential implications for the information transmission in neural systems.

  7. Regulation of slowly activating potassium current (IKs) by secretin in rat pancreatic acinar cells

    Science.gov (United States)

    Kim, Sung Joon; Kim, Jin Kyoung; Pavenstädt, Hermann; Greger, Rainer; Hug, Martin J; Bleich, Markus

    2001-01-01

    The secretagogue-activated K+ conductance is indispensable for the electrogenic Cl− secretion in exocrine tissue. In this study, we investigated the effect of secretin and other cAMP-mediated secretagogues on the slowly activating voltage-dependent K+ current (IKs) of rat pancreatic acinar cells (RPAs) with the whole-cell patch clamp technique. Upon depolarization, RPAs showed IKs superimposed upon the instantaneous background outward current. Secretin (5 nm), vasoactive intestinal peptide (5 nm), forskolin (5 μm), isoprenaline (10 μm) or 3-isobutyl-1-methylxanthine (IBMX, 0.1 mm) increased the amplitude of IKs two- to fourfold. The physiological concentration of secretin (50 pm) had a relatively weak effect on IKs (160 % increase), which was significantly enhanced by transient co-stimulation with carbachol (CCh) (10 μm). However, the secretin-induced production of cAMP, which was measured by enzyme-linked immunosorbent assay, was not augmented by co-stimulation with CCh. This study is the first to demonstrate the regulation of K+ channels in RPAs by cAMP-mediated agonists. The IKs channel is a common target for both Ca2+ and cAMP agonists. The vagal stimulation under the physiological concentration of secretin facilitates IKs, which provides an additional driving force for Cl− secretion. PMID:11533128

  8. Regulation of slowly activating potassium current (I(Ks)) by secretin in rat pancreatic acinar cells.

    Science.gov (United States)

    Kim, S J; Kim, J K; Pavenstädt, H; Greger, R; Hug, M J; Bleich, M

    2001-09-01

    1. The secretagogue-activated K(+) conductance is indispensable for the electrogenic Cl(-) secretion in exocrine tissue. In this study, we investigated the effect of secretin and other cAMP-mediated secretagogues on the slowly activating voltage-dependent K(+) current (I(Ks)) of rat pancreatic acinar cells (RPAs) with the whole-cell patch clamp technique. 2. Upon depolarization, RPAs showed I(Ks) superimposed upon the instantaneous background outward current. Secretin (5 nM), vasoactive intestinal peptide (5 nM), forskolin (5 microM), isoprenaline (10 microM) or 3-isobutyl-1-methylxanthine (IBMX, 0.1 mM) increased the amplitude of I(Ks) two- to fourfold. 3. The physiological concentration of secretin (50 pM) had a relatively weak effect on I(Ks) (160 % increase), which was significantly enhanced by transient co-stimulation with carbachol (CCh) (10 microM). However, the secretin-induced production of cAMP, which was measured by enzyme-linked immunosorbent assay, was not augmented by co-stimulation with CCh. 4. This study is the first to demonstrate the regulation of K(+) channels in RPAs by cAMP-mediated agonists. The I(Ks) channel is a common target for both Ca(2+) and cAMP agonists. The vagal stimulation under the physiological concentration of secretin facilitates I(Ks), which provides an additional driving force for Cl(-) secretion.

  9. Defective glycinergic synaptic transmission in zebrafish motility mutants

    Directory of Open Access Journals (Sweden)

    Hiromi Hirata

    2010-01-01

    Full Text Available Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR β subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch once’ mutants, including beo and sho, and report the identification of a new α2 subunit that revises the phylogeny of zebrafish GlyRs.

  10. Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants

    Science.gov (United States)

    Hirata, Hiromi; Carta, Eloisa; Yamanaka, Iori; Harvey, Robert J.; Kuwada, John Y.

    2009-01-01

    Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo) mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR) β subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho) mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch-once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch-once’ mutants, including beo and sho, and report the identification of a new α2 subunit that revises the phylogeny of zebrafish GlyRs. PMID:20161699

  11. Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders.

    Science.gov (United States)

    Neniskyte, Urte; Gross, Cornelius T

    2017-11-01

    The final stage of brain development is associated with the generation and maturation of neuronal synapses. However, the same period is also associated with a peak in synapse elimination - a process known as synaptic pruning - that has been proposed to be crucial for the maturation of remaining synaptic connections. Recent studies have pointed to a key role for glial cells in synaptic pruning in various parts of the nervous system and have identified a set of critical signalling pathways between glia and neurons. At the same time, brain imaging and post-mortem anatomical studies suggest that insufficient or excessive synaptic pruning may underlie several neurodevelopmental disorders, including autism, schizophrenia and epilepsy. Here, we review current data on the cellular, physiological and molecular mechanisms of glial-cell-dependent synaptic pruning and outline their potential contribution to neurodevelopmental disorders.

  12. Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity.

    Science.gov (United States)

    Maag, Jesper L V; Panja, Debabrata; Sporild, Ida; Patil, Sudarshan; Kaczorowski, Dominik C; Bramham, Clive R; Dinger, Marcel E; Wibrand, Karin

    2015-01-01

    Long-term potentiation (LTP) of synaptic transmission is recognized as a cellular mechanism for learning and memory storage. Although de novo gene transcription is known to be required in the formation of stable LTP, the molecular mechanisms underlying synaptic plasticity remain elusive. Noncoding RNAs have emerged as major regulatory molecules that are abundantly and specifically expressed in the mammalian brain. By combining RNA-seq analysis with LTP induction in the dentate gyrus of live rats, we provide the first global transcriptomic analysis of synaptic plasticity in the adult brain. Expression profiles of mRNAs and long noncoding RNAs (lncRNAs) were obtained at 30 min, 2 and 5 h after high-frequency stimulation of the perforant pathway. The temporal analysis revealed dynamic expression profiles of lncRNAs with many positively, and highly, correlated to protein-coding genes with known roles in synaptic plasticity, suggesting their possible involvement in LTP. In light of observations suggesting a role for retrotransposons in brain function, we examined the expression of various classes of repeat elements. Our analysis identifies dynamic regulation of LINE1 and SINE retrotransposons, and extensive regulation of tRNA. These experiments reveal a hitherto unknown complexity of gene expression in long-term synaptic plasticity involving the dynamic regulation of lncRNAs and repeat elements. These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity in both the healthy brain and in neurodegenerative and neuropsychiatric disorders.

  13. Disruption of cortical synaptic homeostasis in individuals with chronic low back pain

    DEFF Research Database (Denmark)

    Thapa, Tribikram; Graven-Nielsen, Thomas; Chipchase, Lucinda S.

    2018-01-01

    OBJECTIVE: Homeostatic plasticity mechanisms regulate synaptic plasticity in the human brain. Impaired homeostatic plasticity may contribute to maladaptive synaptic plasticity and symptom persistence in chronic musculoskeletal pain. METHODS: We examined homeostatic plasticity in fifty individuals...... with baseline (P plasticity in the primary motor cortex of individuals with cLBP. SIGNIFICANCE: Impaired homeostatic plasticity could explain maladaptive synaptic plasticity and symptom persistence in cLBP....... an excitatory response to tDCS applied alone, and evaluate homeostatic plasticity, respectively. Corticomotor excitability was assessed in the corticomotor representation of the first dorsal interosseous muscle by transcranial magnetic stimulation-induced motor evoked potentials (MEPs) recorded before and 0, 10...

  14. Current State and Future Perspectives for the Regulation of Nuclear Power Plants in the United States. A Regulation Program for the 21st Century

    International Nuclear Information System (INIS)

    Rojo, N. J.

    2004-01-01

    The president of the US NRC, Nils J. Diaz, has at different conferences presented speeches and articles on this view of nuclear and radioactive regulation in this new 21st century. For your interest, a synthesis of this works on this question is presented below in which he explain and analyses the current state and future perspectives for the regulation of nuclear power plants in reference to the USA. (Author)

  15. AMPA Receptor Trafficking in Homeostatic Synaptic Plasticity: Functional Molecules and Signaling Cascades

    Directory of Open Access Journals (Sweden)

    Guan Wang

    2012-01-01

    Full Text Available Homeostatic synaptic plasticity is a negative-feedback response employed to compensate for functional disturbances in the nervous system. Typically, synaptic activity is strengthened when neuronal firing is chronically suppressed or weakened when neuronal activity is chronically elevated. At both the whole cell and entire network levels, activity manipulation leads to a global up- or downscaling of the transmission efficacy of all synapses. However, the homeostatic response can also be induced locally at subcellular regions or individual synapses. Homeostatic synaptic scaling is expressed mainly via the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR trafficking and synaptic expression. Here we review the recently identified functional molecules and signaling pathways that are involved in homeostatic plasticity, especially the homeostatic regulation of AMPAR localization at excitatory synapses.

  16. Synaptic mRNAs are modulated by learning.

    Science.gov (United States)

    Ferrara, Eugenia; Cefaliello, Carolina; Eyman, Maria; De Stefano, Rosanna; Giuditta, Antonio; Crispino, Marianna

    2009-07-01

    We have recently demonstrated that brain plastic events significantly modify synaptic protein synthesis measured by the incorporation of [(35)S]methionine in brain synaptosomal proteins. Notably, in rats learning a two-way active avoidance task, the local synthesis of two synaptic proteins was selectively enhanced. Because this effect may be attributed to transcriptional modulation, we used reverse transcriptase-polymerase chain reaction methods to determine the content of discrete synaptosomal mRNAs in rats exposed to the same training protocol. Correlative analyses between behavioral responses and synaptosomal mRNA content showed that GAT-1 mRNA (a prevalent presynaptic component) correlates with avoidances and escapes in rat cerebellum, while glial fibrillary acid protein mRNA (an astrocytic component) correlates with freezings in cerebellum and cerebral cortex. These observations support the hypothesis that synaptic protein synthesis may be transcriptionally regulated. The cellular origin of synaptic transcripts is briefly discussed, with special regard to those present at large distances from neuron somas. (c) 2009 Wiley-Liss, Inc.

  17. DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment

    Directory of Open Access Journals (Sweden)

    Lara Ianov

    2017-08-01

    Full Text Available The current study investigates DNA methylation as a possible epigenetic regulator of transcription associated with aging and cognitive function. Young and aged male Fischer 344 rats were behaviorally characterized on a set shifting task, and whole genome bisulfite sequencing was employed to profile the DNA methylome of the medial prefrontal cortex (mPFC. DNA methylation was also compared to RNA expression in the mPFC from the same animals. Variability in methylation was mainly observed for CpG sites as opposed to CHG and CHH sites. Gene bodies, specifically introns, contain the highest levels of methylation. During aging, hypermethylation was observed for genes linked to synaptic function and GTPase activity. Furthermore, impaired cognitive flexibility during aging was associated with hypermethylation of genes linked to postsynaptic density, dendrites, the axon terminus, and Ca2+ channels. Finally, comparison with RNA expression confirmed that hypermethylation was correlated with decreased expression of synaptic genes. The results indicate that DNA methylation over the lifespan contributes to synaptic modification observed in brain aging and age-related cognitive impairment.

  18. In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction

    Directory of Open Access Journals (Sweden)

    Manto Mario

    2010-11-01

    Full Text Available Abstract Background A severe encephalitis that associates with auto-antibodies to the NR1 subunit of the NMDA receptor (NMDA-R was recently reported. Patients' antibodies cause a decrease of the density of NMDA-R and synaptic mediated currents, but the in vivo effects on the extracellular glutamate and glutamatergic transmission are unknown. Methods We investigated the acute metabolic effects of patients' CSF and purified IgG injected in vivo. Injections were performed in CA1 area of Ammon's horn and in premotor cortex in rats. Results Patient's CSF increased the concentrations of glutamate in the extracellular space. The increase was dose-dependent and was dramatic with purified IgG. Patients' CSF impaired both the NMDA- and the AMPA-mediated synaptic regulation of glutamate, and did not affect the glial transport of glutamate. Blockade of GABA-A receptors was associated with a marked elevation of extra-cellular levels of glutamate following a pretreatment with patients' CSF. Conclusion These results support a direct role of NMDA-R antibodies upon altering glutamatergic transmission. Furthermore, we provide additional evidence in vivo that NMDA-R antibodies deregulate the glutamatergic pathways and that the encephalitis associated with these antibodies is an auto-immune synaptic disorder.

  19. Current evaluation of the millennium phytomedicine--ginseng (I): etymology, pharmacognosy, phytochemistry, market and regulations.

    Science.gov (United States)

    Jia, Lee; Zhao, Yuqing

    2009-01-01

    The dawning of this millennium broke new ground in life science and technology, presented us genomic and proteomic revolution, nanotechnology innovation, and high performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) used for separating and identifying new chemical entities at pico-, or even femto-concentrations. Applications of these high technologies to the traditional Chinese medicine (TCM) opened a new chapter in the ancient medicine, and prompted us to re-evaluate the thousand-year-old phytomedicine- ginseng from current perspectives. We, therefore, collected the latest information (mostly within 10 years) on ginseng, and condensed the information into two parts of this review serial. The present part covers etymology of ginseng, its pharmacognosy (natural origin, physical appearance, chemical properties, and specie identification), its cultivation and processing-related metabolic changes in active ingredients, standardized analytical methods used for quality control of various ginseng products, modern analytical methods used to identify and classify more than 100 chemical entities (many were recently unfolded) derived from ginseng species and their metabolites. The global markets and production of ginseng and relevant government regulations are herein updated to exchange information and understandings about current people's uses and cultivation of ginseng. The second part of the review serial will classify all these 100 chemical entities separated from various ginseng species into different groups based on their structural similarities, and summarize bioactivities of these entities. The second part of the review serial will also focus on recent findings of ginseng pharmacology and its clinical trials for various diseases, and brief side effects of ginseng.

  20. 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.

  1. Conflict between civil liberties and nuclear energy safeguards: an analysis of current and prospective Federal regulation

    International Nuclear Information System (INIS)

    O'Brien, J.N.

    1977-01-01

    The high regard that the U.S. has traditionally placed on individual rights and liberties makes it imperative that nuclear-safeguards measures currently in use or suggested by evaluated in terms of their social costs. A nuclear-safeguards strategy that minimizes civil-liberties impacts as a social cost and allows adequate protection against the threats of nuclear theft and sabotage in the rapidly developing nuclear energy industry must be arrived at. This study explores the possible civil-liberties impacts and the effectiveness of nuclear-safeguards measures which may be or are being used. Case law and statutory law are extensively analyzed to classify the type of civil-liberties impacts that particular nuclear-safeguards measures may impose. Literature addressing the effectiveness of safeguards measures is examined in various contexts often completely outside of the ''security'' disciplines. A comparison of both the civil liberties impact and effectiveness of each nuclear safeguards measure reveals a cost/benefit factor from which conclusions may be drawn. The real issue is whether or not a nuclear safeguards system will interfere with historic respect governmental institutions have given rights and liberties guaranteed in the U.S. It is concluded that physical access controls present only minor civil liberties costs while providing substantial protection against theft and sabotage. Recommendations are made in the form of suggested statutes, regulations, and regulatory guides. Certain inter-agency relationships and methods for establishing those relationships are also suggested

  2. Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins

    Directory of Open Access Journals (Sweden)

    Joaquin N Lugo

    2014-04-01

    Full Text Available Many genes have been implicated in the underlying cause of autism but each gene accounts for only a small fraction of those diagnosed with autism. There is increasing evidence that activity-dependent changes in neuronal signaling could act as a convergent mechanism for many of the changes in synaptic proteins. One candidate signaling pathway that may have a critical role in autism is the PI3K/AKT/mTOR pathway. A major regulator of this pathway is the negative repressor phosphatase and tensin homolog (PTEN. In the current study we examined the behavioral and molecular consequences in mice with neuron subset-specific deletion of PTEN.The knockout (KO mice showed deficits in social chamber and social partition test. KO mice demonstrated alterations in repetitive behavior, as measured in the marble burying test and hole-board test. They showed no changes in ultrasonic vocalizations emitted on postnatal day 10 or 12 compared to wildtype (WT mice. They exhibited less anxiety in the elevated-plus maze test and were more active in the open field test compared to WT mice. In addition to the behavioral alterations, KO mice had elevation of phosphorylated AKT, phosphorylated S6, and an increase in S6K. KO mice had a decrease in mGluR but an increase in total and phosphorylated fragile x mental retardation protein. The disruptions in intracellular signaling may be why the KO mice had a decrease in the dendritic potassium channel Kv4.2 and a decrease in the synaptic scaffolding proteins PSD-95 and SAP102. These findings demonstrate that deletion of PTEN results in long-term alterations in social behavior, repetitive behavior, activity, and anxiety. In addition, deletion of PTEN significantly alters mGluR signaling and many synaptic proteins in the hippocampus. Our data demonstrates that deletion of PTEN can result in many of the behavioral features of autism and may provide insights into the regulation of intracellular signaling on synaptic proteins.

  3. Network response synchronization enhanced by synaptic plasticity

    Science.gov (United States)

    Lobov, S.; Simonov, A.; Kastalskiy, I.; Kazantsev, V.

    2016-02-01

    Synchronization of neural network response on spatially localized periodic stimulation was studied. The network consisted of synaptically coupled spiking neurons with spike-timing-dependent synaptic plasticity (STDP). Network connectivity was defined by time evolving matrix of synaptic weights. We found that the steady-state spatial pattern of the weights could be rearranged due to locally applied external periodic stimulation. A method for visualization of synaptic weights as vector field was introduced to monitor the evolving connectivity matrix. We demonstrated that changes in the vector field and associated weight rearrangements underlay an enhancement of synchronization range.

  4. 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.

  5. Emerging Link between Alzheimer's Disease and Homeostatic Synaptic Plasticity

    Science.gov (United States)

    Jang, Sung-Soo; Chung, Hee Jung

    2016-01-01

    Alzheimer's disease (AD) is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β (Aβ) peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβ oligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβ levels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets. PMID:27019755

  6. Synaptic Plasticity and Memory Formation

    Science.gov (United States)

    1993-06-30

    suspected of being the substrate of several forms of memory encoded by synapses in the forebrain of humans and other mammals. Work in the past year...of LTP will enhance the encoding of memory . Aniracetam , as noted, prolongs the open time of the AMPA receptor and in this way facilitates excitatory...121 t Iffw,,a" S. FUNO4NG mUMSERS Synaptic Plasticity and Memory Formation F 49620-92-0307 C (ci) b.q F Gary Lynch 7. Pf(RfO*INN ORGAMIZAMNIO NMMW(S

  7. 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.

  8. 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.

  9. Glial Processes at the Drosophila Larval Neuromuscular Junction Match Synaptic Growth

    Science.gov (United States)

    Brink, Deidre L.; Gilbert, Mary; Xie, Xiaojun; Petley-Ragan, Lindsay; Auld, Vanessa J.

    2012-01-01

    Glia are integral participants in synaptic physiology, remodeling and maturation from blowflies to humans, yet how glial structure is coordinated with synaptic growth is unknown. To investigate the dynamics of glial development at the Drosophila larval neuromuscular junction (NMJ), we developed a live imaging system to establish the relationship between glia, neuronal boutons, and the muscle subsynaptic reticulum. Using this system we observed processes from two classes of peripheral glia present at the NMJ. Processes from the subperineurial glia formed a blood-nerve barrier around the axon proximal to the first bouton. Processes from the perineurial glial extended beyond the end of the blood-nerve barrier into the NMJ where they contacted synapses and extended across non-synaptic muscle. Growth of the glial processes was coordinated with NMJ growth and synaptic activity. Increasing synaptic size through elevated temperature or the highwire mutation increased the extent of glial processes at the NMJ and conversely blocking synaptic activity and size decreased the presence and size of glial processes. We found that elevated temperature was required during embryogenesis in order to increase glial expansion at the nmj. Therefore, in our live imaging system, glial processes at the NMJ are likely indirectly regulated by synaptic changes to ensure the coordinated growth of all components of the tripartite larval NMJ. PMID:22666403

  10. Synaptic plasticity modulation by circulating peptides and metaplasticity: Involvement in Alzheimer's disease.

    Science.gov (United States)

    Peineau, Stéphane; Rabiant, Kevin; Pierrefiche, Olivier; Potier, Brigitte

    2018-02-06

    Synaptic plasticity is a cellular process involved in learning and memory whose alteration in its two main forms (Long Term Depression (LTD) and Long Term Potentiation (LTP)), is observed in most brain pathologies, including neurodegenerative disorders such as Alzheimer's disease (AD). In humans, AD is associated at the cellular level with neuropathological lesions composed of extracellular deposits of β-amyloid (Aβ) protein aggregates and intracellular neurofibrillary tangles, cellular loss, neuroinflammation and a general brain homeostasis dysregulation. Thus, a dramatic synaptic environment perturbation is observed in AD patients, involving changes in brain neuropeptides, cytokines, growth factors or chemokines concentration and diffusion. Studies performed in animal models demonstrate that these circulating peptides strongly affect synaptic functions and in particular synaptic plasticity. Besides this neuromodulatory action of circulating peptides, other synaptic plasticity regulation mechanisms such as metaplasticity are altered in AD animal models. Here, we will review new insights into the study of synaptic plasticity regulatory/modulatory mechanisms which could influence the process of synaptic plasticity in the context of AD with a particular attention to the role of metaplasticity and peptide dependent neuromodulation. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. A current-mode voltage regulator with an embedded sub-threshold reference for a passive UHF RFID transponder

    International Nuclear Information System (INIS)

    Liu Zhongqi; Zhang Chun; Li Yongming; Wang Zhihua

    2010-01-01

    This paper presents a current-mode voltage regulator for a passive UHF RFID transponder. The passive tag power is extracted from RF energy through the RF-to-DC rectifier. Due to huge variations of the incoming RF power, the rectifier output voltage should be regulated to achieve a stable power supply. By accurately controlling the current flowing into the load with an embedded sub-threshold reference, the regulated voltage varies in a range of 1-1.3 V from -20 to 80 0 C, and a bandwidth of about 100 kHz is achieved for a fast power recovery. The circuit is fabricated in UMC 0.18 μm mixed-mode CMOS technology, and the current consumption is only 1 μA. (semiconductor integrated circuits)

  12. Design and construction of constant voltage and current regulated source with proper characteristics to be used in electronics laboratory designs

    International Nuclear Information System (INIS)

    Peon A, R.

    1978-01-01

    A regulated direct current feeding source was designed for the Nuclear Energy National Institute Electronics Labortory, with the following characteristics: a) voltage input 105-130V a.c. 50-60 Hz; b) voltage output 0.40 V d.c.; c) output current 0-2 Amp d.c.; d) load regulation 0.001%; e) line regulation 0.001%; f) ripple and noise 200 μ Vpp; g) temperature interval 3-60 0 C; h) stability 0.5%; i) output impedance as voltage source 0.01 ohms; j) transient response 50 μ seg. Besides of operating normally, that is as voltage source or current-source through the front controls, the source can be used and interconnected with one or other compatible sources (autoseries, autoparallel and programmed reference). The source will cost 70,000 pesos approximately. (author)

  13. Focused transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex modulates specific domains of self-regulation.

    Science.gov (United States)

    Pripfl, Jürgen; Lamm, Claus

    2015-02-01

    Recent neuroscience theories suggest that different kinds of self-regulation may share a common psychobiological mechanism. However, empirical evidence for a domain general self-regulation mechanism is scarce. The aim of this study was to investigate whether focused anodal transcranial direct current stimulation (tDCS), facilitating the activity of the dorsolateral prefrontal cortex (dlPFC), acts on a domain general self-regulation mechanism and thus modulates both affective and appetitive self-regulation. Twenty smokers participated in this within-subject sham controlled study. Effects of anodal left, anodal right and sham tDCS over the dlPFC on affective picture appraisal and nicotine craving-cue appraisal were assessed. Anodal right tDCS over the dlPFC reduced negative affect in emotion appraisal, but neither modulated regulation of positive emotion appraisal nor of craving appraisal. Anodal left stimulation did not induce any significant effects. The results of our study show that domain specific self-regulation networks are at work in the prefrontal cortex. Focused tDCS modulation of this specific self-regulation network could probably be used during the first phase of nicotine abstinence, during which negative affect might easily result in relapse. These findings have implications for neuroscience models of self-regulation and are of relevance for the development of brain stimulation based treatment methods for neuropsychiatric disorders associated with self-regulation deficits. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  14. Leptin potentiates GABAergic synaptic transmission in the developing rodent hippocampus.

    Directory of Open Access Journals (Sweden)

    Damien eGuimond

    2014-08-01

    Full Text Available It is becoming increasingly clear that leptin is not only a hormone regulating energy homeostasis but also a neurotrophic factor impacting a number of brain regions, including the hippocampus. Although leptin promotes the development of GABAergic transmission in the hypothalamus, little is known about its action on the GABAergic system in the hippocampus. Here we show that leptin modulates GABAergic transmission onto developing CA3 pyramidal cells of newborn rats. Specifically, leptin induces a long-lasting potentiation (LLP-GABAA of miniature GABAA receptor-mediated postsynaptic current (GABAA-PSC frequency. Leptin also increases the amplitude of evoked GABAA-PSCs in a subset of neurons along with a decrease in the coefficient of variation and no change in the paired-pulse ratio, pointing to an increased recruitment of functional synapses. Adding pharmacological blockers to the recording pipette showed that the leptin-induced LLP-GABAA requires postsynaptic calcium released from internal stores, as well as postsynaptic MAPK/ERK kinases 1 and/or 2 (MEK1/2, phosphoinositide 3 kinase (PI3K and calcium-calmodulin kinase kinase (CaMKK. Finally, study of CA3 pyramidal cells in leptin-deficient ob/ob mice revealed a reduction in the basal frequency of miniature GABAA-PSCs compared to wild type littermates. In addition, presynaptic GAD65 immunostaining was reduced in the CA3 stratum pyramidale of mutant animals, both results converging to suggest a decreased number of functional GABAergic synapses in ob/ob mice. Overall, these results show that leptin potentiates and promotes the development of GABAergic synaptic transmission in the developing hippocampus likely via an increase in the number of functional synapses, and provide insights into the intracellular pathways mediating this effect. This study further extends the scope of leptin’s neurotrophic action to a key regulator of hippocampal development and function, namely GABAergic transmission.

  15. Current advances and strategies towards fully automated sample preparation for regulated LC-MS/MS bioanalysis.

    Science.gov (United States)

    Zheng, Naiyu; Jiang, Hao; Zeng, Jianing

    2014-09-01

    Robotic liquid handlers (RLHs) have been widely used in automated sample preparation for liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalysis. Automated sample preparation for regulated bioanalysis offers significantly higher assay efficiency, better data quality and potential bioanalytical cost-savings. For RLHs that are used for regulated bioanalysis, there are additional requirements, including 21 CFR Part 11 compliance, software validation, system qualification, calibration verification and proper maintenance. This article reviews recent advances in automated sample preparation for regulated bioanalysis in the last 5 years. Specifically, it covers the following aspects: regulated bioanalysis requirements, recent advances in automation hardware and software development, sample extraction workflow simplification, strategies towards fully automated sample extraction, and best practices in automated sample preparation for regulated bioanalysis.

  16. [Nonuniform distribution and contribution of the P- and P/Q-type calcium channels to short-term inhibitory synaptic transmission in cultured hippocampal neurons].

    Science.gov (United States)

    Mizerna, O P; Fedulova, S A; Veselovs'kyĭ, M S

    2010-01-01

    In the present study, we investigated the sensitivity of GABAergic short-term plasticity to the selective P- and P/Q-type calcium channels blocker omega-agatoxin-IVA. To block the P-type channels we used 30 nM of this toxin and 200 nM of the toxin was used to block the P/Q channel types. The evoked inhibitory postsynaptic currents (eIPSC) were studied using patch-clamp technique in whole-cell configuration in postsynaptic neuron and local extracellular stimulation of single presynaptic axon by rectangular pulse. The present data show that the contribution of P- and P/Q-types channels to GABAergic synaptic transmission in cultured hippocampal neurons are 30% and 45%, respectively. It was shown that the mediate contribution of the P- and P/Q-types channels to the amplitudes of eIPSC is different to every discovered neuron. It means that distribution of these channels is non-uniform. To study the short-term plasticity of inhibitory synaptic transmission, axons of presynaptic neurons were paired-pulse stimulated with the interpulse interval of 150 ms. Neurons demonstrated both the depression and facilitation. The application of 30 nM and 200 nM of the blocker decreased the depression and increased facilitation to 8% and 11%, respectively. In addition, we found that the mediate contribution of the P- and P/Q-types channels to realization of synaptic transmission after the second stimuli is 4% less compared to that after the first one. Therefore, blocking of both P- and P/Q-types calcium channels can change the efficiency of synaptic transmission. In this instance it facilitates realization of the transmission via decreased depression or increased facilitation. These results confirm that the P- and P/Q-types calcium channels are involved in regulation of the short-term inhibitory synaptic plasticity in cultured hippocampal neurons.

  17. Ataxias and cerebellar dysfunction: involvement of synaptic plasticity deficits?

    Science.gov (United States)

    Rinaldo, Lorenzo; Hansel, Christian

    2011-01-01

    Summary Adaptive processes within cerebellar circuits, such as long-term depression and long-term potentiation at parallel fiber-Purkinje cell synapses, have long been seen as important to cerebellar motor learning, and yet little attention has been given to any possible significance of these processes for cerebellar dysfunction and disease. Several forms of ataxia are caused by mutations in genes encoding for ion channels located at key junctures in pathways that lead to the induction of synaptic plasticity, suggesting that there might be an association between deficits in plasticity and the ataxic phenotype. Herein we explore this possibility and examine the available evidence linking the two together, highlighting specifically the role of P/Q-type calcium channels and their downstream effector small-conductance calcium-sensitive (SK2) potassium channels in the regulation of synaptic gain and intrinsic excitability, and reviewing their connections to ataxia. PMID:21232209

  18. The developmental stages of synaptic plasticity

    NARCIS (Netherlands)

    Lohmann, Christian; Kessels, Helmut W.

    2014-01-01

    The brain is programmed to drive behaviour by precisely wiring the appropriate neuronal circuits. Wiring and rewiring of neuronal circuits largely depends on the orchestrated changes in the strengths of synaptic contacts. Here, we review how the rules of synaptic plasticity change during development

  19. Seismic Hazard Assessment and Uncertainties Treatment: Discussion on the current French regulation, practices and open issues

    International Nuclear Information System (INIS)

    Berge-Thierry, Catherine

    2014-01-01

    Nuclear Safety Authority. These studies performed by nuclear operators, leading to propose a 'Hard Core' of materials and organizational arrangements to ensure the control of crucial safety functions in extreme situations. The difficulties inherent in the definition of 'extreme situation' in a moderate seismically country as the French metropolitan area will be illustrated and discussed. This presentation gives the current practice of seismic risk management in France for nuclear safety. The regulation is composed by two coherent and complementary references the RFS 2001-01 and the Guide ASN/2/01. We point out the key steps of the seismic hazard assessment following the RFS 2001-01 methodology which is scenario based. We particularly highlight the sensitivity and the influences of seismic parameters choices in their uncertainty domains and their impact on the final hazard. The Tohoku 2011 mega-quake and the Fukushima associated accident resulted in the Complementary Safety Studies in the Nuclear field. The review of the French complementary studies by the ENSREG made the recommendation to complete the scenario based approach by a probabilistic hazard assessment. The presentation then exhibits the specificities and common aspects of a PSHA and DSHA. We underline that these two approaches are strictly founded on common databases and knowledge level: The epistemic uncertainties can be accounted by both PSHA and DSHA through logic trees (see [37] for DSHA). However they clearly differ by two points: - the PSHA accounts for the whole seismic catalogue with its occurrence rate, where the DSHA selects specific scenarios with consideration of occurrence level, - the aleatory variability is differently treated in scenario approach and in probabilistic approach. Finally, performing probabilistic seismic hazard assessment requires defining crucial parameters (i) the safety level target which corresponds a return period value of the hazard curve and (ii) its confidence level. In

  20. All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability Are Coregulated by CaMKIV, Whereas Inhibitory Synaptic Scaling Is Under Independent Control.

    Science.gov (United States)

    Joseph, Annelise; Turrigiano, Gina G

    2017-07-12

    Neocortical circuits use a family of homeostatic plasticity mechanisms to stabilize firing, including excitatory and inhibitory synaptic scaling and homeostatic intrinsic plasticity (Turrigiano and Nelson, 2004). All three mechanisms can be induced in tandem in cultured rat neocortical pyramidal neurons by chronic manipulations of firing, but it is unknown whether they are coinduced by the same activity-sensors and signaling pathways, or whether they are under independent control. Calcium/calmodulin-dependent protein kinase type IV (CaMKIV) is a key sensory/effector in excitatory synaptic scaling that senses perturbations in firing through changes in calcium influx, and translates this into compensatory changes in excitatory quantal amplitude (Ibata et al., 2008; Goold and Nicoll, 2010). Whether CaMKIV also controls inhibitory synaptic scaling and intrinsic homeostatic plasticity was unknown. To test this we manipulated CaMKIV signaling in individual neurons using dominant-negative (dn) or constitutively-active (ca) forms of nuclear-localized CaMKIV and measured the induction of all three forms of homeostatic plasticity. We found that excitatory synaptic scaling and intrinsic plasticity were bidirectionally coinduced by these manipulations. In contrast, these cell-autonomous manipulations had no impact on inhibitory quantal amplitude. Finally, we found that spontaneous firing rates were shifted up or down by dnCaMKIV or caCaMKIV, respectively, suggesting that uncoupling CaMKIV activation from activity generates an error signal in the negative feedback mechanism that controls firing rates. Together, our data show that excitatory synaptic scaling and intrinsic excitability are tightly coordinated through bidirectional changes in the same signaling pathway, whereas inhibitory synaptic scaling is sensed and regulated through an independent control mechanism. SIGNIFICANCE STATEMENT Maintaining stable function in highly interconnected neural circuits is essential for

  1. 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…

  2. Pushing synaptic vesicles over the RIM.

    Science.gov (United States)

    Kaeser, Pascal S

    2011-05-01

    In a presynaptic nerve terminal, neurotransmitter release is largely restricted to specialized sites called active zones. Active zones consist of a complex protein network, and they organize fusion of synaptic vesicles with the presynaptic plasma membrane in response to action potentials. Rab3-interacting molecules (RIMs) are central components of active zones. In a recent series of experiments, we have systematically dissected the molecular mechanisms by which RIMs operate in synaptic vesicle release. We found that RIMs execute two critical functions of active zones by virtue of independent protein domains. They tether presyanptic Ca(2+) channels to the active zone, and they activate priming of synaptic vesicles by monomerizing homodimeric, constitutively inactive Munc13. These data indicate that RIMs orchestrate synaptic vesicle release into a coherent process. In conjunction with previous studies, they suggest that RIMs form a molecular platform on which plasticity of synaptic vesicle release can operate.

  3. Investigating Relationships among Pre-Service Science Teachers' Conceptual Knowledge of Electric Current, Motivational Beliefs and Self-Regulation

    Science.gov (United States)

    Inaltun, Hüseyin; Ates, Salih

    2015-01-01

    The purpose of this study is to examine relationships among pre-service science teachers' conceptual knowledge of electric current, motivational beliefs, and self-regulation. One hundred and twenty-seven students (female = 107, male = 20) enrolled in the science education program of a public university in Ankara participated the study. A concept…

  4. Histamine H3 Heteroreceptors Suppress Glutamatergic and GABAergic Synaptic Transmission in the Rat Insular Cortex

    Directory of Open Access Journals (Sweden)

    Hiroki Takei

    2017-11-01

    Full Text Available Histamine H3 receptors are autoreceptors that regulate histamine release from histaminergic neuronal terminals. The cerebral cortex, including the insular cortex (IC, expresses abundant H3 receptors; however, the functions and mechanisms of H3 receptors remain unknown. The aim of this study was to elucidate the functional roles of H3 in synaptic transmission in layer V of the rat IC. Unitary excitatory and inhibitory postsynaptic currents (uEPSCs and uIPSCs were obtained through paired whole-cell patch-clamp recording in cerebrocortical slice preparations. The H3 receptor agonist, R-α-methylhistamine (RAMH, reduced the uEPSC amplitude obtained from pyramidal cell to pyramidal cell or GABAergic interneuron connections. Similarly, RAMH reduced the uIPSC amplitude in GABAergic interneuron to pyramidal cell connections. RAMH-induced decreases in both the uEPSC and uIPSC amplitudes were accompanied by increases in the failure rate and paired-pulse ratio. JNJ 5207852 dihydrochloride or thioperamide, H3 receptor antagonists, inhibited RAMH-induced suppression of uEPSCs and uIPSCs. Unexpectedly, thioperamide alone increased the uIPSC amplitude, suggesting that thioperamide was likely to act as an inverse agonist. Miniature EPSC or IPSC recordings support the hypothesis that the activation of H3 receptors suppresses the release of glutamate and GABA from presynaptic terminals. The colocalization of H3 receptors and glutamate decarboxylase or vesicular glutamate transport protein 1 in presynaptic axon terminals was confirmed through double pre-embedding microscopy, using a combination of pre-embedding immunogold and immunoperoxidase techniques. The suppressive regulation of H3 heteroreceptors on synaptic transmission might mediate the regulation of sensory information processes, such as gustation and visceral sensation, in the IC.

  5. Visual Stimulation Activates ERK in Synaptic and Somatic Compartments of Rat Cortical Neurons with Parallel Kinetics

    Science.gov (United States)

    Boggio, Elena M.; Putignano, Elena; Sassoè-Pognetto, Marco; Pizzorusso, Tommaso; Giustetto, Maurizio

    2007-01-01

    Background Extracellular signal-regulated kinase (ERK) signalling pathway plays a crucial role in regulating diverse neuronal processes, such as cell proliferation and differentiation, and long-term synaptic plasticity. However, a detailed understanding of the action of ERK in neurons is made difficult by the lack of knowledge about its subcellular localization in response to physiological stimuli. To address this issue, we have studied the effect of visual stimulation in vivo of dark-reared rats on the spatial-temporal dynamics of ERK activation in pyramidal neurons of the visual cortex. Methodology/Principal Findings Using immunogold electron microscopy, we show that phosphorylated ERK (pERK) is present in dendritic spines, both at synaptic and non-synaptic plasma membrane domains. Moreover, pERK is also detected in presynaptic axonal boutons forming connections with dendritic spines. Visual stimulation after dark rearing during the critical period causes a rapid increase in the number of pERK-labelled synapses in cortical layers I–II/III. This visually-induced activation of ERK at synaptic sites occurs in pre- and post-synaptic compartments and its temporal profile is identical to that of ERK activation in neuronal cell bodies. Conclusions/Significance Visual stimulation in vivo increases pERK expression at pre- and post-synaptic sites of axo-spinous junctions, suggesting that ERK plays an important role in the local modulation of synaptic function. The data presented here support a model in which pERK can have early and late actions both centrally in the cell nucleus and peripherally at synaptic contacts. PMID:17622349

  6. 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.

  7. Synaptic plasticity, neural circuits, and the emerging role of altered short-term information processing in schizophrenia.

    Science.gov (United States)

    Crabtree, Gregg W; Gogos, Joseph A

    2014-01-01

    Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point toward a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders (ASDs) may be due to a combination of both short-term and long-term synaptic plasticity alterations.

  8. Comparison of food colour regulations in the EU and the US - a review of current provisions

    OpenAIRE

    LEHTO Sari; BUCHWEITZ Maria; KLIMM Alexandra; STRASSBURGER Raphaela; BECHTOLD CATO; ULBERTH Franz

    2016-01-01

    This review describes the EU and the US regulations applicable to food colours. Despite the different regulatory frameworks, the overall approach is similar, based on well-established risk assessment procedures and risk management measures. However, some differences impacting free movement of goods can be found in the details and implementation of regulations. Using additives approved only in the US or in the EU implies that producers aiming to export need to adjust their product composition ...

  9. Low-level radioactive waste disposal in the United States: An overview of current commercial regulations and concepts

    International Nuclear Information System (INIS)

    Kennedy, W.E. Jr.

    1993-08-01

    Commercial low-level radioactive waste disposal in the United States is regulated by the US Nuclear Regulatory Commission (NRC) under 10 CFR 61 (1991). This regulation was issued in 1981 after a lengthy and thorough development process that considered the radionuclide concentrations and characteristics associated with commercial low-level radioactive waste streams; alternatives for waste classification; alternative technologies for low-level radioactive waste disposal; and data, modeling, and scenario analyses. The development process also included the publication of both draft and final environmental impact statements. The final regulation describes the general provisions; licenses; performance objectives; technical requirements for land disposal; financial assurances; participation by state governments and Indian tribes; and records, reports, tests, and inspections. This paper provides an overview of, and tutorial on, current commercial low-level radioactive waste disposal regulations in the United States

  10. Dancing with Hormones: A Current Perspective of Nitrate Signaling and Regulation in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Peizhu Guan

    2017-09-01

    Full Text Available In nature and agriculture, nitrate availability is a main environmental cue for plant growth, development and stress responses. Nitrate signaling and regulation are hence at the center of communications between plant intrinsic programs and the environment. It is also well known that endogenous phytohormones play numerous critical roles in integrating extrinsic cues and intrinsic responses, regulating and refining almost all aspects of plant growth, development and stress responses. Therefore, interaction between nitrate and phytohormones, such as auxins, cytokinins, abscisic acid, gibberellins, and ethylene, is prevalent. The growing evidence indicates that biosynthesis, de-conjugation, transport, and signaling of hormones are partly controlled by nitrate signaling. Recent advances with nitrate signaling and transcriptional regulation in Arabidopsis give rise to new paradigms. Given the comprehensive nitrate transport, sensing, signaling and regulations at the level of the cell and organism, nitrate itself is a local and long-distance signal molecule, conveying N status at the whole-plant level. A direct molecular link between nitrate signaling and cell cycle progression was revealed with TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR1-20 (TCP20 – NIN-LIKE PROTEIN 6/7 (NLP6/7 regulatory nexus. NLPs are key regulators of nitrogen responses in plants. TCPs function as the main regulators of plant morphology and architecture, with the emerging role as integrators of plant developmental responses to the environment. By analogy with auxin being proposed as a plant morphogen, nitrate may be an environmental morphogen. The morphogen-gradient-dependent and cell-autonomous mechanisms of nitrate signaling and regulation are an integral part of cell growth and cell identification. This is especially true in root meristem growth that is regulated by intertwined nitrate, phytohormones, and glucose-TOR signaling pathways. Furthermore, the nitrate

  11. Dancing with Hormones: A Current Perspective of Nitrate Signaling and Regulation inArabidopsis.

    Science.gov (United States)

    Guan, Peizhu

    2017-01-01

    In nature and agriculture, nitrate availability is a main environmental cue for plant growth, development and stress responses. Nitrate signaling and regulation are hence at the center of communications between plant intrinsic programs and the environment. It is also well known that endogenous phytohormones play numerous critical roles in integrating extrinsic cues and intrinsic responses, regulating and refining almost all aspects of plant growth, development and stress responses. Therefore, interaction between nitrate and phytohormones, such as auxins, cytokinins, abscisic acid, gibberellins, and ethylene, is prevalent. The growing evidence indicates that biosynthesis, de-conjugation, transport, and signaling of hormones are partly controlled by nitrate signaling. Recent advances with nitrate signaling and transcriptional regulation in Arabidopsis give rise to new paradigms. Given the comprehensive nitrate transport, sensing, signaling and regulations at the level of the cell and organism, nitrate itself is a local and long-distance signal molecule, conveying N status at the whole-plant level. A direct molecular link between nitrate signaling and cell cycle progression was revealed with TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR1-20 (TCP20) - NIN-LIKE PROTEIN 6/7 (NLP6/7) regulatory nexus. NLPs are key regulators of nitrogen responses in plants. TCPs function as the main regulators of plant morphology and architecture, with the emerging role as integrators of plant developmental responses to the environment. By analogy with auxin being proposed as a plant morphogen, nitrate may be an environmental morphogen. The morphogen-gradient-dependent and cell-autonomous mechanisms of nitrate signaling and regulation are an integral part of cell growth and cell identification. This is especially true in root meristem growth that is regulated by intertwined nitrate, phytohormones, and glucose-TOR signaling pathways. Furthermore, the nitrate transcriptional

  12. Synaptic NR2A- but not NR2B-containing NMDA receptors increase with blockade of ionotropic glutamate receptors

    Directory of Open Access Journals (Sweden)

    Jakob Von Engelhardt

    2009-10-01

    Full Text Available NMDA receptors are key molecules involved in physiological and pathophysiological brain processes such as plasticity and excitotoxicity. Neuronal activity regulates NMDA receptor levels in the cell membrane. However, little is known on which time scale this regulation occurs and whether the two main diheteromeric NMDA receptor subtypes in forebrain, NR1/NR2A and NR1/NR2B, are regulated in a similar fashion. As these differ considerably in their electrophysiological properties, the NR2A/NR2B ratio affects the neurons’ reaction to NMDA receptor activation. Here we provide evidence that the basal turnover rate in the cell membrane of NR2A- and NR2B-containing receptors is comparable. However, the level of the NR2A subtype in the cell membrane is highly regulated by NMDA receptor activity, resulting in a several-fold increased insertion of new receptors after blocking NMDA receptors for 8 hours. Blocking AMPA receptors also increases the delivery of NR2A-containing receptors to the cell membrane. In contrast, the amount of NR2B-containing receptors in the cell membrane is not affected by ionotropic glutamate receptor block. Moreover, electrophysiological analysis of synaptic currents in hippocampal cultures and CA1 neurons of hippocampal slices revealed that after 8 hours of NMDA receptor blockade the NMDA EPSCs increase as a result of augmented NMDA receptor-mediated currents. In conclusion, synaptic NR2A- but not NR2B-containing receptors are dynamically regulated, enabling neurons to change their NR2A/NR2B ratio within a time scale of hours.

  13. Emotion regulation and mental health: recent findings, current challenges, and future directions.

    Science.gov (United States)

    Berking, Matthias; Wupperman, Peggilee

    2012-03-01

    In recent years, deficits in emotion regulation have been studied as a putative maintaining factor and promising treatment target in a broad range of mental disorders. This article aims to provide an integrative review of the latest theoretical and empirical developments in this rapidly growing field of research. Deficits in emotion regulation appear to be relevant to the development, maintenance, and treatment of various forms of psychopathology. Increasing evidence demonstrates that deficits in the ability to adaptively cope with challenging emotions are related to depression, borderline personality disorder, substance-use disorders, eating disorders, somatoform disorders, and a variety of other psychopathological symptoms. Unfortunately, studies differ with regard to the conceptualization and assessment of emotion regulation, thus limiting the ability to compare findings across studies. Future research should systematically work to use comparable methods in order to clarify the following: which individuals have; what kinds of emotion regulation difficulties with; which types of emotions; and what interventions are most effective in alleviating these difficulties. Despite some yet to be resolved challenges, the concept of emotion regulation has a broad and significant heuristic value for research in mental health.

  14. Methods for growth regulation of greenhouse produced ornamental pot- and bedding plants – a current review

    Directory of Open Access Journals (Sweden)

    Bergstrand Karl-Johan I.

    2017-06-01

    Full Text Available Chemical plant growth regulators (PGRs are used in the production of ornamental potted and bedding plants. Growth control is needed for maximizing production per unit area, reducing transportation costs and to obtain a desired visual quality. However, the use of PGRs is associated with toxicity risks to humans and the environment. In many countries the availability of PGRs is restricted as few substances are registered for use. A number of alternative methods have been suggested. The methods include genetic methods (breeding and crop cultivation practices such as fertigation, temperature and light management. A lot of research into “alternative” growth regulation was performed during the 1980-1990s, revealing several possible ways of using different climatic factors to optimize plant growth with respect to plant height. In recent years, the interest in climatic growth regulation has been resurrected, not least due to the coming phase-out of the plant growth regulator chlormequat chloride (CCC. Today, authorities in many countries are aiming towards reducing the use of agrochemicals. At the same time, there is a strong demand from consumers for products produced without chemicals. This article provides a broad overview of available methods for non-chemical growth control. It is concluded that a combination of plant breeding and management of temperature, fertigation and light management has the potential of replacing chemical growth regulators in the commercial production of ornamental pot- and bedding plants.

  15. Emergent spatial synaptic structure from diffusive plasticity.

    Science.gov (United States)

    Sweeney, Yann; Clopath, Claudia

    2017-04-01

    Some neurotransmitters can diffuse freely across cell membranes, influencing neighbouring neurons regardless of their synaptic coupling. This provides a means of neural communication, alternative to synaptic transmission, which can influence the way in which neural networks process information. Here, we ask whether diffusive neurotransmission can also influence the structure of synaptic connectivity in a network undergoing plasticity. We propose a form of Hebbian synaptic plasticity which is mediated by a diffusive neurotransmitter. Whenever a synapse is modified at an individual neuron through our proposed mechanism, similar but smaller modifications occur in synapses connecting to neighbouring neurons. The effects of this diffusive plasticity are explored in networks of rate-based neurons. This leads to the emergence of spatial structure in the synaptic connectivity of the network. We show that this spatial structure can coexist with other forms of structure in the synaptic connectivity, such as with groups of strongly interconnected neurons that form in response to correlated external drive. Finally, we explore diffusive plasticity in a simple feedforward network model of receptive field development. We show that, as widely observed across sensory cortex, the preferred stimulus identity of neurons in our network become spatially correlated due to diffusion. Our proposed mechanism of diffusive plasticity provides an efficient mechanism for generating these spatial correlations in stimulus preference which can flexibly interact with other forms of synaptic organisation. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  16. Bi-directional astrocytic regulation of neuronal activity within a network.

    Science.gov (United States)

    Gordleeva, S Yu; Stasenko, S V; Semyanov, A V; Dityatev, A E; Kazantsev, V B

    2012-01-01

    The concept of a tripartite synapse holds that astrocytes can affect both the pre- and post-synaptic compartments through the Ca(2+)-dependent release of gliotransmitters. Because astrocytic Ca(2+) transients usually last for a few seconds, we assumed that astrocytic regulation of synaptic transmission may also occur on the scale of seconds. Here, we considered the basic physiological functions of tripartite synapses and investigated astrocytic regulation at the level of neural network activity. The firing dynamics of individual neurons in a spontaneous firing network was described by the Hodgkin-Huxley model. The neurons received excitatory synaptic input driven by the Poisson spike train with variable frequency. The mean field concentration of the released neurotransmitter was used to describe the presynaptic dynamics. The amplitudes of the excitatory postsynaptic currents (PSCs) obeyed the gamma distribution law. In our model, astrocytes depressed the presynaptic release and enhanced the PSCs. As a result, low frequency synaptic input was suppressed while high frequency input was amplified. The analysis of the neuron spiking frequency as an indicator of network activity revealed that tripartite synaptic transmission dramatically changed the local network operation compared to bipartite synapses. Specifically, the astrocytes supported homeostatic regulation of the network activity by increasing or decreasing firing of the neurons. Thus, the astrocyte activation may modulate a transition of neural network into bistable regime of activity with two stable firing levels and spontaneous transitions between them.

  17. Design of a low temperature superconducting coil to be applied to current regulators

    International Nuclear Information System (INIS)

    Garcia-Tabares, L.; Grau Carles, A

    1998-05-01

    We study the magnetic design and the cryogenic stability of a superconducting coil cooled with liquid helium, which works both in DC and AC modes. In DC mode, we obtain the maximum quench current; while in AC mode, we analyze Joule losses produced by the superconductor magnetization and the generation of eddy currents inside the copper matrix. (Author)

  18. Synaptic Control of Secretory Trafficking in Dendrites

    Directory of Open Access Journals (Sweden)

    Cyril Hanus

    2014-06-01

    Full Text Available Localized signaling in neuronal dendrites requires tight spatial control of membrane composition. Upon initial synthesis, nascent secretory cargo in dendrites exits the endoplasmic reticulum (ER from local zones of ER complexity that are spatially coupled to post-ER compartments. Although newly synthesized membrane proteins can be processed locally, the mechanisms that control the spatial range of secretory cargo transport in dendritic segments are unknown. Here, we monitored the dynamics of nascent membrane proteins in dendritic post-ER compartments under regimes of low or increased neuronal activity. In response to activity blockade, post-ER carriers are highly mobile and are transported over long distances. Conversely, increasing synaptic activity dramatically restricts the spatial scale of post-ER trafficking along dendrites. This activity-induced confinement of secretory cargo requires site-specific phosphorylation of the kinesin motor KIF17 by Ca2+/calmodulin-dependent protein kinases (CaMK. Thus, the length scales of early secretory trafficking in dendrites are tuned by activity-dependent regulation of microtubule-dependent transport.

  19. Development of auditory cortical synaptic receptive fields.

    Science.gov (United States)

    Froemke, Robert C; Jones, Bianca J

    2011-11-01

    The central nervous system is plastic throughout life, but is most sensitive to the statistics of the sensory environment during critical periods of early postnatal development. In the auditory cortex, various forms of acoustic experience have been found to shape the formation of receptive fields and influence the overall rate of cortical organization. The synaptic mechanisms that control cortical receptive field plasticity are beginning to be described, particularly for frequency tuning in rodent primary auditory cortex. Inhibitory circuitry plays a major role in critical period regulation, and new evidence suggests that the formation of excitatory-inhibitory balance determines the duration of critical period plasticity for auditory cortical frequency tuning. Cortical inhibition is poorly tuned in the infant brain, but becomes co-tuned with excitation in an experience-dependent manner over the first postnatal month. We discuss evidence suggesting that this may be a general feature of the developing cortex, and describe the functional implications of such transient excitatory-inhibitory imbalance. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. Purines released from astrocytes inhibit excitatory synaptic transmission in the ventral horn of the spinal cord

    DEFF Research Database (Denmark)

    Carlsen, Eva Maria Meier; Perrier, Jean-Francois Marie

    2014-01-01

    . Neurons responded to electrical stimulation by monosynaptic EPSCs (excitatory monosynaptic postsynaptic currents). We used mice expressing the enhanced green fluorescent protein under the promoter of the glial fibrillary acidic protein to identify astrocytes. Chelating calcium with BAPTA in a single...... by different neuromodulators. These substances are usually thought of being released by dedicated neurons. However, in other networks from the central nervous system synaptic transmission is also modulated by transmitters released from astrocytes. The star-shaped glial cell responds to neurotransmitters...... by releasing gliotransmitters, which in turn modulate synaptic transmission. Here we investigated if astrocytes present in the ventral horn of the spinal cord modulate synaptic transmission. We evoked synaptic inputs in ventral horn neurons recorded in a slice preparation from the spinal cord of neonatal mice...

  1. Control of synaptic function by endocannabinoid-mediated retrograde signaling

    Science.gov (United States)

    KANO, Masanobu

    2014-01-01

    Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca2+ elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation. PMID:25169670

  2. Current and new formulations of the plant growth regulator Primo MAXX® (trinexapac-ethyl) for turfgrass

    OpenAIRE

    Vågen, Ingunn Molund; Niemeläinen, Oiva; Espevig, Tatsiana; Pettersen, Trond; Ruuttunen, Pentti; Aamlid, Trygve

    2013-01-01

    This report presents results and recommendations based on based on four field trials with increasing rates of two different formulations of the plant growth regulator Primo MAXX® (trinexapac-ethyl) on golf course greens and fairways in Norway and Finland in 2013.

  3. A compilation of current regulations, standards and guidelines in remote afterloading brachytherapy

    Energy Technology Data Exchange (ETDEWEB)

    Tortorelli, J.P.; Simion, G.P.; Kozlowski, S.D. [Idaho National Engineering Lab., Idaho Falls, ID (United States)

    1994-10-01

    Over a dozen government and professional organizations in the United States and Europe have issued regulations and guidance concerning quality management in the practice of remote afterloading brachytherapy. Information from the publications of these organizations was collected and collated for this report. This report provides the brachytherapy licensee access to a broad field of quality management information in a single, topically organized document.

  4. The current status and countermeasures of nuclear and radiation safety regulation in China

    International Nuclear Information System (INIS)

    Guo Chengzhan

    2013-01-01

    Nuclear power utilization is an inevitable choice for the development of energy science and technology civilization of human. As a kind of clean and low-carbon energy, nuclear energy plays an irreplaceable role in optimizing the energy structure, promoting energy-saving, discharge reduction and reducing resource constraints. But it is inevitably to face the risk of nuclear safety during the application of nuclear energy. Ensuring nuclear and radiation safety is the precondition and foundation of achieving the sustainable development of nuclear energy and technology utilization. As the main body of nuclear and radiation safety regulation work development, the Chinese dream of National Nuclear Safety Administration is to insure nuclear and radiation safety, boost the construction of ecological civilization, guarantee the harmonious and healthy development of human and environmental. The necessary means to deal with the new situation of nuclear and radiation safety and to promote the work of nuclear and radiation safety regulation is to summarize the experiences and lessons learned, to innovate the regulation ideas, methods and measures, to plan the nuclear and radiation safety regulation development strategy. (author)

  5. A compilation of current regulations, standards and guidelines in remote afterloading brachytherapy

    International Nuclear Information System (INIS)

    Tortorelli, J.P.; Simion, G.P.; Kozlowski, S.D.

    1994-10-01

    Over a dozen government and professional organizations in the United States and Europe have issued regulations and guidance concerning quality management in the practice of remote afterloading brachytherapy. Information from the publications of these organizations was collected and collated for this report. This report provides the brachytherapy licensee access to a broad field of quality management information in a single, topically organized document

  6. Models of Short-Term Synaptic Plasticity.

    Science.gov (United States)

    Barroso-Flores, Janet; Herrera-Valdez, Marco A; Galarraga, Elvira; Bargas, José

    2017-01-01

    We focus on dynamical descriptions of short-term synaptic plasticity. Instead of focusing on the molecular machinery that has been reviewed recently by several authors, we concentrate on the dynamics and functional significance of synaptic plasticity, and review some mathematical models that reproduce different properties of the dynamics of short term synaptic plasticity that have been observed experimentally. The complexity and shortcomings of these models point to the need of simple, yet physiologically meaningful models. We propose a simplified model to be tested in synapses displaying different types of short-term plasticity.

  7. Depolarization-induced calcium-independent synaptic vesicle exo- and endocytosis at frog motor nerve terminals.

    Science.gov (United States)

    Abdrakhmanov, M M; Petrov, A M; Grigoryev, P N; Zefirov, A L

    2013-10-01

    The transmitter release and synaptic vesicle exo- and endocytosis induced by constant current depolarization of nerve terminals were studied by microelectode extracellular recording of miniature endplate currents and fluorescent microscopy (FM 1-43 styryl dye). Depolarization of the plasma membrane of nerve terminals in the control specimen was shown to significantly increase the MEPC frequency (quantal transmitter release) and exocytotic rate (FM 1-43 unloading from the synaptic vesicles preliminarily stained with the dye), which was caused by a rise in the intracellular Ca(2+) concentration due to opening of voltage-gated Ca channels. A slight increase in the MEPC frequency and in the rate of synaptic vesicle exocytosis was observed under depolarization in case of blockade of Ca channels and chelating of intracellular Ca(2+) ions (cooperative action of Cd(2+) and EGTA-AM). The processes of synaptic vesicle endocytosis (FM 1-43 loading) were proportional to the number of synaptic vesicles that had undergone exocytosis both in the control and in case of cooperative action of Cd(2+) and EGTA-AM. A hypothesis has been put forward that Ca-independent synaptic vesicle exo- and endocytosis that can be induced directly by depolarization of the membrane exists in the frog motor terminal in addition to the conventional Ca-dependent process.

  8. GABA Metabolism and Transport: Effects on Synaptic Efficacy

    Directory of Open Access Journals (Sweden)

    Fabian C. Roth

    2012-01-01

    Full Text Available GABAergic inhibition is an important regulator of excitability in neuronal networks. In addition, inhibitory synaptic signals contribute crucially to the organization of spatiotemporal patterns of network activity, especially during coherent oscillations. In order to maintain stable network states, the release of GABA by interneurons must be plastic in timing and amount. This homeostatic regulation is achieved by several pre- and postsynaptic mechanisms and is triggered by various activity-dependent local signals such as excitatory input or ambient levels of neurotransmitters. Here, we review findings on the availability of GABA for release at presynaptic terminals of interneurons. Presynaptic GABA content seems to be an important determinant of inhibitory efficacy and can be differentially regulated by changing synthesis, transport, and degradation of GABA or related molecules. We will discuss the functional impact of such regulations on neuronal network patterns and, finally, point towards pharmacological approaches targeting these processes.

  9. Long-term Relationships between Cholinergic Tone, Synchronous Bursting and Synaptic Remodeling

    Science.gov (United States)

    Kaufman, Maya; Corner, Michael A.; Ziv, Noam E.

    2012-01-01

    Cholinergic neuromodulation plays key roles in the regulation of neuronal excitability, network activity, arousal, and behavior. On longer time scales, cholinergic systems play essential roles in cortical development, maturation, and plasticity. Presumably, these processes are associated with substantial synaptic remodeling, yet to date, long-term relationships between cholinergic tone and synaptic remodeling remain largely unknown. Here we used automated microscopy combined with multielectrode array recordings to study long-term relationships between cholinergic tone, excitatory synapse remodeling, and network activity characteristics in networks of cortical neurons grown on multielectrode array substrates. Experimental elevations of cholinergic tone led to the abrupt suppression of episodic synchronous bursting activity (but not of general activity), followed by a gradual growth of excitatory synapses over hours. Subsequent blockage of cholinergic receptors led to an immediate restoration of synchronous bursting and the gradual reversal of synaptic growth. Neither synaptic growth nor downsizing was governed by multiplicative scaling rules. Instead, these occurred in a subset of synapses, irrespective of initial synaptic size. Synaptic growth seemed to depend on intrinsic network activity, but not on the degree to which bursting was suppressed. Intriguingly, sustained elevations of cholinergic tone were associated with a gradual recovery of synchronous bursting but not with a reversal of synaptic growth. These findings show that cholinergic tone can strongly affect synaptic remodeling and synchronous bursting activity, but do not support a strict coupling between the two. Finally, the reemergence of synchronous bursting in the presence of elevated cholinergic tone indicates that the capacity of cholinergic neuromodulation to indefinitely suppress synchronous bursting might be inherently limited. PMID:22911726

  10. Design considerations for high current regulated DC power supplies with reference to 600 kW variable DC power supply

    International Nuclear Information System (INIS)

    Ushakumari; Garud, A.N.; Nadkarni, S.S.

    1980-01-01

    High current regulated dc power supplies find increasing applications in industry and research. The power rating of these supplies vary from few killowatts to megawatts. The general requirements of these supplies for various applications and the techniques used to achieve the desired performance are presented. The design and selection of various circuit blocks namely the rectifier transformer, multiphase rectifier arrangement, SCR paralleling and current sensing techniques, are discussed in detail for a 600 killowatt current controlled supply developed in the Bhabha Atomic Research Centre, Bombay, and used for the thermal studies of reactor components. The power supply incorporates paralleled phase controlled thyristors with a closed loop feedback circuitary to achieve a current stability of 0.1% and smooth output variation from 10 to 100%. (auth.)

  11. Risk informed regulation of nuclear facilities: Overview of the current status

    International Nuclear Information System (INIS)

    2005-02-01

    This report provides guidance on the use of risk information by regulatory bodies as part of an integrated decision making process. This addresses the way in which risk information is being used in decisions about safety issues at nuclear plants, sometimes referred to as risk informed decision making, and how risk information is being used by regulatory bodies as an input into the activities that they carry out, sometimes referred to as risk informed regulation

  12. Current major advances in the regulation of milk protein gene expression.

    Science.gov (United States)

    Qian, Xi; Zhao, Feng-Qi

    2014-01-01

    During lactation, functionally differentiated mammary epithelial cells convert circulating nutrients into various milk components, providing all essential nutrients for the growth and development of mammal neonates. One of the major milk components is milk protein, which includes the casein and whey proteins. Regulation of milk protein gene expression is dependent on hormonal and developmental cues that modulate the activity of specific transcription factors and change the chromatin structure in mammary epithelial cells. Understanding the underlying mechanisms involved in mammary-specific milk protein gene regulation will help improve the yield, quality, and efficiency of milk production and identify important signaling factors and pathways involved in mammary development, differentiation, lactation, and disease. In this review we first review advances in the understanding of the regulatory mechanisms of milk protein genes by hormones, growth factors, and the extracellular matrix, with a focus on transcriptional regulation. We then discuss the relationship between chromatin structure and milk protein gene expression from an epigenetic perspective. Finally, we summarize recent achievements using the mammary gland as a bioreactor for producing pharmaceutical proteins for human use.

  13. Quantitative Proteomics of Synaptic and Nonsynaptic Mitochondria: Insights for Synaptic Mitochondrial Vulnerability

    Science.gov (United States)

    2015-01-01

    Synaptic mitochondria are essential for maintaining calcium homeostasis and producing ATP, processes vital for neuronal integrity and synaptic transmission. Synaptic mitochondria exhibit increased oxidative damage during aging and are more vulnerable to calcium insult than nonsynaptic mitochondria. Why synaptic mitochondria are specifically more susceptible to cumulative damage remains to be determined. In this study, the generation of a super-SILAC mix that served as an appropriate internal standard for mouse brain mitochondria mass spectrometry based analysis allowed for the quantification of the proteomic differences between synaptic and nonsynaptic mitochondria isolated from 10-month-old mice. We identified a total of 2260 common proteins between synaptic and nonsynaptic mitochondria of which 1629 were annotated as mitochondrial. Quantitative proteomic analysis of the proteins common between synaptic and nonsynaptic mitochondria revealed significant differential expression of 522 proteins involved in several pathways including oxidative phosphorylation, mitochondrial fission/fusion, calcium transport, and mitochondrial DNA replication and maintenance. In comparison to nonsynaptic mitochondria, synaptic mitochondria exhibited increased age-associated mitochondrial DNA deletions and decreased bioenergetic function. These findings provide insights into synaptic mitochondrial susceptibility to damage. PMID:24708184

  14. A Low Input Current and Wide Conversion Ratio Buck Regulator with 75% Efficiency for High-Voltage Triboelectric Nanogenerators

    Science.gov (United States)

    Luo, Li-Chuan; Bao, De-Chun; Yu, Wu-Qi; Zhang, Zhao-Hua; Ren, Tian-Ling

    2016-01-01

    It is meaningful to research the Triboelectric Nanogenerators (TENG), which can create electricity anywhere and anytime. There are many researches on the structures and materials of TENG to explain the phenomenon that the maximum voltage is stable and the current is increasing. The output voltage of the TENG is high about 180-400 V, and the output current is small about 39 μA, which the electronic devices directly integration of TENG with Li-ion batteries will result in huge energy loss due to the ultrahigh TENG impedance. A novel interface circuit with the high-voltage buck regulator for TENG is introduced firstly in this paper. The interface circuit can transfer the output signal of the TENG into the signal fit to a lithium ion battery. Through the circuit of the buck regulator, the average output voltage is about 4.0 V and the average output current is about 1.12 mA. Further, the reliability and availability for the lithium ion battery and the circuit are discussed. The interface circuit is simulated using the Cadence software and verified through PCB experiment. The buck regulator can achieve 75% efficiency for the High-Voltage TENG. This will lead to a research hot and industrialization applications.

  15. Characterization of emergent synaptic topologies in noisy neural networks

    Science.gov (United States)

    Miller, Aaron James

    Learned behaviors are one of the key contributors to an animal's ultimate survival. It is widely believed that the brain's microcircuitry undergoes structural changes when a new behavior is learned. In particular, motor learning, during which an animal learns a sequence of muscular movements, often requires precisely-timed coordination between muscles and becomes very natural once ingrained. Experiments show that neurons in the motor cortex exhibit precisely-timed spike activity when performing a learned motor behavior, and constituent stereotypical elements of the behavior can last several hundred milliseconds. The subject of this manuscript concerns how organized synaptic structures that produce stereotypical spike sequences emerge from random, dynamical networks. After a brief introduction in Chapter 1, we begin Chapter 2 by introducing a spike-timing-dependent plasticity (STDP) rule that defines how the activity of the network drives changes in network topology. The rule is then applied to idealized networks of leaky integrate-and-fire neurons (LIF). These neurons are not subjected to the variability that typically characterize neurons in vivo. In noiseless networks, synapses develop closed loops of strong connectivity that reproduce stereotypical, precisely-timed spike patterns from an initially random network. We demonstrate the characteristics of the asymptotic synaptic configuration are dependent on the statistics of the initial random network. The spike timings of the neurons simulated in Chapter 2 are generated exactly by a computationally economical, nonlinear mapping which is extended to LIF neurons injected with fluctuating current in Chapter 3. Development of an economical mapping that incorporates noise provides a practical solution to the long simulation times required to produce asymptotic synaptic topologies in networks with STDP in the presence of realistic neuronal variability. The mapping relies on generating numerical solutions to the dynamics

  16. Synaptic proteome changes in the hypothalamus of mother rats.

    Science.gov (United States)

    Udvari, Edina Brigitta; Völgyi, Katalin; Gulyássy, Péter; Dimén, Diána; Kis, Viktor; Barna, János; Szabó, Éva Rebeka; Lubec, Gert; Juhász, Gábor; Kékesi, Katalin Adrienna; Dobolyi, Árpád

    2017-04-21

    To establish synaptic proteome changes associated with motherhood, we isolated synaptosome fractions from the hypothalamus of mother rats and non-maternal control females at the 11th postpartum day. Proteomic analysis by two-dimensional differential gel electrophoresis combined with mass spectrometric protein identification established 26 significant proteins, 7 increasing and 19 decreasing protein levels in the dams. The altered proteins are mainly involved in energy homeostasis, protein folding, and metabolic processes suggesting the involvement of these cellular processes in maternal adaptations. The decrease in a significantly altered protein, complement component 1q subcomponent-binding protein (C1qbp) was validated with Western blotting. Furthermore, immunohistochemistry showed its presence in hypothalamic fibers and terminals in agreement with its presence in synaptosomes. We also found the expression of C1qbp in different hypothalamic nuclei including the preoptic area and the paraventricular hypothalamic nucleus at the protein and at the mRNA level using immunohistochemistry and in situ hybridization histochemistry, respectively. Bioinformatical network analysis revealed that cytokines, growth factors, and protein kinases are common regulators, which indicates a complex regulation of the proteome change in mothers. The results suggest that maternal responsiveness is associated with synaptic proteins level changes in the hypothalamus, and that growth factors and cytokines may govern these alterations. The period of motherhood is accompanied with several behavioral, neuroendocrine, emotional and metabolic adaptations in the brain. Although it is established that various hypothalamic networks participate in the maternal adaptations of the rodent brain, our knowledge on the molecular background of these alterations remains seriously limited. In the present study, we first determined that the functional alterations of the maternal brain can be detected at the

  17. Monitoring of heavy metals in selected Water Supply Systems in Poland, in relation to current regulations

    Science.gov (United States)

    Szuster-Janiaczyk, Agnieszka; Zeuschner, Piotr; Noga, Paweł; Skrzypczak, Marta

    2018-02-01

    The study presents an analysis of water quality monitoring in terms of the content of heavy metals, which is conducted in three independent water supply systems in Poland. The analysis showed that the monitoring of heavy metals isn't reliable - both the quantity of tested water samples and the location of the monitoring points are the problem. The analysis of changes in water quality from raw water to tap water was possible only for one of the analysed systems and indicate a gradual deterioration of water quality, although still within acceptable limits of legal regulations.

  18. CURRENT WAGE AND LABOR REGULATION PROBLEMS IN RUSSIAN RESTRAURANTS END HOTELS

    Directory of Open Access Journals (Sweden)

    E. Sh. Kachalova

    2012-01-01

    Full Text Available At present, considerable disproportions take place in Russia between organizational, regulatory, social and economic relations actually existing in restaurant and hotel business enterprises on one part and provisions of their legal law basic norms and regulations on the other part. Labor organization and normative practice improvement directions are proposed for enterprises of the branch. Economic essence of the “tipping” phenomenon is revealed. Measures aimed at elimination of overcoming wage rise rates in comparison with those of the labor productivity presently existing in the branch.

  19. The method of using current regulations and standards in designing management and technologies of construction

    Directory of Open Access Journals (Sweden)

    Sinenko Sergey

    2017-01-01

    Full Text Available Economic efficiency of using funds in construction of buildings and structures begins from an effective, proper design, which is based on modern, cutting-edge, advanced equipment, streamlined organization and process solutions of construction operations. In the light of this it is considered application of “Self-Organization and Technology of Building” multifunctional software package capable of solving various engineering tasks on designing management of construction operations in accordance with the applicable rules and regulations in view of using software for automatic generation of workflow. Implementing this software in the construction management processes may help to solve management tasks at the construction site.

  20. Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility.

    Science.gov (United States)

    Devenyi, Ryan A; Ortega, Francis A; Groenendaal, Willemijn; Krogh-Madsen, Trine; Christini, David J; Sobie, Eric A

    2017-04-01

    Arrhythmias result from disruptions to cardiac electrical activity, although the factors that control cellular action potentials are incompletely understood. We combined mathematical modelling with experiments in heart cells from guinea pigs to determine how cellular electrical activity is regulated. A mismatch between modelling predictions and the experimental results allowed us to construct an improved, more predictive mathematical model. The balance between two particular potassium currents dictates how heart cells respond to perturbations and their susceptibility to arrhythmias. Imbalances of ionic currents can destabilize the cardiac action potential and potentially trigger lethal cardiac arrhythmias. In the present study, we combined mathematical modelling with information-rich dynamic clamp experiments to determine the regulation of action potential morphology in guinea pig ventricular myocytes. Parameter sensitivity analysis was used to predict how changes in ionic currents alter action potential duration, and these were tested experimentally using dynamic clamp, a technique that allows for multiple perturbations to be tested in each cell. Surprisingly, we found that a leading mathematical model, developed with traditional approaches, systematically underestimated experimental responses to dynamic clamp perturbations. We then re-parameterized the model using a genetic algorithm, which allowed us to estimate ionic current levels in each of the cells studied. This unbiased model adjustment consistently predicted an increase in the rapid delayed rectifier K + current and a drastic decrease in the slow delayed rectifier K + current, and this prediction was validated experimentally. Subsequent simulations with the adjusted model generated the clinically relevant prediction that the slow delayed rectifier is better able to stabilize the action potential and suppress pro-arrhythmic events than the rapid delayed rectifier. In summary, iterative coupling of

  1. 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.

  2. Implementation issues on the design of current loops based on resonant regulators for isolated microgrids

    DEFF Research Database (Denmark)

    Federico, de Bosio; Pastorelli, Michele; Antonio DeSouza Ribeiro, Luiz

    2016-01-01

    This paper analyzes the influence of state feedback coupling between the capacitor voltage and inductor current in voltage source inverters (VSI) operating in stand-alone microgrids. A decoupling technique is proposed as an effective measure to enhance the dynamics. Further implementation issues...... and control structures are also considered. Lab-scale experimental results prove the validity of the approaches....

  3. Shared Solar. Current Landscape, Market Potential, and the Impact of Federal Securities Regulation

    Energy Technology Data Exchange (ETDEWEB)

    Feldman, David [National Renewable Energy Lab. (NREL), Golden, CO (United States); Brockway, Anna M. [Office of Energy Efficiency and Renewable Energy (EERE), Washington, DC (United States); Ulrich, Elaine [Office of Energy Efficiency and Renewable Energy (EERE), Washington, DC (United States); Margolis, Robert [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2015-04-01

    This report provides a high-level overview of the current U.S. shared solar landscape and the impact that a given shared solar program’s structure has on requiring federal securities oversight, as well as an estimate of market potential for U.S. shared solar deployment.

  4. Shared Solar. Current Landscape, Market Potential, and the Impact of Federal Securities Regulation

    Energy Technology Data Exchange (ETDEWEB)

    Feldman, David [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Brockway, Anna M. [U.S. Department of Energy, Washington, DC (United States); Ulrich, Elaine [U.S. Department of Energy, Washington, DC (United States); Margolis, Robert [National Renewable Energy Laboratory (NREL), Golden, CO (United States)

    2015-04-07

    This report provides a high-level overview of the current U.S. shared solar landscape, the impact that a given shared solar program’s structure has on requiring federal securities oversight, as well as an estimate of market potential for U.S. shared solar deployment.

  5. Synaptic Wnt/GSK3β Signaling Hub in Autism

    Science.gov (United States)

    Caracci, Mario O.; Ávila, Miguel E.; De Ferrari, Giancarlo V.

    2016-01-01

    Hundreds of genes have been associated with autism spectrum disorders (ASDs) and the interaction of weak and de novo variants derive from distinct autistic phenotypes thus making up the “spectrum.” The convergence of these variants in networks of genes associated with synaptic function warrants the study of cell signaling pathways involved in the regulation of the synapse. The Wnt/β-catenin signaling pathway plays a central role in the development and regulation of the central nervous system and several genes belonging to the cascade have been genetically associated with ASDs. In the present paper, we review basic information regarding the role of Wnt/β-catenin signaling in excitatory/inhibitory balance (E/I balance) through the regulation of pre- and postsynaptic compartments. Furthermore, we integrate information supporting the role of the glycogen synthase kinase 3β (GSK3β) in the onset/development of ASDs through direct modulation of Wnt/β-catenin signaling. Finally, given GSK3β activity as key modulator of synaptic plasticity, we explore the potential of this kinase as a therapeutic target for ASD. PMID:26881141

  6. Activity-dependent modulation of neural circuit synaptic connectivity

    Directory of Open Access Journals (Sweden)

    Charles R Tessier

    2009-07-01

    Full Text Available In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; 1 early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and 2 subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circuits are “hard-wired” in a purely activity-independent manner. This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution. These recent studies reveal that activity-dependent mechanisms are indeed required to refine circuit maps in Drosophila during precise, restricted windows of late-phase development. Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function. This review focuses on our current understanding of activity-dependent synaptic connectivity in Drosophila, primarily through analyzing the role of the fragile X mental retardation protein (FMRP in the Drosophila FXS disease model. The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail.

  7. Nuclear respiratory factor 2 regulates the expression of the same NMDA receptor subunit genes as NRF-1: both factors act by a concurrent and parallel mechanism to couple energy metabolism and synaptic transmission.

    Science.gov (United States)

    Priya, Anusha; Johar, Kaid; Wong-Riley, Margaret T T

    2013-01-01

    Neuronal activity and energy metabolism are tightly coupled processes. Previously, we found that nuclear respiratory factor 1 (NRF-1) transcriptionally co-regulates energy metabolism and neuronal activity by regulating all 13 subunits of the critical energy generating enzyme, cytochrome c oxidase (COX), as well as N-methyl-d-aspartate (NMDA) receptor subunits 1 and 2B, GluN1 (Grin1) and GluN2B (Grin2b). We also found that another transcription factor, nuclear respiratory factor 2 (NRF-2 or GA-binding protein) regulates all subunits of COX as well. The goal of the present study was to test our hypothesis that NRF-2 also regulates specific subunits of NMDA receptors, and that it functions with NRF-1 via one of three mechanisms: complementary, concurrent and parallel, or a combination of complementary and concurrent/parallel. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation of mouse neuroblastoma cells and rat visual cortical tissue, promoter mutations, real-time quantitative PCR, and western blot analysis, NRF-2 was found to functionally regulate Grin1 and Grin2b genes, but not any other NMDA subunit genes. Grin1 and Grin2b transcripts were up-regulated by depolarizing KCl, but silencing of NRF-2 prevented this up-regulation. On the other hand, over-expression of NRF-2 rescued the down-regulation of these subunits by the impulse blocker TTX. NRF-2 binding sites on Grin1 and Grin2b are conserved among species. Our data indicate that NRF-2 and NRF-1 operate in a concurrent and parallel manner in mediating the tight coupling between energy metabolism and neuronal activity at the molecular level. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. A pragmatic analysis of the regulation of consumer transcranial direct current stimulation (TDCS) devices in the United States.

    Science.gov (United States)

    Wexler, Anna

    2015-11-01

    Several recent articles have called for the regulation of consumer transcranial direct current stimulation (tDCS) devices, which provide low levels of electrical current to the brain. However, most of the discussion to-date has focused on ethical or normative considerations; there has been a notable absence of scholarship regarding the actual legal framework in the United States. This article aims to fill that gap by providing a pragmatic analysis of the consumer tDCS market and relevant laws and regulations. In the five main sections of this manuscript, I take into account (a) the history of the do-it-yourself tDCS movement and the subsequent emergence of direct-to-consumer devices; (b) the statutory language of the Federal Food, Drug and Cosmetic Act and how the definition of a medical device-which focuses on the intended use of the device rather than its mechanism of action-is of paramount importance for discussions of consumer tDCS device regulation; (c) how both the Food and Drug Administration (FDA) and courts have understood the FDA's jurisdiction over medical devices in cases where the meaning of 'intended use' has been challenged; (d) an analysis of consumer tDCS regulatory enforcement action to-date; and (e) the multiple US authorities, other than the FDA, that can regulate consumer brain stimulation devices. Taken together, this paper demonstrates that rather than a 'regulatory gap,' there are multiple, distinct pathways by which consumer tDCS can be regulated in the United States.

  9. A pragmatic analysis of the regulation of consumer transcranial direct current stimulation (TDCS) devices in the United States

    Science.gov (United States)

    2015-01-01

    Several recent articles have called for the regulation of consumer transcranial direct current stimulation (tDCS) devices, which provide low levels of electrical current to the brain. However, most of the discussion to-date has focused on ethical or normative considerations; there has been a notable absence of scholarship regarding the actual legal framework in the United States. This article aims to fill that gap by providing a pragmatic analysis of the consumer tDCS market and relevant laws and regulations. In the five main sections of this manuscript, I take into account (a) the history of the do-it-yourself tDCS movement and the subsequent emergence of direct-to-consumer devices; (b) the statutory language of the Federal Food, Drug and Cosmetic Act and how the definition of a medical device—which focuses on the intended use of the device rather than its mechanism of action—is of paramount importance for discussions of consumer tDCS device regulation; (c) how both the Food and Drug Administration (FDA) and courts have understood the FDA's jurisdiction over medical devices in cases where the meaning of ‘intended use’ has been challenged; (d) an analysis of consumer tDCS regulatory enforcement action to-date; and (e) the multiple US authorities, other than the FDA, that can regulate consumer brain stimulation devices. Taken together, this paper demonstrates that rather than a ‘regulatory gap,’ there are multiple, distinct pathways by which consumer tDCS can be regulated in the United States. PMID:27774217

  10. The Roles of Cortical Slow Waves in Synaptic Plasticity and Memory Consolidation

    Directory of Open Access Journals (Sweden)

    Daisuke Miyamoto

    2017-11-01

    Full Text Available Sleep plays important roles in sensory and motor memory consolidation. Sleep oscillations, reflecting neural population activity, involve the reactivation of learning-related neurons and regulate synaptic strength and, thereby affect memory consolidation. Among sleep oscillations, slow waves (0.5–4 Hz are closely associated with memory consolidation. For example, slow-wave power is regulated in an experience-dependent manner and correlates with acquired memory. Furthermore, manipulating slow waves can enhance or impair memory consolidation. During slow wave sleep, inter-areal interactions between the cortex and hippocampus (HC have been proposed to consolidate declarative memory; however, interactions for non-declarative (HC-independent memory remain largely uninvestigated. We recently showed that the directional influence in a slow-wave range through a top-down cortical long-range circuit is involved in the consolidation of non-declarative memory. At the synaptic level, the average cortical synaptic strength is known to be potentiated during wakefulness and depressed during sleep. Moreover, learning causes plasticity in a subset of synapses, allocating memory to them. Sleep may help to differentiate synaptic strength between allocated and non-allocated synapses (i.e., improving the signal-to-noise ratio, which may facilitate memory consolidation. Herein, we offer perspectives on inter-areal interactions and synaptic plasticity for memory consolidation during sleep.

  11. Analysis of synaptic growth and function in Drosophila with an extended larval stage.

    Science.gov (United States)

    Miller, Daniel L; Ballard, Shannon L; Ganetzky, Barry

    2012-10-03

    The Drosophila larval neuromuscular junction (NMJ) is a powerful system for the genetic and molecular analysis of neuronal excitability, synaptic transmission, and synaptic development. However, its use for studying age-dependent processes, such as maintenance of neuronal viability and synaptic stability, are temporally limited by the onset of pupariation and metamorphosis. Here we characterize larval NMJ growth, growth regulation, structure, and function in a developmental variant with an extended third instar (ETI). RNAi-knockdown of the prothoracicotropic hormone receptor, torso, in the ring gland of developing larvae leaves the timing of first and second instar molts largely unchanged, but triples duration of the third instar from 3 to 9.5 d (McBrayer et al., 2007; Rewitz et al., 2009). During this ETI period, NMJs undergo additional growth (adding >50 boutons/NMJ), and this growth remains under the control of the canonical regulators Highwire and the TGFβ/BMP pathway. NMJ growth during the ETI period occurs via addition of new branches, satellite boutons, and interstitial boutons, and continues even after muscle growth levels off. Throughout the ETI, organization of synapses and active zones remains normal, and synaptic transmission is unchanged. These results establish the ETI larval system as a viable model for studying motor neuron diseases and for investigating time-dependent effects of perturbations that impair mechanisms of neuroprotection, synaptic maintenance, and response to neural injury.

  12. Nitric oxide signaling is recruited as a compensatory mechanism for sustaining synaptic plasticity in Alzheimer's disease mice.

    Science.gov (United States)

    Chakroborty, Shreaya; Kim, Joyce; Schneider, Corinne; West, Anthony R; Stutzmann, Grace E

    2015-04-29

    Synaptic plasticity deficits are increasingly recognized as causing the memory impairments which define Alzheimer's disease (AD). In AD mouse models, evidence of abnormal synaptic function is present before the onset of cognitive deficits, and presents as increased synaptic depression revealed only when synaptic homeostasis is challenged, such as with suppression of ryanodine receptor (RyR)-evoked calcium signaling. Otherwise, at early disease stages, the synaptic physiology phenotype appears normal. This suggests compensatory mechanisms are recruited to maintain a functionally normal net output of the hippocampal circuit. A candidate calcium-regulated synaptic modulator is nitric oxide (NO), which acts presynaptically to boost vesicle release and glutamatergic transmission. Here we tested whether there is a feedforward cycle between the increased RyR calcium release seen in presymptomatic AD mice and aberrant NO signaling which augments synaptic plasticity. Using a combination of electrophysiological approaches, two-photon calcium imaging, and protein biochemistry in hippocampal tissue from presymptomatic 3xTg-AD and NonTg mice, we show that blocking NO synthesis results in markedly augmented synaptic depression mediated through presynaptic mechanisms in 3xTg-AD mice. Additionally, blocking NO reduces the augmented synaptically evoked dendritic calcium release mediated by enhanced RyR calcium release. This is accompanied by increased nNOS levels in the AD mice and is reversed upon normalization of RyR-evoked calcium release with chronic dantrolene treatment. Thus, recruitment of NO is serving a compensatory role to boost synaptic transmission and plasticity during early AD stages. However, NO's dual role in neuroprotection and neurodegeneration may convert to maladaptive functions as the disease progresses. Copyright © 2015 the authors 0270-6474/15/356893-10$15.00/0.

  13. Fishing profiles of Danish seiners and bottom trawlers in relation to current EU management regulations

    DEFF Research Database (Denmark)

    Noack, Thomas; Frandsen, R. P.; Wieland, Kai

    2017-01-01

    species are higher for trawlers. The results do not directly suggest a separation of the gears in terms of legislation as the quantities of fish below current minimum size were similar, but for example future survival studies may reach different conclusions. Additional factors were found to be important...... disagreement on current gear classification. This study compared both gears in terms of their fishing characteristics and catches of commercial species based on 16 years of observer data. Danish seining is a specialised fishing method that targeted few species but with higher total catch rates than bottom...... trawlers. Bottom trawling is a more all-purpose fishing method that targets a larger number of species, and bottom trawlers use larger engines than Danish seiners. A generalised additive mixed model indicated that catch rates of flatfish are generally higher for Danish seines, and catch rates of roundfish...

  14. The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

    Science.gov (United States)

    Korol, Sergiy V.; Jin, Zhe; Birnir, Bryndis

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA-activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 μM), an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC) amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM) plus diazepam (1 μM), only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons. PMID:25927918

  15. The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons.

    Directory of Open Access Journals (Sweden)

    Sergiy V Korol

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA-activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 μM, an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM plus diazepam (1 μM, only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons.

  16. The mechanism of action of aniracetam at synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors: indirect and direct effects on desensitization.

    Science.gov (United States)

    Lawrence, J Josh; Brenowitz, Stephan; Trussell, Laurence O

    2003-08-01

    The mechanism of action of aniracetam on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors was examined in outside-out patches and at glutamatergic synapses in neurons of the chick cochlear nucleus. A combination of rapid-flow analysis, using glutamate as an agonist, and kinetic modeling indicated that aniracetam slows both the rate of channel closing, and the microscopic rates of desensitization, even for partially liganded receptors. Little effect was observed on the rate of recovery from desensitization or on the response to the weakly desensitizing agonist kainate. Aniracetam's effects on receptor deactivation saturated at lower concentrations than its effects on desensitization, suggesting that cooperativity between homologous binding sites was required to regulate desensitization. Analysis of responses to paired pulses of agonist also indicated that AMPA receptors must desensitize partially even after agonist exposures too brief to permit rebinding. In the presence of aniracetam, evoked excitatory synaptic currents (EPSCs) and miniature EPSCs in low quantal-content conditions had decay times similar to the time course of receptor deactivation. Under these conditions, the time course of both transmitter release and clearance must be aniracetam decayed with a time course intermediate between deactivation and desensitization, suggesting that the time course of transmitter clearance is prolonged because of pooling of transmitter in the synaptic cleft. Moreover, by comparing the amounts of paired-pulse synaptic depression and patch desensitization prevented by aniracetam, we conclude that significant desensitization occurs in response to rebinding of transmitter to the AMPA receptors.

  17. Current Evidence for a Role of Neuropeptides in the Regulation of Autophagy

    Directory of Open Access Journals (Sweden)

    Elisabetta Catalani

    2017-01-01

    Full Text Available Neuropeptides drive a wide diversity of biological actions and mediate multiple regulatory functions involving all organ systems. They modulate intercellular signalling in the central and peripheral nervous systems as well as the cross talk among nervous and endocrine systems. Indeed, neuropeptides can function as peptide hormones regulating physiological homeostasis (e.g., cognition, blood pressure, feeding behaviour, water balance, glucose metabolism, pain, and response to stress, neuroprotection, and immunomodulation. We aim here to describe the recent advances on the role exerted by neuropeptides in the control of autophagy and its molecular mechanisms since increasing evidence indicates that dysregulation of autophagic process is related to different pathological conditions, including neurodegeneration, metabolic disorders, and cancer.

  18. Review of current and anticipated regulations on air protection in the Czech Republic

    Energy Technology Data Exchange (ETDEWEB)

    Jilek, P.; Novotny, V. [Ministry of the Environment of the Czech Republic, Prague (Czechoslovakia)

    1995-12-01

    Environmental issues, especially the solution of the air pollution problem, have taken on great significance in the Czech Republic (which was a part of the Czech and Slovak Federal Republic until the end of 1992) since the 1989 {open_quotes}Velvet{close_quotes} Revolution. The former CSFR Federal Committee for the Environment and both the Republic Ministries started immediately with creating new environmental legislation, which is the main governmental tool for protecting the environment in the newly developing democracy state system with a market oriented economy. The inspiration for that activity was found in legislation of developed countries - member states of the European Union, and in German environmental law in particular. This paper surveys the major laws and regulations that gradually came into force in the Czech Republic since 1990. The provisions of the primary significance are the Act No.309/1991 S.B., dated July 9, 1991, on the protection of the air against pollutants - The Clean Air Act, the Act No.218/1992 S.B., dated April 27, 1992, which changes and supplements the Act No.309 - The Clean Air Act, the Measure of the Federal Committee for the Environment of October 1, 1991 to the Clean Air Act, and its amended wordings of June 23, 1992, 84/1991 S.B., and 84/1992 S.B., the Act No.389/1991 S.B., dated September 10, 1991 on the state administration of air protection and charges for the pollution of air, and several regulations based on the Act No.389/1991 S.B., issued in the period 1992 -1993.

  19. β-Secretase BACE1 regulates hippocampal and reconstituted M-currents in a β-subunit-like fashion.

    Science.gov (United States)

    Hessler, Sabine; Zheng, Fang; Hartmann, Stephanie; Rittger, Andrea; Lehnert, Sandra; Völkel, Meike; Nissen, Matthias; Edelmann, Elke; Saftig, Paul; Schwake, Michael; Huth, Tobias; Alzheimer, Christian

    2015-02-25

    The β-secretase BACE1 is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease, but how its action on transmembrane proteins other than the amyloid precursor protein affects the nervous system is only beginning to be understood. We report here that BACE1 regulates neuronal excitability through an unorthodox, nonenzymatic interaction with members of the KCNQ (Kv7) family that give rise to the M-current, a noninactivating potassium current with slow kinetics. In hippocampal neurons from BACE1(-/-) mice, loss of M-current enhanced neuronal excitability. We relate the diminished M-current to the previously reported epileptic phenotype of BACE1-deficient mice. In HEK293T cells, BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation. Biochemical evidence strongly suggested that BACE1 physically associates with channel proteins in a β-subunit-like fashion. Our results establish BACE1 as a physiologically essential constituent of regular M-current function and elucidate a striking new feature of how BACE1 impacts on neuronal activity in the intact and diseased brain. Copyright © 2015 the authors 0270-6474/15/353298-14$15.00/0.

  20. Spike Pattern Structure Influences Synaptic Efficacy Variability under STDP and Synaptic Homeostasis. II: Spike Shuffling Methods on LIF Networks

    Science.gov (United States)

    Bi, Zedong; Zhou, Changsong

    2016-01-01

    Synapses may undergo variable changes during plasticity because of the variability of spike patterns such as temporal stochasticity and spatial randomness. Here, we call the variability of synaptic weight changes during plasticity to be efficacy variability. In this paper, we investigate how four aspects of spike pattern statistics (i.e., synchronous firing, burstiness/regularity, heterogeneity of rates and heterogeneity of cross-correlations) influence the efficacy variability under pair-wise additive spike-timing dependent plasticity (STDP) and synaptic homeostasis (the mean strength of plastic synapses into a neuron is bounded), by implementing spike shuffling methods onto spike patterns self-organized by a network of excitatory and inhibitory leaky integrate-and-fire (LIF) neurons. With the increase of the decay time scale of the inhibitory synaptic currents, the LIF network undergoes a transition from asynchronous state to weak synchronous state and then to synchronous bursting state. We first shuffle these spike patterns using a variety of methods, each designed to evidently change a specific pattern statistics; and then investigate the change of efficacy variability of the synapses under STDP and synaptic homeostasis, when the neurons in the network fire according to the spike patterns before and after being treated by a shuffling method. In this way, we can understand how the change of pattern statistics may cause the change of efficacy variability. Our results are consistent with those of our previous study which implements spike-generating models on converging motifs. We also find that burstiness/regularity is important to determine the efficacy variability under asynchronous states, while heterogeneity of cross-correlations is the main factor to cause efficacy variability when the network moves into synchronous bursting states (the states observed in epilepsy). PMID:27555816

  1. Spike Pattern Structure Influences Synaptic Efficacy Variability Under STDP and Synaptic Homeostasis. II: Spike Shuffling Methods on LIF Networks

    Directory of Open Access Journals (Sweden)

    Zedong Bi

    2016-08-01

    Full Text Available Synapses may undergo variable changes during plasticity because of the variability of spike patterns such as temporal stochasticity and spatial randomness. Here, we call the variability of synaptic weight changes during plasticity to be efficacy variability. In this paper, we investigate how four aspects of spike pattern statistics (i.e., synchronous firing, burstiness/regularity, heterogeneity of rates and heterogeneity of cross-correlations influence the efficacy variability under pair-wise additive spike-timing dependent plasticity (STDP and synaptic homeostasis (the mean strength of plastic synapses into a neuron is bounded, by implementing spike shuffling methods onto spike patterns self-organized by a network of excitatory and inhibitory leaky integrate-and-fire (LIF neurons. With the increase of the decay time scale of the inhibitory synaptic currents, the LIF network undergoes a transition from asynchronous state to weak synchronous state and then to synchronous bursting state. We first shuffle these spike patterns using a variety of methods, each designed to evidently change a specific pattern statistics; and then investigate the change of efficacy variability of the synapses under STDP and synaptic homeostasis, when the neurons in the network fire according to the spike patterns before and after being treated by a shuffling method. In this way, we can understand how the change of pattern statistics may cause the change of efficacy variability. Our results are consistent with those of our previous study which implements spike-generating models on converging motifs. We also find that burstiness/regularity is important to determine the efficacy variability under asynchronous states, while heterogeneity of cross-correlations is the main factor to cause efficacy variability when the network moves into synchronous bursting states (the states observed in epilepsy.

  2. Regulation of phosphorus uptake and utilization: transitioning from current knowledge to practical strategies.

    Science.gov (United States)

    Hasan, Md Mahmudul; Hasan, Md Mainul; Teixeira da Silva, Jaime A; Li, Xuexian

    2016-01-01

    Phosphorus is a poorly bioavailable macronutrient that is essential for crop growth and yield. Overuse of phosphorus fertilizers results in low phosphorus use efficiency (PUE), has serious environmental consequences and accelerates the depletion of phosphorus mineral reserves. It has become extremely challenging to improve PUE while preserving global food supplies and maintaining environmental sustainability. Molecular and genetic analyses have revealed the primary mechanisms of phosphorus uptake and utilization and their relationships to phosphorus transporters, regulators, root architecture, metabolic adaptations, quantitative trait loci, hormonal signaling and microRNA. The ability to improve PUE requires a transition from this knowledge of molecular mechanisms and plant architecture to practical strategies. These could include: i) the use of arbuscular mycorrhizal fungal symbioses for efficient phosphorus mining and uptake; ii) intercropping with suitable crop species to achieve phosphorus activation and mobilization in the soil; and iii) tissue-specific overexpression of homologous genes with advantageous agronomic properties for higher PUE along with breeding for phosphorus-efficient varieties and introgression of key quantitative trait loci. More effort is required to further dissect the mechanisms controlling phosphorus uptake and utilization within plants and provide new insight into the means to efficiently improve PUE.

  3. Current Models for Transcriptional Regulation of Secondary Cell Wall Biosynthesis in Grasses

    Directory of Open Access Journals (Sweden)

    Xiaolan Rao

    2018-04-01

    Full Text Available Secondary cell walls mediate many crucial biological processes in plants including mechanical support, water and nutrient transport and stress management. They also provide an abundant resource of renewable feed, fiber, and fuel. The grass family contains the most important food, forage, and biofuel crops. Understanding the regulatory mechanism of secondary wall formation in grasses is necessary for exploiting these plants for agriculture and industry. Previous research has established a detailed model of the secondary wall regulatory network in the dicot model species Arabidopsis thaliana. Grasses, branching off from the dicot ancestor 140–150 million years ago, display distinct cell wall morphology and composition, suggesting potential for a different secondary wall regulation program from that established for dicots. Recently, combined application of molecular, genetic and bioinformatics approaches have revealed more transcription factors involved in secondary cell wall biosynthesis in grasses. Compared with the dicots, grasses exhibit a relatively conserved but nevertheless divergent transcriptional regulatory program to activate their secondary cell wall development and to coordinate secondary wall biosynthesis with other physiological processes.

  4. Regulation of zebrafish sleep and arousal states: current and prospective approaches

    Directory of Open Access Journals (Sweden)

    Cindy N Chiu

    2013-04-01

    Full Text Available Every day, we shift among various states of sleep and arousal to meet the many demands of our bodies and environment. A central puzzle in neurobiology is how the brain controls these behavioral states, which are essential to an animal’s well-being and survival. Mammalian models have predominated sleep and arousal research, although in the past decade, invertebrate models have made significant contributions to our understanding of the genetic underpinnings of behavioral states. More recently, the zebrafish has emerged as a promising model system for sleep and arousal research. Here we review experimental evidence that the zebrafish, a diurnal vertebrate, exhibits fundamental behavioral and neurochemical characteristics of mammalian sleep and arousal. We also propose how specific advantages of the zebrafish can be harnessed to advance the field. These include tractable genetics to identify and manipulate molecular and cellular regulators of behavioral states, optical transparency to facilitate in vivo observation of neural structure and function, and amenability to high-throughput drug screens to discover novel therapies for neurological disorders.

  5. Recent experimental results of effects of perfluoroalkyl substances in laboratory animals - Relation to current regulations and guidance values.

    Science.gov (United States)

    Lilienthal, Hellmuth; Dieter, Hermann H; Hölzer, Jürgen; Wilhelm, Michael

    2017-06-01

    The detection of perfluoroalkyl substances (PFAS) in surface and drinking water from various countries raised the attention to the presence of these chemicals in environmental probes and led to several regulatory actions to limit exposure in human beings. There was particular concern about perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), due to their former wide-spread use. Recently, several institutions published revisions of former regulatory or recommended maximum concentrations in drinking water and food, which are markedly lower than the former values. The present short overview describes the current regulations for PFAS and compares them with the outcome of several experimental studies in laboratory animals at low-level exposure to PFOA and PFOS. In addition, regulations for short-chain PFAS are presented which, due to lack of toxicological information, are evaluated according to the concepts of Threshold of Toxicological Concern (TTC) or the Health-related Indication Values (HRIV). Copyright © 2017 Elsevier GmbH. All rights reserved.

  6. Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels

    Directory of Open Access Journals (Sweden)

    Caixia Lv

    2016-06-01

    Full Text Available Synaptic ribbons are structures made largely of the protein Ribeye that hold synaptic vesicles near release sites in non-spiking cells in some sensory systems. Here, we introduce frameshift mutations in the two zebrafish genes encoding for Ribeye and thus remove Ribeye protein from neuromast hair cells. Despite Ribeye depletion, vesicles collect around ribbon-like structures that lack electron density, which we term “ghost ribbons.” Ghost ribbons are smaller in size but possess a similar number of smaller vesicles and are poorly localized to synapses and calcium channels. These hair cells exhibit enhanced exocytosis, as measured by capacitance, and recordings from afferent neurons post-synaptic to hair cells show no significant difference in spike rates. Our results suggest that Ribeye makes up most of the synaptic ribbon density in neuromast hair cells and is necessary for proper localization of calcium channels and synaptic ribbons.

  7. Effects of active conductance distribution over dendrites on the synaptic integration in an identified nonspiking interneuron.

    Directory of Open Access Journals (Sweden)

    Akira Takashima

    Full Text Available The synaptic integration in individual central neuron is critically affected by how active conductances are distributed over dendrites. It has been well known that the dendrites of central neurons are richly endowed with voltage- and ligand-regulated ion conductances. Nonspiking interneurons (NSIs, almost exclusively characteristic to arthropod central nervous systems, do not generate action potentials and hence lack voltage-regulated sodium channels, yet having a variety of voltage-regulated potassium conductances on their dendritic membrane including the one similar to the delayed-rectifier type potassium conductance. It remains unknown, however, how the active conductances are distributed over dendrites and how the synaptic integration is affected by those conductances in NSIs and other invertebrate neurons where the cell body is not included in the signal pathway from input synapses to output sites. In the present study, we quantitatively investigated the functional significance of active conductance distribution pattern in the spatio-temporal spread of synaptic potentials over dendrites of an identified NSI in the crayfish central nervous system by computer simulation. We systematically changed the distribution pattern of active conductances in the neuron's multicompartment model and examined how the synaptic potential waveform was affected by each distribution pattern. It was revealed that specific patterns of nonuniform distribution of potassium conductances were consistent, while other patterns were not, with the waveform of compound synaptic potentials recorded physiologically in the major input-output pathway of the cell, suggesting that the possibility of nonuniform distribution of potassium conductances over the dendrite cannot be excluded as well as the possibility of uniform distribution. Local synaptic circuits involving input and output synapses on the same branch or on the same side were found to be potentially affected under

  8. Synaptic Plasticity and NO-cGMP-PKG Signaling Coordinately Regulate ERK-Driven Gene Expression in the Lateral Amygdala and in the Auditory Thalamus Following Pavlovian Fear Conditioning

    Science.gov (United States)

    Ota, Kristie T.; Monsey, Melissa S.; Wu, Melissa S.; Young, Grace J.; Schafe, Glenn E.

    2010-01-01

    We have recently hypothesized that NO-cGMP-PKG signaling in the lateral nucleus of the amygdala (LA) during auditory fear conditioning coordinately regulates ERK-driven transcriptional changes in both auditory thalamic (MGm/PIN) and LA neurons that serve to promote pre- and postsynaptic alterations at thalamo-LA synapses, respectively. In the…

  9. Current Understanding and Future Prospects of Host Selection, Acceptance, Discrimination, and Regulation of Phorid Fly Parasitoids That Attack Ants

    Directory of Open Access Journals (Sweden)

    Kaitlyn A. Mathis

    2012-01-01

    Full Text Available Phorid fly parasitoids (Diptera: Phoridae have evolved a diverse array of cues used to successfully parasitize their ant hosts. Successful parasitism often involves (a host habitat location, (b host location, (c host acceptance, (d host discrimination, and (e host regulation. In this paper we discuss our current understanding of how phorid flies use each of these steps to successfully parasitize ant hosts. We examine the wide variety of strategies and cues used by a multiple species of phorid flies within three separate genera that most commonly parasitize ants (Apocephalus, Pseudacteon, and Neodohrniphora and discuss future directions within this field of study.

  10. Distributed Nonlinear Control with Event-Triggered Communication to Achieve Current-Sharing and Voltage Regulation in DC Microgrids

    DEFF Research Database (Denmark)

    Han, Renke; Meng, Lexuan; Guerrero, Josep M.

    2018-01-01

    combining the state-dependent tolerance with a nonnegative offset. In order to design the event-triggered principle and guarantee the global stability, a generalized dc microgrid model is proposed and proven to be positive definite, based on which Lyapunov-based approach is applied. Furthermore, considering......A distributed nonlinear controller is presented to achieve both accurate current-sharing and voltage regulation simultaneously in dc microgrids considering different line impedances’ effects among converters. Then, an improved event-triggered principle for the controller is introduced through...

  11. cAMP-dependent insulin modulation of synaptic inhibition in neurons of the dorsal motor nucleus of the vagus is altered in diabetic mice

    Science.gov (United States)

    Blake, Camille B.

    2014-01-01

    Pathologies in which insulin is dysregulated, including diabetes, can disrupt central vagal circuitry, leading to gastrointestinal and other autonomic dysfunction. Insulin affects whole body metabolism through central mechanisms and is transported into the brain stem dorsal motor nucleus of the vagus (DMV) and nucleus tractus solitarius (NTS), which mediate parasympathetic visceral regulation. The NTS receives viscerosensory vagal input and projects heavily to the DMV, which supplies parasympathetic vagal motor output. Normally, insulin inhibits synaptic excitation of DMV neurons, with no effect on synaptic inhibition. Modulation of synaptic inhibition in DMV, however, is often sensitive to cAMP-dependent mechanisms. We hypothesized that an effect of insulin on GABAergic synaptic transmission may be uncovered by elevating resting cAMP levels in GABAergic terminals. We used whole cell patch-clamp recordings in brain stem slices from control and diabetic mice to identify insulin effects on inhibitory neurotransmission in the DMV in the presence of forskolin to elevate cAMP levels. In the presence of forskolin, insulin decreased the frequency of inhibitory postsynaptic currents (IPSCs) and the paired-pulse ratio of evoked IPSCs in DMV neurons from control mice. This effect was blocked by brefeldin-A, a Golgi-disrupting agent, or indinavir, a GLUT4 blocker, indicating that protein trafficking and glucose transport were involved. In streptozotocin-treated, diabetic mice, insulin did not affect IPSCs in DMV neurons in the presence of forskolin. Results suggest an impairment of cAMP-induced insulin effects on GABA release in the DMV, which likely involves disrupted protein trafficking in diabetic mice. These findings provide insight into mechanisms underlying vagal dysregulation associated with diabetes. PMID:24990858

  12. 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.

  13. Coexistence of Multiple Types of Synaptic Plasticity in Individual Hippocampal CA1 Pyramidal Neurons.

    Science.gov (United States)

    Edelmann, Elke; Cepeda-Prado, Efrain; Leßmann, Volkmar

    2017-01-01

    brain. We hypothesize that resolving the subcellular location of t-LTP and t-LTD mechanisms that are regulated by distinct neuromodulator systems will be essential to reach a more cohesive understanding of synaptic plasticity in memory formation.

  14. The Hypoxia Mimetic Protocatechuic Acid Ethyl Ester Inhibits Synaptic Signaling and Plasticity in the Rat Hippocampus.

    Science.gov (United States)

    Lanigan, Sinead M; O'Connor, John J

    2018-01-15

    During hypoxia a number of physiological changes occur within neurons including the stabilization of hypoxia-inducible factors (HIFs). The activity of these proteins is regulated by O 2 , Fe 2+ , 2-OG and ascorbate-dependant hydroxylases which contain prolyl-4-hydroxylase domains (PHDs). PHD inhibitors have been widely used and have been shown to have a preconditioning and protective effect against a later and more severe hypoxic insult. In this study we have investigated the neuroprotective effects of the PHD inhibitor, protocatechuic acid ethyl ester (ethyl 3,4, dihydroxybenzoate: EDHB), as well as its effects on synaptic transmission and plasticity in the rat hippocampus using electrophysiological techniques. We report for the first time, an acute concentration-dependent and reversible inhibitory effect of EDHB (10-100 μM) on synaptic transmission in the dentate gyrus but not Cornu Ammonis 1 (CA1) region which does not affect cell viability. This effect was attenuated through the application of the NMDA or GABA A receptor antagonists, AP-5 and picrotoxin in the dentate gyrus. There were no changes in the ratio of paired responses after EDHB application suggesting a post-synaptic mechanism of action. EDHB (100 μM), was found to inhibit synaptic plasticity in both the dentate gyrus and CA1 regions. Application of exogenous Fe 2+ (100 μM) or digoxin (100 nM) did not reverse EDHB's inhibitory effect on synaptic transmission or plasticity in both regions, suggesting that its effects may be HIF-independent. These results highlight a novel modulatory role for the PHD inhibitor EDHB in hippocampal synaptic transmission and plasticity. A novel post-synaptic mechanism of action may be involved, possibly involving NMDA and GABA A receptor activation. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Bi-directional astrocytic regulation of neuronal activity within a network

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    Susan Yu Gordleeva

    2012-11-01

    Full Text Available The concept of a tripartite synapse holds that astrocytes can affect both the pre- and postsynaptic compartments through the Ca2+-dependent release of gliotransmitters. Because astrocytic Ca2+ transients usually last for a few seconds, we assumed that astrocytic regulation of synaptic transmission may also occur on the scale of seconds. Here, we considered the basic physiological functions of tripartite synapses and investigated astrocytic regulation at the level of neural network activity. The firing dynamics of individual neurons in a spontaneous firing network was described by the Hodgkin-Huxley model. The neurons received excitatory synaptic input driven by the Poisson spike train with variable frequency. The mean field concentration of the released neurotransmitter was used to describe the presynaptic dynamics. The amplitudes of the excitatory postsynaptic currents (PSCs obeyed the gamma distribution law. In our model, astrocytes depressed the presynaptic release and enhanced the postsynaptic currents. As a result, low frequency synaptic input was suppressed while high frequency input was amplified. The analysis of the neuron spiking frequency as an indicator of network activity revealed that tripartite synaptic transmission dramatically changed the local network operation compared to bipartite synapses. Specifically, the astrocytes supported homeostatic regulation of the network activity by increasing or decreasing firing of the neurons. Thus, the astrocyte activation may modulate a transition of neural network into bistable regime of activity with two stable firing levels and spontaneous transitions between them.

  16. Current research, regulation, risk, analytical methods and monitoring results for nicarbazin in chicken meat: A perspective review.

    Science.gov (United States)

    Bacila, Danniele Miranda; Feddern, Vivian; Mafra, Luciana Igarashi; Scheuermann, Gerson Neudí; Molognoni, Luciano; Daguer, Heitor

    2017-09-01

    This review presents up-to-date information about current research on nicarbazin, one of the most used anticoccidials in poultry production. The focus is to elucidate regulation concerning nicarbazin, limits for its residues in food, how maximum residue limits in different countries are calculated regarding edible chicken tissues and the possible implications in human health. Analytical methods to extract and quantify this residue, expressed as dinitrocarbanilide (DNC) are presented and discussed, including qualitative screening and quantitative/confirmatory analytical methods. Monitoring results and occurrence of DNC residues in chicken meat are discussed. Additionally, the causes of eventual chicken meat contamination and possible solutions to reduce or eliminate DNC residue in tissues are also presented. The paper concludes with perspectives, the current state of DNC residue analysis and suggestions for future research, especially considering the gap in the study of residue recycling effect due to continuous chicken litter use. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Two aspects of ASIC function: Synaptic plasticity and neuronal injury.

    Science.gov (United States)

    Huang, Yan; Jiang, Nan; Li, Jun; Ji, Yong-Hua; Xiong, Zhi-Gang; Zha, Xiang-ming

    2015-07-01

    Extracellular brain pH fluctuates in both physiological and disease conditions. The main postsynaptic proton receptor is the acid-sensing ion channels (ASICs). During the past decade, much progress has been made on protons, ASICs, and neurological disease. This review summarizes the recent progress on synaptic role of protons and our current understanding of how ASICs contribute to various types of neuronal injury in the brain. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Synaptic plasticity in health and disease: introduction and overview

    Science.gov (United States)

    Bliss, T. V. P.; Collingridge, G. L.; Morris, R. G. M.

    2014-01-01

    We summarize the reviews and research papers submitted by speakers at a discussion meeting on Synaptic Plasticity in Health and Disease held at the Royal Society, London on 2–3 December 2013, and a subsequent satellite meeting convened at the Royal Society/Kavli Centre at Chicheley Hall on 4–5 December 2013. Together, these contributions give an overview of current research and controversies in a vibrant branch of neuroscience with important implications for the understanding of many forms of learning and memory, and a wide spectrum of neurological and cognitive disorders. PMID:24298133

  19. CURRENT SHEET REGULATION OF SOLAR NEAR-RELATIVISTIC ELECTRON INJECTION HISTORIES

    Energy Technology Data Exchange (ETDEWEB)

    Agueda, N.; Sanahuja, B. [Departament d' Astronomia i Meteorologia, Institut de Ciencies del Cosmos, Universitat de Barcelona (Spain); Vainio, R. [Department of Physics, University of Helsinki (Finland); Dalla, S. [Jeremiah Horrocks Institute, University of Central Lancashire (United Kingdom); Lario, D. [Applied Physics Laboratory, Johns Hopkins University (United States)

    2013-03-10

    We present a sample of three large near-relativistic (>50 keV) electron events observed in 2001 by both the ACE and the Ulysses spacecraft, when Ulysses was at high-northern latitudes (>60 Degree-Sign ) and close to 2 AU. Despite the large latitudinal distance between the two spacecraft, electrons injected near the Sun reached both heliospheric locations. All three events were associated with large solar flares, strong decametric type II radio bursts and accompanied by wide (>212 Degree-Sign ) and fast (>1400 km s{sup -1}) coronal mass ejections (CMEs). We use advanced interplanetary transport simulations and make use of the directional intensities observed in situ by the spacecraft to infer the electron injection profile close to the Sun and the interplanetary transport conditions at both low and high latitudes. For the three selected events, we find similar interplanetary transport conditions at different heliolatitudes for a given event, with values of the mean free path ranging from 0.04 AU to 0.27 AU. We find differences in the injection profiles inferred for each spacecraft. We investigate the role that sector boundaries of the heliospheric current sheet (HCS) have on determining the characteristics of the electron injection profiles. Extended injection profiles, associated with coronal shocks, are found if the magnetic footpoints of the spacecraft lay in the same magnetic sector as the associated flare, while intermittent sparse injection episodes appear when the spacecraft footpoints are in the opposite sector or a wrap in the HCS bounded the CME structure.

  20. AMP kinase regulates K-ATP currents evoked by NMDA receptor stimulation in rat subthalamic nucleus neurons.

    Science.gov (United States)

    Shen, K-Z; Yakhnitsa, V; Munhall, A C; Johnson, S W

    2014-08-22

    Our lab recently showed that N-methyl-D-aspartate (NMDA) evokes ATP-sensitive K(+) (K-ATP) currents in subthalamic nucleus (STN) neurons in slices of the rat brain. Both K-ATP channels and 5'-adenosine monophosphate-activated protein kinase (AMPK) are considered cellular energy sensors because their activities are influenced by the phosphorylation state of adenosine nucleotides. Moreover, AMPK has been shown to regulate K-ATP function in a variety of tissues including pancreas, cardiac myocytes, and hypothalamus. We used whole-cell patch clamp recordings to study the effect of AMPK activation on K-ATP channel function in STN neurons in slices of the rat brain. We found that bath or intracellular application of the AMPK activators A769662 and PT1 augmented tolbutamide-sensitive K-ATP currents evoked by NMDA receptor stimulation. The effect of AMPK activators was blocked by the AMPK inhibitor dorsomorphin (compound C), and by STO609, an inhibitor of the upstream AMPK activator CaMKKβ. AMPK augmentation of NMDA-induced K-ATP current was also blocked by intracellular BAPTA and by inhibitors of nitric oxide synthase and guanylyl cyclase. However, A769662 did not augment currents evoked by the K-ATP channel opener diazoxide. In the presence of NMDA, A769662 inhibited depolarizing plateau potentials and burst firing, both of which could be antagonized by tolbutamide or dorsomorphin. These studies show that AMPK augments NMDA-induced K-ATP currents by a Ca(2+)-dependent process that involves nitric oxide and cGMP. By augmenting K-ATP currents, AMPK activation would be expected to dampen the excitatory effect of glutamate-mediated transmission in the STN. Published by Elsevier Ltd.

  1. Heterosynaptic Plasticity Prevents Runaway Synaptic Dynamics

    Science.gov (United States)

    Chen, Jen-Yung; Lonjers, Peter; Lee, Christopher; Chistiakova, Marina; Volgushev, Maxim

    2013-01-01

    Spike timing-dependent plasticity (STDP) and other conventional Hebbian-type plasticity rules are prone to produce runaway dynamics of synaptic weights. Once potentiated, a synapse would have higher probability to lead to spikes and thus to be further potentiated, but once depressed, a synapse would tend to be further depressed. The runaway synaptic dynamics can be prevented by precisely balancing STDP rules for potentiation and depression; however, experimental evidence shows a great variety of potentiation and depression windows and magnitudes. Here we show that modifications of synapses to layer 2/3 pyramidal neurons from rat visual and auditory cortices in slices can be induced by intracellular tetanization: bursts of postsynaptic spikes without presynaptic stimulation. Induction of these heterosynaptic changes depended on the rise of intracellular calcium, and their direction and magnitude correlated with initial state of release mechanisms. We suggest that this type of plasticity serves as a mechanism that stabilizes the distribution of synaptic weights and prevents their runaway dynamics. To test this hypothesis, we develop a cortical neuron model implementing both homosynaptic (STDP) and heterosynaptic plasticity with properties matching the experimental data. We find that heterosynaptic plasticity effectively prevented runaway dynamics for the tested range of STDP and input parameters. Synaptic weights, although shifted from the original, remained normally distributed and nonsaturated. Our study presents a biophysically constrained model of how the interaction of different forms of plasticity—Hebbian and heterosynaptic—may prevent runaway synaptic dynamics and keep synaptic weights unsaturated and thus capable of further plastic changes and formation of new memories. PMID:24089497

  2. Epsin 1 Promotes Synaptic Growth by Enhancing BMP Signal Levels in Motoneuron Nuclei.

    Directory of Open Access Journals (Sweden)

    Phillip A Vanlandingham

    Full Text Available Bone morphogenetic protein (BMP retrograde signaling is crucial for neuronal development and synaptic plasticity. However, how the BMP effector phospho-Mother against decapentaplegic (pMad is processed following receptor activation remains poorly understood. Here we show that Drosophila Epsin1/Liquid facets (Lqf positively regulates synaptic growth through post-endocytotic processing of pMad signaling complex. Lqf and the BMP receptor Wishful thinking (Wit interact genetically and biochemically. lqf loss of function (LOF reduces bouton number whereas overexpression of lqf stimulates bouton growth. Lqf-stimulated synaptic overgrowth is suppressed by genetic reduction of wit. Further, synaptic pMad fails to accumulate inside the motoneuron nuclei in lqf mutants and lqf suppresses synaptic overgrowth in spinster (spin mutants with enhanced BMP signaling by reducing accumulation of nuclear pMad. Interestingly, lqf mutations reduce nuclear pMad levels without causing an apparent blockage of axonal transport itself. Finally, overexpression of Lqf significantly increases the number of multivesicular bodies (MVBs in the synapse whereas lqf LOF reduces MVB formation, indicating that Lqf may function in signaling endosome recycling or maturation. Based on these observations, we propose that Lqf plays a novel endosomal role to ensure efficient retrograde transport of BMP signaling endosomes into motoneuron nuclei.

  3. 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.

  4. Synaptic network activity induces neuronal differentiation of adult hippocampal precursor cells through BDNF signaling

    Directory of Open Access Journals (Sweden)

    Harish Babu

    2009-09-01

    Full Text Available Adult hippocampal neurogenesis is regulated by activity. But how do neural precursor cells in the hippocampus respond to surrounding network activity and translate increased neural activity into a developmental program? Here we show that long-term potential (LTP-like synaptic activity within a cellular network of mature hippocampal neurons promotes neuronal differentiation of newly generated cells. In co-cultures of precursor cells with primary hippocampal neurons, LTP-like synaptic plasticity induced by addition of glycine in Mg2+-free media for 5 min, produced synchronous network activity and subsequently increased synaptic strength between neurons. Furthermore, this synchronous network activity led to a significant increase in neuronal differentiation from the co-cultured neural precursor cells. When applied directly to precursor cells, glycine and Mg2+-free solution did not induce neuronal differentiation. Synaptic plasticity-induced neuronal differentiation of precursor cells was observed in the presence of GABAergic neurotransmission blockers but was dependent on NMDA-mediated Ca2+ influx. Most importantly, neuronal differentiation required the release of brain-derived neurotrophic factor (BDNF from the underlying substrate hippocampal neurons as well as TrkB receptor phosphorylation in precursor cells. This suggests that activity-dependent stem cell differentiation within the hippocampal network is mediated via synaptically evoked BDNF signaling.

  5. The Krebs Cycle Enzyme Isocitrate Dehydrogenase 3A Couples Mitochondrial Metabolism to Synaptic Transmission.

    Science.gov (United States)

    Ugur, Berrak; Bao, Huan; Stawarski, Michal; Duraine, Lita R; Zuo, Zhongyuan; Lin, Yong Qi; Neely, G Gregory; Macleod, Gregory T; Chapman, Edwin R; Bellen, Hugo J

    2017-12-26

    Neurotransmission is a tightly regulated Ca 2+ -dependent process. Upon Ca 2+ influx, Synaptotagmin1 (Syt1) promotes fusion of synaptic vesicles (SVs) with the plasma membrane. This requires regulation at multiple levels, but the role of metabolites in SV release is unclear. Here, we uncover a role for isocitrate dehydrogenase 3a (idh3a), a Krebs cycle enzyme, in neurotransmission. Loss of idh3a leads to a reduction of the metabolite, alpha-ketoglutarate (αKG), causing defects in synaptic transmission similar to the loss of syt1. Supplementing idh3a flies with αKG suppresses these defects through an ATP or neurotransmitter-independent mechanism. Indeed, αKG, but not glutamate, enhances Syt1-dependent fusion in a reconstitution assay. αKG promotes interaction between the C2-domains of Syt1 and phospholipids. The data reveal conserved metabolic regulation of synaptic transmission via αKG. Our studies provide a synaptic role for αKG, a metabolite that has been proposed as a treatment for aging and neurodegenerative disorders. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. Nuclear Calcium Signaling Induces Expression of the Synaptic Organizers Lrrtm1 and Lrrtm2*

    Science.gov (United States)

    Hayer, Stefanie N.; Bading, Hilmar

    2015-01-01

    Calcium transients in the cell nucleus evoked by synaptic activity in hippocampal neurons function as a signaling end point in synapse-to-nucleus communication. As an important regulator of neuronal gene expression, nuclear calcium is involved in the conversion of synaptic stimuli into functional and structural changes of neurons. Here we identify two synaptic organizers, Lrrtm1 and Lrrtm2, as targets of nuclear calcium signaling. Expression of both Lrrtm1 and Lrrtm2 increased in a synaptic NMDA receptor- and nuclear calcium-dependent manner in hippocampal neurons within 2–4 h after the induction of action potential bursting. Induction of Lrrtm1 and Lrrtm2 occurred independently of the need for new protein synthesis and required calcium/calmodulin-dependent protein kinases and the nuclear calcium signaling target CREB-binding protein. Analysis of reporter gene constructs revealed a functional cAMP response element in the proximal promoter of Lrrtm2, indicating that at least Lrrtm2 is regulated by the classical nuclear Ca2+/calmodulin-dependent protein kinase IV-CREB/CREB-binding protein pathway. These results suggest that one mechanism by which nuclear calcium signaling controls neuronal network function is by regulating the expression of Lrrtm1 and Lrrtm2. PMID:25527504

  7. Nuclear calcium signaling induces expression of the synaptic organizers Lrrtm1 and Lrrtm2.

    Science.gov (United States)

    Hayer, Stefanie N; Bading, Hilmar

    2015-02-27

    Calcium transients in the cell nucleus evoked by synaptic activity in hippocampal neurons function as a signaling end point in synapse-to-nucleus communication. As an important regulator of neuronal gene expression, nuclear calcium is involved in the conversion of synaptic stimuli into functional and structural changes of neurons. Here we identify two synaptic organizers, Lrrtm1 and Lrrtm2, as targets of nuclear calcium signaling. Expression of both Lrrtm1 and Lrrtm2 increased in a synaptic NMDA receptor- and nuclear calcium-dependent manner in hippocampal neurons within 2-4 h after the induction of action potential bursting. Induction of Lrrtm1 and Lrrtm2 occurred independently of the need for new protein synthesis and required calcium/calmodulin-dependent protein kinases and the nuclear calcium signaling target CREB-binding protein. Analysis of reporter gene constructs revealed a functional cAMP response element in the proximal promoter of Lrrtm2, indicating that at least Lrrtm2 is regulated by the classical nuclear Ca(2+)/calmodulin-dependent protein kinase IV-CREB/CREB-binding protein pathway. These results suggest that one mechanism by which nuclear calcium signaling controls neuronal network function is by regulating the expression of Lrrtm1 and Lrrtm2. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Deciphering resting microglial morphology and process motility from a synaptic prospect

    Directory of Open Access Journals (Sweden)

    Ines eHristovska

    2016-01-01

    Full Text Available Microglia, the resident immune cells of the central nervous system (CNS, were traditionally believed to be set into action only in case of injury or disease. Accordingly, microglia were assumed to be inactive or resting in the healthy brain. However, recent studies revealed that microglia carry out active tissue sampling in the intact brain by extending and retracting their ramified processes while periodically contacting synapses. Microglial morphology and motility as well as the frequency and duration of physical contacts with synaptic elements were found to be modulated by neuronal activity, sensory experience and neurotransmission; however findings have not been straightforward. Microglial cells are the most morphologically plastic element of the CNS. This unique feature confers them the possibility to locally sense activity, and to respond adequately by establishing synaptic contacts to regulate synaptic inputs by the secretion of signaling molecules. Indeed, microglial cells can hold new roles as critical players in maintaining brain homeostasis and regulating synaptic number, maturation and plasticity. For this reason, a better characterization of microglial cells and cues mediating neuron-to-microglia communication under physiological conditions may help advance our understanding of the microglial behavior and its regulation in the healthy brain. This review highlights recent findings on the instructive role of neuronal activity on microglial motility and microglia-synapse interactions, focusing on the main transmitters involved in this communication and including newly described communication at the tripartite synapse.

  9. Addiction-like Synaptic Impairments in Diet-Induced Obesity.

    Science.gov (United States)

    Brown, Robyn Mary; Kupchik, Yonatan Michael; Spencer, Sade; Garcia-Keller, Constanza; Spanswick, David C; Lawrence, Andrew John; Simonds, Stephanie Elise; Schwartz, Danielle Joy; Jordan, Kelsey Ann; Jhou, Thomas Clayton; Kalivas, Peter William

    2017-05-01

    There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core considered hallmarks of addiction. Sprague Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed ratio 1, 3, and 5 and progressive ratio schedules. Subsequently, nucleus accumbens brain slices were prepared, and we tested for changes in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate currents and the ability to exhibit long-term depression. We found that propensity to develop DIO is linked to deficits in the ability to induce long-term depression in the nucleus accumbens, as well as increased potentiation at these synapses as measured by AMPA/N-methyl-D-aspartate currents. Consistent with these impairments, we observed addictive-like behavior in DIO-prone rats, including 1) heightened motivation for palatable food; 2) excessive intake; and 3) increased food seeking when food was unavailable. Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction. Copyright © 2016 Society of Biological Psychiatry. All rights reserved.

  10. The stressed cytoskeleton: How actin dynamics can shape stress-related consequences on synaptic plasticity and complex behavior.

    Science.gov (United States)

    van der Kooij, Michael A; Masana, Mercè; Rust, Marco B; Müller, Marianne B

    2016-03-01

    Stress alters synaptic plasticity but the molecular and cellular mechanisms through which environmental stimuli modulate synaptic function remain to be elucidated. Actin filaments are the major structural component of synapses and their rearrangements by actin-binding proteins (ABPs) are critical for fine-tuning synaptic plasticity. Accumulating evidence suggests that some ABPs are specifically regulated by stress and stress-related effectors such as glucocorticoids and corticotropin releasing hormone. ABPs may thus be central in stress-induced perturbations at the level of synaptic plasticity, leading to impairments in behavioral domains including cognitive performance and social behavior. Identified stress-responsive ABPs include: tumor suppressor down-regulated in renal cell carcinoma 1 (DRR1), ADF/cofilin, LIMK1, caldesmon and myosin VI. Here we discuss how stress may impact synaptic plasticity through specific effects on these ABPs and how these adaptations might modulate complex behavior, predisposing individuals at genetic risk for the development of mental dysfunctions. We argue that a precise understanding of the mechanisms underlying stress-associated changes in synaptic function could stimulate the development of innovative treatment strategies against stress-related mental disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Different effects of bisphenol-A on memory behavior and synaptic modification in intact and estrogen-deprived female mice.

    Science.gov (United States)

    Xu, Xiaohong; Gu, Ting; Shen, Qiaoqiao

    2015-03-01

    Bisphenol-A (BPA) has the capability of interfering with the effects of estrogens on modulating brain function. The purpose of this study was to investigate the effects of BPA on memory and synaptic modification in the hippocampus of female mice under different levels of cycling estrogen. BPA exposure (40, 400 μg/kg/day) for 8 weeks did not affect spatial memory and passive avoidance task of gonadally intact mice but improved ovariectomy (Ovx)-induced memory impairment, whereas co-exposure of BPA with estradiol benzoate (EB) diminished the rescue effect of EB on memory behavior of Ovx mice. The results of morphometric measurement showed that BPA positively modified the synaptic interface structure and increased the synaptic density of CA1 pyramidal cell in the hippocampus of Ovx females, but inhibited the enhancement of EB on synaptic modification and synaptogenesis of Ovx mice. Furthermore, BPA up-regulated synaptic proteins synapsin I and PSD-95 and NMDA receptor NR2B but inhibited EB-induced increase in PSD-95 and NR2B in the hippocampus of Ovx mice. These results suggest that BPA interfered with normal hormonal regulation in synaptic plasticity and memory of female mice as a potent estrogen mimetic and as a disruptor of estrogen under various concentrations of cycling estrogen. © 2014 International Society for Neurochemistry.

  12. Effect of Neuroinflammation on Synaptic Organization and Function in the Developing Brain: Implications for Neurodevelopmental and Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Amin Mottahedin

    2017-07-01

    Full Text Available The brain is a plastic organ where both the intrinsic CNS milieu and extrinsic cues play important roles in shaping and wiring neural connections. The perinatal period constitutes a critical time in central nervous system development with extensive refinement of neural connections, which are highly sensitive to fetal and neonatal compromise, such as inflammatory challenges. Emerging evidence suggests that inflammatory cells in the brain such as microglia and astrocytes are pivotal in regulating synaptic structure and function. In this article, we will review the role of glia cells in synaptic physiology and pathophysiology, including microglia-mediated elimination of synapses. We propose that activation of the immune system dynamically affects synaptic organization and function in the developing brain. We will discuss the role of neuroinflammation in altered synaptic plasticity following perinatal inflammatory challenges and potential implications for neurodevelopmental and neurodegenerative disorders.

  13. Prevention of Synaptic Alterations and Neurotoxic Effects of PAMAM Dendrimers by Surface Functionalization

    Directory of Open Access Journals (Sweden)

    Felipe Vidal

    2017-12-01

    Full Text Available One of the most studied nanocarriers for drug delivery are polyamidoamine (PAMAM dendrimers. However, the alterations produced by PAMAM dendrimers in neuronal function have not been thoroughly investigated, and important aspects such as effects on synaptic transmission remain unexplored. We focused on the neuronal activity disruption induced by dendrimers and the possibility to prevent these effects by surface chemical modifications. Therefore, we studied the effects of fourth generation PAMAM with unmodified positively charged surface (G4 in hippocampal neurons, and compared the results with dendrimers functionalized in 25% of their surface groups with folate (PFO25 and polyethylene glycol (PPEG25. G4 dendrimers significantly reduced cell viability at 1 µM, which was attenuated by both chemical modifications, PPEG25 being the less cytotoxic. Patch clamp recordings demonstrated that G4 induced a 7.5-fold increment in capacitive currents as a measure of membrane permeability. Moreover, treatment with this dendrimer increased intracellular Ca2+ by 8-fold with a complete disruption of transients pattern, having as consequence that G4 treatment increased the synaptic vesicle release and frequency of synaptic events by 2.4- and 3-fold, respectively. PFO25 and PPEG25 treatments did not alter membrane permeability, total Ca2+ intake, synaptic vesicle release or synaptic activity frequency. These results demonstrate that cationic G4 dendrimers have neurotoxic effects and induce alterations in normal synaptic activity, which are generated by the augmentation of membrane permeability and a subsequent intracellular Ca2+ increase. Interestingly, these toxic effects and synaptic alterations are prevented by the modification of 25% of PAMAM surface with either folate or polyethylene glycol.

  14. Nanoscale Molecular Reorganization of the Inhibitory Postsynaptic Density Is a Determinant of GABAergic Synaptic Potentiation.

    Science.gov (United States)

    Pennacchietti, Francesca; Vascon, Sebastiano; Nieus, Thierry; Rosillo, Christian; Das, Sabyasachi; Tyagarajan, Shiva K; Diaspro, Alberto; Del Bue, Alessio; Petrini, Enrica Maria; Barberis, Andrea; Cella Zanacchi, Francesca

    2017-02-15

    Gephyrin is a key scaffold protein mediating the anchoring of GABAA receptors at inhibitory synapses. Here, we exploited superresolution techniques combined with proximity-based clustering analysis and model simulations to investigate the single-molecule gephyrin reorganization during plasticity of inhibitory synapses in mouse hippocampal cultured neurons. This approach revealed that, during the expression of inhibitory LTP, the increase of gephyrin density at postsynaptic sites is associated with the promoted formation of gephyrin nanodomains. We demonstrate that the gephyrin rearrangement in nanodomains stabilizes the amplitude of postsynaptic currents, indicating that, in addition to the number of synaptic GABAA receptors, the nanoscale distribution of GABAA receptors in the postsynaptic area is a crucial determinant for the expression of inhibitory synaptic plasticity. In addition, the methodology implemented here clears the way to the application of the graph-based theory to single-molecule data for the description and quantification of the spatial organization of the synapse at the single-molecule level. SIGNIFICANCE STATEMENT The mechanisms of inhibitory synaptic plasticity are poorly understood, mainly because the size of the synapse is below the diffraction limit, thus reducing the effectiveness of conventional optical and imaging techniques. Here, we exploited superresolution approaches combined with clustering analysis to study at unprecedented resolution the distribution of the inhibitory scaffold protein gephyrin in response to protocols inducing LTP of inhibitory synaptic responses (iLTP). We found that, during the expression of iLTP, the increase of synaptic gephyrin is associated with the fragmentation of gephyrin in subsynaptic nanodomains. We demonstrate that such synaptic gephyrin nanodomains stabilize the amplitude of inhibitory postsynaptic responses, thus identifying the nanoscale gephyrin rearrangement as a key determinant for inhibitory

  15. Synaptic transistor with a reversible and analog conductance modulation using a Pt/HfOx/n-IGZO memcapacitor.

    Science.gov (United States)

    Yang, Paul; Jun Kim, Hyung; Zheng, Hong; Won Beom, Geon; Park, Jong-Sung; Jung Kang, Chi; Yoon, Tae-Sik

    2017-06-02

    A synaptic transistor emulating the biological synaptic motion is demonstrated using the memcapacitance characteristics in a Pt/HfOx/n-indium-gallium-zinc-oxide (IGZO) memcapacitor. First, the metal-oxide-semiconductor (MOS) capacitor with Pt/HfOx/n-IGZO structure exhibits analog, polarity-dependent, and reversible memcapacitance in capacitance-voltage (C-V), capacitance-time (C-t), and voltage-pulse measurements. When a positive voltage is applied repeatedly to the Pt electrode, the accumulation capacitance increases gradually and sequentially. The depletion capacitance also increases consequently. The capacitances are restored by repeatedly applying a negative voltage, confirming the reversible memcapacitance. The analog and reversible memcapacitance emulates the potentiation and depression synaptic motions. The synaptic thin-film transistor (TFT) with this memcapacitor also shows the synaptic motion with gradually increasing drain current by repeatedly applying the positive gate and drain voltages and reversibly decreasing one by applying the negative voltages, representing synaptic weight modulation. The reversible and analog conductance change in the transistor at both the voltage sweep and pulse operations is obtained through the memcapacitance and threshold voltage shift at the same time. These results demonstrate the synaptic transistor operations with a MOS memcapacitor gate stack consisting of Pt/HfOx/n-IGZO.

  16. Synaptic transistor with a reversible and analog conductance modulation using a Pt/HfOx/n-IGZO memcapacitor

    Science.gov (United States)

    Yang, Paul; Kim, Hyung Jun; Zheng, Hong; Beom, Geon Won; Park, Jong-Sung; Kang, Chi Jung; Yoon, Tae-Sik

    2017-06-01

    A synaptic transistor emulating the biological synaptic motion is demonstrated using the memcapacitance characteristics in a Pt/HfOx/n-indium-gallium-zinc-oxide (IGZO) memcapacitor. First, the metal-oxide-semiconductor (MOS) capacitor with Pt/HfOx/n-IGZO structure exhibits analog, polarity-dependent, and reversible memcapacitance in capacitance-voltage (C-V), capacitance-time (C-t), and voltage-pulse measurements. When a positive voltage is applied repeatedly to the Pt electrode, the accumulation capacitance increases gradually and sequentially. The depletion capacitance also increases consequently. The capacitances are restored by repeatedly applying a negative voltage, confirming the reversible memcapacitance. The analog and reversible memcapacitance emulates the potentiation and depression synaptic motions. The synaptic thin-film transistor (TFT) with this memcapacitor also shows the synaptic motion with gradually increasing drain current by repeatedly applying the positive gate and drain voltages and reversibly decreasing one by applying the negative voltages, representing synaptic weight modulation. The reversible and analog conductance change in the transistor at both the voltage sweep and pulse operations is obtained through the memcapacitance and threshold voltage shift at the same time. These results demonstrate the synaptic transistor operations with a MOS memcapacitor gate stack consisting of Pt/HfOx/n-IGZO.

  17. Research progress on the roles of microRNAs in governing synaptic plasticity, learning and memory.

    Science.gov (United States)

    Wei, Chang-Wei; Luo, Ting; Zou, Shan-Shan; Wu, An-Shi

    2017-11-01

    The importance of non-coding RNA involved in biological processes has become apparent in recent years and the mechanism of transcriptional regulation has also been identified. MicroRNAs (miRNAs) represent a class of small regulatory non-coding RNAs of 22bp in length that mediate gene silencing by identifying specific sequences in the target messenger RNAs (mRNAs). Many miRNAs are highly expressed in the central nervous system in a spatially and temporally controlled manner in normal physiology, as well as in certain pathological conditions. There is growing evidence that a considerable number of specific miRNAs play important roles in synaptic plasticity, learning and memory function. In addition, the dysfunction of these molecules may also contribute to the etiology of several neurodegenerative diseases. Here we provide an overview of the current literatures, which support non-coding RNA-mediated gene function regulation represents an important but underappreciated, layer of epigenetic control that facilitates learning and memory functions. Copyright © 2017. Published by Elsevier Inc.

  18. Input significance analysis: feature selection through synaptic ...

    African Journals Online (AJOL)

    This work is interested in ISA methods that can manipulate synaptic weights namely. Connection Weights (CW) and Garson's Algorithm (GA) and the classifier selected is. Evolving Fuzzy Neural Networks (EFuNNs). Firstly, it test FS method on a dataset selected from the UCI Machine Learning Repository and executed in an ...

  19. 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.

  20. P2X Receptors and Synaptic Plasticity

    Czech Academy of Sciences Publication Activity Database

    Pankratov, Y.; Lalo, U.; Krishtal, A.; Verkhratsky, Alexei

    2009-01-01

    Roč. 158, č. 1 (2009), s. 137-148 ISSN 0306-4522 Institutional research plan: CEZ:AV0Z50390512 Keywords : ATP * P2X receptors * synaptic plasticity Subject RIV: FH - Neurology Impact factor: 3.292, year: 2009

  1. An assessment of the fire protection requirements throughout a NPP life related to current IAEA regulations and American, Canadian and UE regulations

    International Nuclear Information System (INIS)

    Branzeu, N.; Necula, D.; Badea, M.; Teodorescu, D.; Peteu, M.

    2006-01-01

    Statistics on fires has surprisingly shown that the frequency of fires in a nuclear power plant are as high as in the conventional industrial units. The analyses on fires occurred in a NPP need to consider both their well-known severe damages and the nuclear consequences. In 1975 a severe fire occurred in BROWNS FERRY NPP due to the ignition of the polyurethane foam used in the electric cable penetration sealings. The fire propagated to the cable channels and damaged over 1600 cables. The fire event revealed important shortcomings in the fire protection design and procedures. The fire represented a crucial event that changed fundamentally the fire protection regulation in the United States nuclear industry. The fire protection programs, standards and guides currently applied, have been developed on basis of this fire analysis and gained conclusions/experience. The purpose of the article is to be a short presentation of the fire protection requirements for all NPP life stages (i.e. design, construction, commissioning, operation and decommissioning), including the most recent issues of the standards, codes, guides and regulations in US, Canada, IAEA and some European countries. Such documentation represented the main technical support in establishing the national fire protection standard design regarding all the stages of a CANDU-6 NPP life, all the types of operational NPPs, particularly for Cernavoda NPP Unit 1 and Unit 2 (now in an advanced stage of construction). In order to satisfy the requirements provided by this documentation, as practically as possible, a list of analyses and fire protection improvement measures for Cernavoda NPP is presented. (authors)

  2. Basic mechanisms for recognition and transport of synaptic cargos

    NARCIS (Netherlands)

    M.A. Schlager (Max); C.C. Hoogenraad (Casper)

    2009-01-01

    textabstractSynaptic 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

  3. Functional dissection of synaptic circuits: in vivo patch-clamp recording in neuroscience.

    Science.gov (United States)

    Tao, Can; Zhang, Guangwei; Xiong, Ying; Zhou, Yi

    2015-01-01

    Neuronal activity is dominated by synaptic inputs from excitatory or inhibitory neural circuits. With the development of in vivo patch-clamp recording, especially in vivo voltage-clamp recording, researchers can not only directly measure neuronal activity, such as spiking responses or membrane potential dynamics, but also quantify synaptic inputs from excitatory and inhibitory circuits in living animals. This approach enables researchers to directly unravel different synaptic components and to understand their underlying roles in particular brain functions. Combining in vivo patch-clamp recording with other techniques, such as two-photon imaging or optogenetics, can provide even clearer functional dissection of the synaptic contributions of different neurons or nuclei. Here, we summarized current applications and recent research progress using the in vivo patch-clamp recording method and focused on its role in the functional dissection of different synaptic inputs. The key factors of a successful in vivo patch-clamp experiment and possible solutions based on references and our experiences were also discussed.

  4. Radiation and Reason Why radiation at modest dose rates is quite harmless and current radiation safety regulations are flawed

    CERN Multimedia

    CERN. Geneva

    2013-01-01

    Data on the impact of ionising radiation on life are examined in the light of evolutionary biology. This comparison confirms that fear of nuclear radiation is not justified by science itself; rather it originates in a failure of public trust in nuclear science, a relic of the international politics of the Cold War era. Current ionisation safety regulations appease this fear but without scientific support and they need fundamental reformulation. This should change the reaction to accidents like Fukushima, the cost of nuclear energy and the application of nuclear technology to the supply of food and fresh water. Such a boost to the world economy would require that more citizens study and appreciate the science involved – and then tell others -- not as much fun as the Higgs, perhaps, but no less important! www.radiationandreason.com

  5. Bioprocessing of plant-derived virus-like particles of Norwalk virus capsid protein under current Good Manufacture Practice regulations

    Science.gov (United States)

    Lai, Huafang; Chen, Qiang

    2012-01-01

    Despite the success in expressing a variety of subunit vaccine proteins in plants and the recent stride in improving vaccine accumulation levels by transient expression systems, there is still no plant-derived vaccine that has been licensed for human use. The lack of commercial success of plant-made vaccines lies in several technical and regulatory barriers that remain to be overcome. These challenges include the lack of scalable downstream processing procedures, the uncertainty of regulatory compliance of production processes, and the lack of demonstration of plant-derived products that meet the required standards of regulatory agencies in identity, purity, potency and safety. In this study, we addressed these remaining challenges and successfully demonstrate the ability of using plants to produce a pharmaceutical grade Norwalk virus (NV) vaccine under current Good Manufacture Practice (cGMP) guidelines at multiple gram scales. Our results demonstrate that an efficient and scalable extraction and purification scheme can established for processing virus-like particles (VLP) of NV capsid protein (NVCP). We successfully operated the upstream and downstream NVCP production processes under cGMP regulations. Furthermore, plant-derived NVCP VLP demonstrates the identity, purity, potency and safety that meet the preset release specifications. This material is being tested in a Phase I human clinical trial. This research provides the first report of producing a plant-derived vaccine at scale under cGMP regulations in an academic setting and an important step for plant-produced vaccines to become a commercial reality. PMID:22134876

  6. Bilinearity in spatiotemporal integration of synaptic inputs.

    Directory of Open Access Journals (Sweden)

    Songting Li

    2014-12-01

    Full Text Available Neurons process information via integration of synaptic inputs from dendrites. Many experimental results demonstrate dendritic integration could be highly nonlinear, yet few theoretical analyses have been performed to obtain a precise quantitative characterization analytically. Based on asymptotic analysis of a two-compartment passive cable model, given a pair of time-dependent synaptic conductance inputs, we derive a bilinear spatiotemporal dendritic integration rule. The summed somatic potential can be well approximated by the linear summation of the two postsynaptic potentials elicited separately, plus a third additional bilinear term proportional to their product with a proportionality coefficient [Formula: see text]. The rule is valid for a pair of synaptic inputs of all types, including excitation-inhibition, excitation-excitation, and inhibition-inhibition. In addition, the rule is valid during the whole dendritic integration process for a pair of synaptic inputs with arbitrary input time differences and input locations. The coefficient [Formula: see text] is demonstrated to be nearly independent of the input strengths but is dependent on input times and input locations. This rule is then verified through simulation of a realistic pyramidal neuron model and in electrophysiological experiments of rat hippocampal CA1 neurons. The rule is further generalized to describe the spatiotemporal dendritic integration of multiple excitatory and inhibitory synaptic inputs. The integration of multiple inputs can be decomposed into the sum of all possible pairwise integration, where each paired integration obeys the bilinear rule. This decomposition leads to a graph representation of dendritic integration, which can be viewed as functionally sparse.

  7. Postnatal aniracetam treatment improves prenatal ethanol induced attenuation of AMPA receptor-mediated synaptic transmission.

    Science.gov (United States)

    Wijayawardhane, Nayana; Shonesy, Brian C; Vaglenova, Julia; Vaithianathan, Thirumalini; Carpenter, Mark; Breese, Charles R; Dityatev, Alexander; Suppiramaniam, Vishnu

    2007-06-01

    Aniracetam is a nootropic compound and an allosteric modulator of AMPA receptors (AMPARs) which mediate synaptic mechanisms of learning and memory. Here we analyzed impairments in AMPAR-mediated synaptic transmission caused by moderate prenatal ethanol exposure and investigated the effects of postnatal aniracetam treatment on these abnormalities. Pregnant Sprague-Dawley rats were gavaged with ethanol or isocaloric sucrose throughout pregnancy, and subsequently the offspring were treated with aniracetam on postnatal days (PND) 18 to 27. Hippocampal slices prepared from these pups on PND 28 to 34 were used for the whole-cell patch-clamp recordings of AMPAR-mediated spontaneous and miniature excitatory postsynaptic currents in CA1 pyramidal cells. Our results indicate that moderate ethanol exposure during pregnancy results in impaired hippocampal AMPAR-mediated neurotransmission, and critically timed aniracetam treatment can abrogate this deficiency. These results highlight the possibility that aniracetam treatment can restore synaptic transmission and ameliorate cognitive deficits associated with the fetal alcohol syndrome.

  8. Synaptic and network consequences of monosynaptic nociceptive inputs of parabrachial nucleus origin in the central amygdala

    Science.gov (United States)

    Sugimura, Yae K.; Takahashi, Yukari; Watabe, Ayako M.

    2016-01-01

    A large majority of neurons in the superficial layer of the dorsal horn projects to the lateral parabrachial nucleus (LPB). LPB neurons then project to the capsular part of the central amygdala (CeA; CeC), a key structure underlying the nociception-emotion link. LPB-CeC synaptic transmission is enhanced in various pain models by using electrical stimulation of putative fibers of LPB origin in brain slices. However, this approach has limitations for examining direct monosynaptic connections devoid of directly stimulating fibers from other structures and local GABAergic neurons. To overcome these limitations, we infected the LPB of rats with an adeno-associated virus vector expressing channelrhodopsin-2 and prepared coronal and horizontal brain slices containing the amygdala. We found that blue light stimulation resulted in monosynaptic excitatory postsynaptic currents (EPSCs), with very small latency fluctuations, followed by a large polysynaptic inhibitory postsynaptic current in CeC neurons, regardless of the firing pattern type. Intraplantar formalin injection at 24 h before slice preparation significantly increased EPSC amplitude in late firing-type CeC neurons. These results indicate that direct monosynaptic glutamatergic inputs from the LPB not only excite CeC neurons but also regulate CeA network signaling through robust feed-forward inhibition, which is under plastic modulation in response to persistent inflammatory pain. PMID:26888105

  9. Cholinergic Synaptic Transmissions Were Altered after Single Sevoflurane Exposure in Drosophila Pupa

    Directory of Open Access Journals (Sweden)

    Rongfa Chen

    2015-01-01

    Full Text Available Purpose. Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. Methods. Wide types of Drosophila (canton-s flies were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. Results. The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs was significantly reduced P<0.05. Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure P<0.05. Conclusions. All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure.

  10. Cholinergic synaptic transmissions were altered after single sevoflurane exposure in Drosophila pupa.

    Science.gov (United States)

    Chen, Rongfa; Zhang, Tao; Kuang, Liting; Chen, Zhen; Ran, Dongzhi; Niu, Yang; Xu, Kangqing; Gu, Huaiyu

    2015-01-01

    . Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. Wide types of Drosophila (canton-s flies) were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane) were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced (P < 0.05). Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure (P < 0.05). All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure.

  11. SAD-B Phosphorylation of CAST Controls Active Zone Vesicle Recycling for Synaptic Depression

    Directory of Open Access Journals (Sweden)

    Sumiko Mochida

    2016-09-01

    Full Text Available Short-term synaptic depression (STD is a common form of activity-dependent plasticity observed widely in the nervous system. Few molecular pathways that control STD have been described, but the active zone (AZ release apparatus provides a possible link between neuronal activity and plasticity. Here, we show that an AZ cytomatrix protein CAST and an AZ-associated protein kinase SAD-B coordinately regulate STD by controlling reloading of the AZ with release-ready synaptic vesicles. SAD-B phosphorylates the N-terminal serine (S45 of CAST, and S45 phosphorylation increases with higher firing rate. A phosphomimetic CAST (S45D mimics CAST deletion, which enhances STD by delaying reloading of the readily releasable pool (RRP, resulting in a pool size decrease. A phosphonegative CAST (S45A inhibits STD and accelerates RRP reloading. Our results suggest that the CAST/SAD-B reaction serves as a brake on synaptic transmission by temporal calibration of activity and synaptic depression via RRP size regulation.

  12. Nicotinic ACh receptors in the hippocampal circuit; functional expression and role in synaptic plasticity.

    Science.gov (United States)

    Yakel, Jerrel L

    2014-10-01

    Acetylcholine (ACh) can regulate neuronal excitability in the hippocampus, an important area in the brain for learning and memory, by acting on both nicotinic (nAChRs) and muscarinic ACh receptors. The primary cholinergic input to the hippocampus arises from the medial septum and diagonal band of Broca (MS-DBB), and we investigated how their activation regulated hippocampal synaptic plasticity. We found that activation of these endogenous cholinergic inputs can directly induce different forms of hippocampal synaptic plasticity with a timing precision in the millisecond range. Furthermore, we observed a prolonged enhancement of excitability both pre- and postsynaptically. Lastly we found that the presence of the α7 nAChR subtype to both pre- and postsynaptic sites appeared to be required to induce this plasticity. We propose that α7 nAChRs coordinate pre- and postsynaptic activities to induce glutamatergic synaptic plasticity, and thus provide a novel mechanism underlying physiological neuronal communication that could lead to timing-dependent synaptic plasticity in the hippocampus. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

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

    Directory of Open Access Journals (Sweden)

    Idan eElbaz

    2013-02-01

    Full Text Available 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.

  14. 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.

  15. Identifying and tracking simulated synaptic inputs from neuronal firing: insights from in vitro experiments.

    Directory of Open Access Journals (Sweden)

    Maxim Volgushev

    2015-03-01

    Full Text Available Accurately describing synaptic interactions between neurons and how interactions change over time are key challenges for systems neuroscience. Although intracellular electrophysiology is a powerful tool for studying synaptic integration and plasticity, it is limited by the small number of neurons that can be recorded simultaneously in vitro and by the technical difficulty of intracellular recording in vivo. One way around these difficulties may be to use large-scale extracellular recording of spike trains and apply statistical methods to model and infer functional connections between neurons. These techniques have the potential to reveal large-scale connectivity structure based on the spike timing alone. However, the interpretation of functional connectivity is often approximate, since only a small fraction of presynaptic inputs are typically observed. Here we use in vitro current injection in layer 2/3 pyramidal neurons to validate methods for inferring functional connectivity in a setting where input to the neuron is controlled. In experiments with partially-defined input, we inject a single simulated input with known amplitude on a background of fluctuating noise. In a fully-defined input paradigm, we then control the synaptic weights and timing of many simulated presynaptic neurons. By analyzing the firing of neurons in response to these artificial inputs, we ask 1 How does functional connectivity inferred from spikes relate to simulated synaptic input? and 2 What are the limitations of connectivity inference? We find that individual current-based synaptic inputs are detectable over a broad range of amplitudes and conditions. Detectability depends on input amplitude and output firing rate, and excitatory inputs are detected more readily than inhibitory. Moreover, as we model increasing numbers of presynaptic inputs, we are able to estimate connection strengths more accurately and detect the presence of connections more quickly. These results

  16. Stochastic single-molecule dynamics of synaptic membrane protein domains

    Science.gov (United States)

    Kahraman, Osman; Li, Yiwei; Haselwandter, Christoph A.

    2016-09-01

    Motivated by single-molecule experiments on synaptic membrane protein domains, we use a stochastic lattice model to study protein reaction and diffusion processes in crowded membranes. We find that the stochastic reaction-diffusion dynamics of synaptic proteins provide a simple physical mechanism for collective fluctuations in synaptic domains, the molecular turnover observed at synaptic domains, key features of the single-molecule trajectories observed for synaptic proteins, and spatially inhomogeneous protein lifetimes at the cell membrane. Our results suggest that central aspects of the single-molecule and collective dynamics observed for membrane protein domains can be understood in terms of stochastic reaction-diffusion processes at the cell membrane.

  17. The N-ethylmaleimide-sensitive factor and dysbindin interact to modulate synaptic plasticity.

    Science.gov (United States)

    Gokhale, Avanti; Mullin, Ariana P; Zlatic, Stephanie A; Easley, Charles A; Merritt, Megan E; Raj, Nisha; Larimore, Jennifer; Gordon, David E; Peden, Andrew A; Sanyal, Subhabrata; Faundez, Victor

    2015-05-13

    Dysbindin is a schizophrenia susceptibility factor and subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) required for lysosome-related organelle biogenesis, and in neurons, synaptic vesicle assembly, neurotransmission, and plasticity. Protein networks, or interactomes, downstream of dysbindin/BLOC-1 remain partially explored despite their potential to illuminate neurodevelopmental disorder mechanisms. Here, we conducted a proteome-wide search for polypeptides whose cellular content is sensitive to dysbindin/BLOC-1 loss of function. We identified components of the vesicle fusion machinery as factors downregulated in dysbindin/BLOC-1 deficiency in neuroectodermal cells and iPSC-derived human neurons, among them the N-ethylmaleimide-sensitive factor (NSF). Human dysbindin/BLOC-1 coprecipitates with NSF and vice versa, and both proteins colocalized in a Drosophila model synapse. To test the hypothesis that NSF and dysbindin/BLOC-1 participate in a pathway-regulating synaptic function, we examined the role for NSF in dysbindin/BLOC-1-dependent synaptic homeostatic plasticity in Drosophila. As previously described, we found that mutations in dysbindin precluded homeostatic synaptic plasticity elicited by acute blockage of postsynaptic receptors. This dysbindin mutant phenotype is fully rescued by presynaptic expression of either dysbindin or Drosophila NSF. However, neither reduction of NSF alone or in combination with dysbindin haploinsufficiency impaired homeostatic synaptic plasticity. Our results demonstrate that dysbindin/BLOC-1 expression defects result in altered cellular content of proteins of the vesicle fusion apparatus and therefore influence synaptic plasticity. Copyright © 2015 the authors 0270-6474/15/357643-11$15.00/0.

  18. Intracellular accumulation of amyloid-beta - a predictor for synaptic dysfunction and neuron loss in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Thomas A Bayer

    2010-03-01

    Full Text Available Despite of long-standing evidence that beta-amyloid (Aβ peptides have detrimental effects on synaptic function, the relationship between Aβ, synaptic and neuron loss is largely unclear. During the last years there is growing evidence that early intraneuronal accumulation of Aβ peptides is one of the key events leading to synaptic and neuronal dysfunction. Many studies have been carried out using transgenic mouse models of Alzheimer’s disease (AD which have been proven to be valuable model system in modern AD research. The present review discusses the impact of intraneuronal Aβ accumulation on synaptic impairment and neuron loss and provides an overview of currently available AD mouse models showing these pathological alterations.

  19. Influence of Synaptic Depression on Memory Storage Capacity

    Science.gov (United States)

    Otsubo, Yosuke; Nagata, Kenji; Oizumi, Masafumi; Okada, Masato

    2011-08-01

    Synaptic efficacy between neurons is known to change within a short time scale dynamically. Neurophysiological experiments show that high-frequency presynaptic inputs decrease synaptic efficacy between neurons. This phenomenon is called synaptic depression, a short term synaptic plasticity. Many researchers have investigated how the synaptic depression affects the memory storage capacity. However, the noise has not been taken into consideration in their analysis. By introducing ``temperature'', which controls the level of the noise, into an update rule of neurons, we investigate the effects of synaptic depression on the memory storage capacity in the presence of the noise. We analytically compute the storage capacity by using a statistical mechanics technique called Self Consistent Signal to Noise Analysis (SCSNA). We find that the synaptic depression decreases the storage capacity in the case of finite temperature in contrast to the case of the low temperature limit, where the storage capacity does not change.

  20. Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer’s disease

    Science.gov (United States)

    Berchtold, Nicole C.; Coleman, Paul D.; Cribbs, David H.; Rogers, Joseph; Gillen, Daniel L.; Cotman, Carl W.

    2014-01-01

    Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer’s disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20–99 years) and AD across 4 brain regions from 81 cases. The analysis revealed an unexpectedly large number of significant expression changes in synapse-related genes in aging, with many undergoing progressive downregulation across aging and AD. Functional classification of the genes showing altered expression revealed that multiple aspects of synaptic function are affected, notably synaptic vesicle trafficking and release, neurotransmitter receptors and receptor trafficking, postsynaptic density scaffolding, cell adhesion regulating synaptic stability, and neuromodulatory systems. The widespread declines in synaptic gene expression in normal aging suggests that function of existing synapses might be impaired, and that a common set of synaptic genes are vulnerable to change in aging and AD. PMID:23273601

  1. Current regulators for I/SUP 2/L circuits to be operated from low-voltage power supplies

    DEFF Research Database (Denmark)

    Bruun, Erik; Hansen, Ole

    1980-01-01

    A new bandgap current reference is described which can be used to control the injector current of I/SUP 2/L circuits for supply voltages down to about 1 V. For small currents the total injector current is obtained as a mirror of the reference current. For large injector currents the current contr...

  2. The role of cAMP in synaptic homeostasis in response to environmental temperature challenges and hyperexcitability mutations

    Directory of Open Access Journals (Sweden)

    Atsushi eUeda

    2015-02-01

    Full Text Available Homeostasis is the ability of physiological systems to regain functional balance following environment or experimental insults and synaptic homeostasis has been demonstrated in various species following genetic or pharmacological disruptions. Among environmental challenges, homeostatic responses to temperature extremes are critical to animal survival under natural conditions. We previously reported that axon terminal arborization in Drosophila larval neuromuscular junctions is enhanced at elevated temperatures; however, the amplitude of excitatory junctional potentials (EJPs remains unaltered despite the increase in synaptic bouton numbers. Here we determine the cellular basis of this homeostatic adjustment in larvae reared at high temperature (HT, 29 ˚C. We found that synaptic current focally recorded from individual synaptic boutons was unaffected by rearing temperature (30 ˚C. However, HT rearing decreased the quantal size (amplitude of spontaneous miniature EJPs, or mEJPs, which compensates for the increased number of synaptic releasing sites to retain a normal EJP size. The quantal size decrease is accounted for by a decrease in input resistance of the postsynaptic muscle fiber, indicating an increase in membrane area that matches the synaptic growth at HT. Interestingly, a mutation in rutabaga (rut encoding adenylyl cyclase (AC exhibited no obvious changes in quantal size or input resistance of postsynaptic muscle cells after HT rearing, suggesting an important role for rut AC in temperature-induced synaptic homeostasis in Drosophila. This extends our previous finding of rut-dependent synaptic homeostasis in hyperexcitable mutants, e.g. slowpoke (slo. In slo larvae, the lack of BK channel function is partially ameliorated by upregulation of presynaptic Sh IA current to limit excessive transmitter release in addition to postsynaptic glutamate receptor recomposition that reduces the quantal size.

  3. Disruption of an Evolutionarily Novel Synaptic Expression Pattern in Autism.

    Directory of Open Access Journals (Sweden)

    Xiling Liu

    2016-09-01

    Full Text Available Cognitive defects in autism spectrum disorder (ASD include socialization and communication: key behavioral capacities that separate humans from other species. Here, we analyze gene expression in the prefrontal cortex of 63 autism patients and control individuals, as well as 62 chimpanzees and macaques, from natal to adult age. We show that among all aberrant expression changes seen in ASD brains, a single aberrant expression pattern overrepresented in genes involved synaptic-related pathways is enriched in nucleotide variants linked to autism. Furthermore, only this pattern contains an excess of developmental expression features unique to humans, thus resulting in the disruption of human-specific developmental programs in autism. Several members of the early growth response (EGR transcription factor family can be implicated in regulation of this aberrant developmental change. Our study draws a connection between the genetic risk architecture of autism and molecular features of cortical development unique to humans.

  4. Disruption of an Evolutionarily Novel Synaptic Expression Pattern in Autism

    Science.gov (United States)

    Jiang, Xi; Hu, Haiyang; Guijarro, Patricia; Mitchell, Amanda; Ely, John J.; Sherwood, Chet C.; Hof, Patrick R.; Qiu, Zilong; Pääbo, Svante; Akbarian, Schahram; Khaitovich, Philipp

    2016-01-01

    Cognitive defects in autism spectrum disorder (ASD) include socialization and communication: key behavioral capacities that separate humans from other species. Here, we analyze gene expression in the prefrontal cortex of 63 autism patients and control individuals, as well as 62 chimpanzees and macaques, from natal to adult age. We show that among all aberrant expression changes seen in ASD brains, a single aberrant expression pattern overrepresented in genes involved synaptic-related pathways is enriched in nucleotide variants linked to autism. Furthermore, only this pattern contains an excess of developmental expression features unique to humans, thus resulting in the disruption of human-specific developmental programs in autism. Several members of the early growth response (EGR) transcription factor family can be implicated in regulation of this aberrant developmental change. Our study draws a connection between the genetic risk architecture of autism and molecular features of cortical development unique to humans. PMID:27685936

  5. Pesticide regulation, utilization, and retailers' selling practices in Trinidad and Tobago, West Indies: current situation and needed changes.

    Science.gov (United States)

    Pinto Pereira, Lexley M; Boysielal, Kim; Siung-Chang, Avril

    2007-08-01

    To explore pesticide regulation in Trinidad and Tobago, and to ascertain pesticide utilization and retailers' selling practices on Trinidad, which is the larger of twin islands that constitute the republic of Trinidad and Tobago. Between February and June 2005, agrochemical retailers in Trinidad were surveyed about the most frequently sold pesticides and their knowledge and practices of pesticide sale. The Poisons and Toxic Chemicals Control Board of the Ministry of Health informed on legislature. Of 107 actively trading licensed pesticide outlets, 97 participated (91% response rate) in the survey. Currently only 2.9% (21) of 720 registered products from four chemical classes are frequently utilized. Paraquat, methomyl, and alpha-cypermethrin (respective trade names are Gramoxone, Lannate, and Fastac) from World Health Organization (WHO) Hazard Classes I and II, and glyphosate isopropylamine (Swiper, Class U) are the most frequently purchased pesticides. Pet shops constitute 39.2% (38) of retail shops selling pesticides. No regulations guide pesticide sale to agriculturists, and children may purchase them. Inadequate human and technical resources render legislative controls ineffective and disciplinary action against offenders is weak. Extensive governmental resources are employed in legislative procedures and product approval for the very low, 2.9% utilization rate, negatively impacting on monitoring pesticide sales. The Poisons Information Centre (PIC) does not liaise with the Poisons and Toxic Chemicals Control Board or provide educational interventions for the community. As a result of this survey, it was possible to develop the first database to include the chemical, brand, and colloquial names of pesticides used in Trinidad and Tobago; WHO classification of approved pesticides; manufacturers; packaging; and antidotes and their availability for use by the Board and health professionals in Trinidad. Urgent critical evaluation of legislation regarding pesticide

  6. Ultrafast Synaptic Events in a Chalcogenide Memristor

    Science.gov (United States)

    Li, Yi; Zhong, Yingpeng; Xu, Lei; Zhang, Jinjian; Xu, Xiaohua; Sun, Huajun; Miao, Xiangshui

    2013-04-01

    Compact and power-efficient plastic electronic synapses are of fundamental importance to overcoming the bottlenecks of developing a neuromorphic chip. Memristor is a strong contender among the various electronic synapses in existence today. However, the speeds of synaptic events are relatively slow in most attempts at emulating synapses due to the material-related mechanism. Here we revealed the intrinsic memristance of stoichiometric crystalline Ge2Sb2Te5 that originates from the charge trapping and releasing by the defects. The device resistance states, representing synaptic weights, were precisely modulated by 30 ns potentiating/depressing electrical pulses. We demonstrated four spike-timing-dependent plasticity (STDP) forms by applying programmed pre- and postsynaptic spiking pulse pairs in different time windows ranging from 50 ms down to 500 ns, the latter of which is 105 times faster than the speed of STDP in human brain. This study provides new opportunities for building ultrafast neuromorphic computing systems and surpassing Von Neumann architecture.

  7. The Role of Co-chaperones in Synaptic Proteostasis and Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Erica L. Gorenberg

    2017-05-01

    Full Text Available Synapses must be preserved throughout an organism's lifespan to allow for normal brain function and behavior. Synapse maintenance is challenging given the long distances between the termini and the cell body, reliance on axonal transport for delivery of newly synthesized presynaptic proteins, and high rates of synaptic vesicle exo- and endocytosis. Hence, synapses rely on efficient proteostasis mechanisms to preserve their structure and function. To this end, the synaptic compartment has specific chaperones to support its functions. Without proper synaptic chaperone activity, local proteostasis imbalances lead to neurotransmission deficits, dismantling of synapses, and neurodegeneration. In this review, we address the roles of four synaptic chaperones in the maintenance of the nerve terminal, as well as their genetic links to neurodegenerative disease. Three of these are Hsp40 co-chaperones (DNAJs: Cysteine String Protein alpha (CSPα; DNAJC5, auxilin (DNAJC6, and Receptor-Mediated Endocytosis 8 (RME-8; DNAJC13. These co-chaperones contain a conserved J domain through which they form a complex with heat shock cognate 70 (Hsc70, enhancing the chaperone's ATPase activity. CSPα is a synaptic vesicle protein known to chaperone the t-SNARE SNAP-25 and the endocytic GTPase dynamin-1, thereby regulating synaptic vesicle exocytosis and endocytosis. Auxilin binds assembled clathrin cages, and through its interactions with Hsc70 leads to the uncoating of clathrin-coated vesicles, a process necessary for the regeneration of synaptic vesicles. RME-8 is a co-chaperone on endosomes and may have a role in clathrin-coated vesicle endocytosis on this organelle. These three co-chaperones maintain client function by preserving folding and assembly to prevent client aggregation, but they do not break down aggregates that have already formed. The fourth synaptic chaperone we will discuss is Heat shock protein 110 (Hsp110, which interacts with Hsc70, DNAJAs, and

  8. Hippocampal synaptic plasticity, spatial memory and anxiety

    OpenAIRE

    Bannerman, David M.; Sprengel, Rolf; Sanderson, David J.; McHugh, Stephen B.; Rawlins, J. Nicholas P.; Monyer, Hannah; Seeburg, Peter H.

    2014-01-01

    Recent studies using transgenic mice lacking NMDA receptors in the hippocampus challenge the long-standing hypothesis that hippocampal long-term potentiation-like mechanisms underlie the encoding and storage of associative long-term spatial memories. However, it may not be the synaptic plasticity-dependent memory hypothesis that is wrong; instead, it may be the role of the hippocampus that needs to be re-examined. We present an account of hippocampal function that explains its role in both me...

  9. Learned EEG-based regulation of motor-related brain oscillations during application of transcranial electric currents: feasibility and limitations

    Directory of Open Access Journals (Sweden)

    Surjo R Soekadar

    2014-03-01

    Full Text Available Objective: Transcranial direct current stimulation (tDCS improves motor learning and can influence emotional processing or attention. However, it remained unclear whether learned electroencephalography (EEG-based brain-machine interface (BMI control during tDCS is feasible and how application of transcranial electric currents during BMI control would interfere with feature-extraction of physiological brain signals. Here we tested this combination and evaluated stimulation-dependent artifacts across different EEG frequencies and stability of motor imagery-based BMI control. Approach: Ten healthy volunteers were invited to two BMI-sessions, each comprising two 60-trial blocks. During the trials, modulation of mu-rhythms (8-15Hz associated with motor imagery recorded over C4 was translated into online cursor movements on a computer screen. During block 2, either sham (session A or anodal tDCS (session B was applied at 1mA with the stimulation electrode placed 1cm anterior of C4. Main results: tDCS was associated with a significant signal power increase in the lower frequencies most evident in the signal spectrum of the EEG channel closest to the stimulation electrode. Stimulation-dependent signal power increase exhibited a decay of 12dB per decade, leaving frequencies above 9Hz unaffected. Analysis of BMI control performance did not indicate a difference between blocks and tDCS conditions. Conclusion: Application of tDCS during learned EEG-based self-regulation of brain oscillations above 9Hz is feasible and safe, and might improve applicability of BMI systems in patient populations.

  10. Synaptic theory of Replicator-like melioration

    Directory of Open Access Journals (Sweden)

    Yonatan Loewenstein

    2010-06-01

    Full Text Available According to the theory of Melioration, organisms in repeated choice settings shift their choice preference in favor of the alternative that provides the highest return. The goal of this paper is to explain how this learning behavior can emerge from microscopic changes in the efficacies of synapses, in the context of two-alternative repeated-choice experiment. I consider a large family of synaptic plasticity rules in which changes in synaptic efficacies are driven by the covariance between reward and neural activity. I construct a general framework that predicts the learning dynamics of any decision-making neural network that implements this synaptic plasticity rule and show that melioration naturally emerges in such networks. Moreover, the resultant learning dynamics follows the Replicator equation which is commonly used to phenomenologically describe changes in behavior in operant conditioning experiments. Several examples demonstrate how the learning rate of the network is affected by its properties and by the specifics of the plasticity rule. These results help bridge the gap between cellular physiology and learning behavior.

  11. Characterization and extraction of the synaptic apposition surface for synaptic geometry analysis

    Science.gov (United States)

    Morales, Juan; Rodríguez, Angel; Rodríguez, José-Rodrigo; DeFelipe, Javier; Merchán-Pérez, Angel

    2013-01-01

    Geometrical features of chemical synapses are relevant to their function. Two critical components of the synaptic junction are the active zone (AZ) and the postsynaptic density (PSD), as they are related to the probability of synaptic release and the number of postsynaptic receptors, respectively. Morphological studies of these structures are greatly facilitated by the use of recent electron microscopy techniques, such as combined focused ion beam milling and scanning electron microscopy (FIB/SEM), and software tools that permit reconstruction of large numbers of synapses in three dimensions. Since the AZ and the PSD are in close apposition and have a similar surface area, they can be represented by a single surface—the synaptic apposition surface (SAS). We have developed an efficient computational technique to automatically extract this surface from synaptic junctions that have previously been three-dimensionally reconstructed from actual tissue samples imaged by automated FIB/SEM. Given its relationship with the release probability and the number of postsynaptic receptors, the surface area of the SAS is a functionally relevant measure of the size of a synapse that can complement other geometrical features like the volume of the reconstructed synaptic junction, the equivalent ellipsoid size and the Feret's diameter. PMID:23847474

  12. Characterization and extraction of the synaptic apposition surface for synaptic geometry analysis.

    Directory of Open Access Journals (Sweden)

    Juan eMorales

    2013-07-01

    Full Text Available Geometrical features of chemical synapses are relevant to their function. Two critical components of the synaptic junction are the active zone and the postsynaptic density, as they are related to the probability of synaptic release and the number of postsynaptic receptors, respectively. Morphological studies of these structures are greatly facilitated by the use of recent electron microscopy techniques, such as combined focused ion beam milling and scanning electron microscopy (FIB/SEM, and software tools that permit reconstruction of large numbers of synapses in three dimensions. Since the active zone and the postsynaptic density are in close apposition and have a similar surface area, they can be represented by a single surface — the synaptic apposition surface (SAS. We have developed an efficient computational technique to automatically extract this surface from synaptic junctions that have previously been three-dimensionally reconstructed from actual tissue samples imaged by automated FIB/SEM. Given its relationship with the release probability and the number of postsynaptic receptors, the surface area of the SAS is a functionally relevant measure of the size of a synapse that can complement other geometrical features like the volume of the reconstructed synaptic junction, the equivalent ellipsoid size and the Feret’s diameter.

  13. The Yeast PHO Promoters as Paradigm for Transcriptional Regulation by Chromatin Remodelling: Current State of the Art

    Directory of Open Access Journals (Sweden)

    Slobodan Barbarić

    2014-01-01

    Full Text Available It has been widely acknowledged that modulation of chromatin structure at the promoter region influences the usage of factor binding sites and thus provides first, important level of transcriptional regulation. Chromatin-remodelling complexes utilize the energy of ATP hydrolysis to disassemble nucleosomes, and their functions are prominently correlated with promoter activation and also repression. Mechanistic details of individual steps and their orchestration in complex remodelling events, as well as regulatory mechanisms controlling remodeller activity, are subjects of current and future studies. The yeast PHO5 promoter was the first and still is one of the best characterized examples of a massive chromatin transition associated with transcriptional activation. Studies with this promoter provided several breakthrough findings and established basic principles of chromatin-remodelling process. Recent studies have revealed a network of five remodellers from all four remodeller subfamilies involved in this chromatin transition. Importantly, requirement for chromatin remodellers at the PHO8 as well as at PHO84 promoter, activated by the same transactivator as PHO5, are rather different. All these findings point out that chromatin remodelling process is in general even more complex than presumed, and it could be expected that further studies with the well-established PHO promoter system will be rather valuable for its further understanding.

  14. Alteration of AMPA Receptor-Mediated Synaptic Transmission by Alexa Fluor 488 and 594 in Cerebellar Stellate Cells.

    Science.gov (United States)

    Maroteaux, Matthieu; Liu, Siqiong June

    2016-01-01

    The fluorescent dyes, Alexa Fluor 488 and 594 are commonly used to visualize dendritic structures and the localization of synapses, both of which are critical for the spatial and temporal integration of synaptic inputs. However, the effect of the dyes on synaptic transmission is not known. Here we investigated whether Alexa Fluor dyes alter the properties of synaptic currents mediated by two subtypes of AMPA receptors (AMPARs) at cerebellar stellate cell synapses. In naive mice, GluA2-lacking AMPAR-mediated synaptic currents displayed an inwardly rectifying current-voltage (I-V) relationship due to blockade by cytoplasmic spermine at depolarized potentials. We found that the inclusion of 100 µm Alexa Fluor dye, but not 10 µm, in the pipette solution led to a gradual increase in the amplitude of EPSCs at +40 mV and a change in the I-V relationship from inwardly rectifying to more linear. In mice exposed to an acute stress, AMPARs switched to GluA2-containing receptors, and 100 µm Alexa Fluor 594 did not alter the I-V relationship of synaptic currents. Therefore, a high concentration of Alexa Fluor dye changed the I-V relationship of EPSCs at GluA2-lacking AMPAR synapses.

  15. Synaptic transmission and plasticity in an active cortical network.

    Directory of Open Access Journals (Sweden)

    Ramon Reig

    Full Text Available BACKGROUND: The cerebral cortex is permanently active during both awake and sleep states. This ongoing cortical activity has an impact on synaptic transmission and short-term plasticity. An activity pattern generated by the cortical network is a slow rhythmic activity that alternates up (active and down (silent states, a pattern occurring during slow wave sleep, anesthesia and even in vitro. Here we have studied 1 how network activity affects short term synaptic plasticity and, 2 how synaptic transmission varies in up versus down states. METHODOLOGY/PRINCIPAL FINDINGS: Intracellular recordings obtained from cortex in vitro and in vivo were used to record synaptic potentials, while presynaptic activation was achieved either with electrical or natural stimulation. Repetitive activation of layer 4 to layer 2/3 synaptic connections from ferret visual cortex slices displayed synaptic augmentation that was larger and longer lasting in active than in silent slices. Paired-pulse facilitation was also significantly larger in an active network and it persisted for longer intervals (up to 200 ms than in silent slices. Intracortical synaptic potentials occurring during up states in vitro increased their amplitude while paired-pulse facilitation disappeared. Both intracortical and thalamocortical synaptic potentials were also significantly larger in up than in down states in the cat visual cortex in vivo. These enhanced synaptic potentials did not further facilitate when pairs of stimuli were given, thus paired-pulse facilitation during up states in vivo was virtually absent. Visually induced synaptic responses displayed larger amplitudes when occurring during up versus down states. This was further tested in rat barrel cortex, where a sensory activated synaptic potential was also larger in up states. CONCLUSIONS/SIGNIFICANCE: These results imply that synaptic transmission in an active cortical network is more secure and efficient due to larger amplitude of

  16. INVOLVEMENT OF SYNAPTIC GENES IN THE PATHOGENESIS OF AUTISM SPECTRUM DISORDERS: THE CASE OF SYNAPSINS

    Directory of Open Access Journals (Sweden)

    Silvia eGiovedi

    2014-09-01

    Full Text Available Autism spectrum disorders (ASDs are heterogeneous neurodevelopmental disorders characterized by deficits in social interaction and social communication, restricted interests and repetitive behaviors. Many synaptic protein genes are linked to the pathogenesis of ASDs, making them prototypical synaptopathies. An array of mutations in the synapsin (Syn genes in humans have been recently associated with ASD and epilepsy, diseases that display a frequent comorbidity. Synapsins are presynaptic proteins regulating synaptic vesicle traffic, neurotransmitter release and short-term synaptic plasticity. In doing so, Syn isoforms control the tone of activity of neural circuits and the balance between excitation and inhibition. As ASD pathogenesis is believed to result from dysfunctions in the balance between excitatory and inhibitory transmissions in neocortical areas, Syns are novel ASD candidate genes. Accordingly, deletion of single Syn genes in mice, in addition to epilepsy, causes core symptoms of ASD by affecting social behavior, social communication and repetitive behaviors. Thus, Syn knockout mice represent a good experimental model to define synaptic alterations involved in the pathogenesis of ASD and epilepsy.

  17. Anesthetic action on extra-synaptic receptors: effects in neural population models of EEG activity

    Directory of Open Access Journals (Sweden)

    Meysam eHashemi

    2014-12-01

    Full Text Available The role of extra-synaptic receptors in the regulation of excitation and inhibition in the brainhas attracted increasing attention. Because activity in the extra-synaptic receptors plays a role inregulating the level of excitation and inhibition in the brain, they may be important in determiningthe level of consciousness. This paper reviews briefly the literature on extra-synaptic GABAand NMDA receptors and their affinity to anesthetic drugs. We propose a neural populationmodel that illustrates how the effect of the anesthetic drug propofol on GABAergic extra-synapticreceptors results in changes in neural population activity and the electroencephalogram (EEG. Our results show that increased tonic inhibition in inhibitory cortical neurons cause a dramaticincrease in the power of both delta and alpha bands. Conversely, the effects of increased tonicinhibition in cortical excitatory neurons and thalamic relay neurons have the opposite effect anddecrease the power in these bands. The increased delta activity is in accord with observed datafor deepening propofol anesthesia; but is absolutely dependent on the inclusion of extra synaptic(tonic GABA action in the model.

  18. LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis.

    Science.gov (United States)

    Matta, Samer; Van Kolen, Kristof; da Cunha, Raquel; van den Bogaart, Geert; Mandemakers, Wim; Miskiewicz, Katarzyna; De Bock, Pieter-Jan; Morais, Vanessa A; Vilain, Sven; Haddad, Dominik; Delbroek, Lore; Swerts, Jef; Chávez-Gutiérrez, Lucía; Esposito, Giovanni; Daneels, Guy; Karran, Eric; Holt, Matthew; Gevaert, Kris; Moechars, Diederik W; De Strooper, Bart; Verstreken, Patrik

    2012-09-20

    LRRK2 is a kinase mutated in Parkinson's disease, but how the protein affects synaptic function remains enigmatic. We identified LRRK2 as a critical regulator of EndophilinA. Using genetic and biochemical studies involving Lrrk loss-of-function mutants and Parkinson-related LRRK2(G2019S) gain-of-kinase function, we show that LRRK2 affects synaptic endocytosis by phosphorylating EndoA at S75, a residue in the BAR domain. We show that LRRK2-mediated EndoA phosphorylation has profound effects on EndoA-dependent membrane tubulation and membrane association in vitro and in vivo and on synaptic vesicle endocytosis at Drosophila neuromuscular junctions in vivo. Our work uncovers a regulatory mechanism that indicates that reduced LRRK2 kinase activity facilitates EndoA membrane association, while increased kinase activity inhibits membrane association. Consequently, both too much and too little LRRK2-dependent EndoA phosphorylation impedes synaptic endocytosis, and we propose a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Hsp90 chaperone inhibitor 17-AAG attenuates Aβ-induced synaptic toxicity and memory impairment.

    Science.gov (United States)

    Chen, Yaomin; Wang, Bin; Liu, Dan; Li, Jing Jing; Xue, Yueqiang; Sakata, Kazuko; Zhu, Ling-qiang; Heldt, Scott A; Xu, Huaxi; Liao, Francesca-Fang

    2014-02-12

    The excessive accumulation of soluble amyloid peptides (Aβ) plays a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly in synaptic dysfunction. The role of the two major chaperone proteins, Hsp70 and Hsp90, in clearing misfolded protein aggregates has been established. Despite their abundant presence in synapses, the role of these chaperones in synapses remains elusive. Here, we report that Hsp90 inhibition by 17-AAG elicited not only a heat shock-like response but also upregulated presynaptic and postsynaptic proteins, such as synapsin I, synaptophysin, and PSD95 in neurons. 17-AAG treatment enhanced high-frequency stimulation-evoked LTP and protected neurons from synaptic damage induced by soluble Aβ. In AD transgenic mice, the daily administration of 17-AAG over 7 d resulted in a marked increase in PSD95 expression in hippocampi. 17-AAG treatments in wild-type C57BL/6 mice challenged by soluble Aβ significantly improved contextual fear memory. Further, we demonstrate that 17-AAG activated synaptic protein expression via transcriptional mechanisms through the heat shock transcription factor HSF1. Together, our findings identify a novel function of Hsp90 inhibition in regulating synaptic plasticity, in addition to the known neuroprotective effects of the chaperones against Aβ and tau toxicity, thus further supporting the potential of Hsp90 inhibitors in treating neurodegenerative diseases.

  20. Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

    Science.gov (United States)

    Brito, Verónica; Giralt, Albert; Enriquez-Barreto, Lilian; Puigdellívol, Mar; Suelves, Nuria; Zamora-Moratalla, Alfonsa; Ballesteros, Jesús J.; Martín, Eduardo D.; Dominguez-Iturza, Nuria; Morales, Miguel; Alberch, Jordi; Ginés, Sílvia

    2014-01-01

    Learning and memory deficits are early clinical manifestations of Huntington’s disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75NTR negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75NTR function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75NTR are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75NTR levels in HD mutant mice heterozygous for p75NTR prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75NTR in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75NTR in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75NTR mediates synaptic, learning, and memory dysfunction in HD. PMID:25180603

  1. "The seven sins" of the Hebbian synapse: can the hypothesis of synaptic plasticity explain long-term memory consolidation?

    Science.gov (United States)

    Arshavsky, Yuri I

    2006-10-01

    Memorizing new facts and events means that entering information produces specific physical changes within the brain. According to the commonly accepted view, traces of memory are stored through the structural modifications of synaptic connections, which result in changes of synaptic efficiency and, therefore, in formations of new patterns of neural activity (the hypothesis of synaptic plasticity). Most of the current knowledge on learning and initial stages of memory consolidation ("synaptic consolidation") is based on this hypothesis. However, the hypothesis of synaptic plasticity faces a number of conceptual and experimental difficulties when it deals with potentially permanent consolidation of declarative memory ("system consolidation"). These difficulties are rooted in the major intrinsic self-contradiction of the hypothesis: stable declarative memory is unlikely to be based on such a non-stable foundation as synaptic plasticity. Memory that can last throughout an entire lifespan should be "etched in stone." The only "stone-like" molecules within living cells are DNA molecules. Therefore, I advocate an alternative, genomic hypothesis of memory, which suggests that acquired information is persistently stored within individual neurons through modifications of DNA, and that these modifications serve as the carriers of elementary memory traces.

  2. Regulation of Synaptic Transmission by Ambient Extracellular Glutamate

    OpenAIRE

    FEATHERSTONE, DAVID E.; SHIPPY, SCOTT A.

    2007-01-01

    Many neuroscientists assume that ambient extracellular glutamate concentrations in the nervous system are biologically negligible under nonpathological conditions. This assumption is false. Hundreds of studies over several decades suggest that ambient extracellular glutamate levels in the intact mammalian brain are ~0.5 to ~5 μM. This has important implications. Glutamate receptors are desensitized by glutamate concentrations significantly lower than needed for receptor activation; 0.5 to 5 μ...

  3. Caenorhabditis elegans intersectin: a synaptic protein regulating neurotransmission

    DEFF Research Database (Denmark)

    Rose, Simon; Malabarba, Maria Grazia; Krag, Claudia

    2007-01-01

    the characterization of intersectin function in Caenorhabditis elegans. Nematode intersectin (ITSN-1) is expressed in the nervous system, and it is enriched in presynaptic regions. The C. elegans intersectin gene (itsn-1) is nonessential for viability. In addition, itsn-1-null worms do not display any evident...

  4. Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function

    Directory of Open Access Journals (Sweden)

    Andrew J. Kennedy

    2016-09-01

    Full Text Available Human haploinsufficiency of the transcription factor Tcf4 leads to a rare autism spectrum disorder called Pitt-Hopkins syndrome (PTHS, which is associated with severe language impairment and development delay. Here, we demonstrate that Tcf4 haploinsufficient mice have deficits in social interaction, ultrasonic vocalization, prepulse inhibition, and spatial and associative learning and memory. Despite learning deficits, Tcf4(+/− mice have enhanced long-term potentiation in the CA1 area of the hippocampus. In translationally oriented studies, we found that small-molecule HDAC inhibitors normalized hippocampal LTP and memory recall. A comprehensive set of next-generation sequencing experiments of hippocampal mRNA and methylated DNA isolated from Tcf4-deficient and WT mice before or shortly after experiential learning, with or without administration of vorinostat, identified “memory-associated” genes modulated by HDAC inhibition and dysregulated by Tcf4 haploinsufficiency. Finally, we observed that Hdac2 isoform-selective knockdown was sufficient to rescue memory deficits in Tcf4(+/− mice.

  5. Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function.

    Science.gov (United States)

    Kennedy, Andrew J; Rahn, Elizabeth J; Paulukaitis, Brynna S; Savell, Katherine E; Kordasiewicz, Holly B; Wang, Jing; Lewis, John W; Posey, Jessica; Strange, Sarah K; Guzman-Karlsson, Mikael C; Phillips, Scott E; Decker, Kyle; Motley, S Timothy; Swayze, Eric E; Ecker, David J; Michael, Todd P; Day, Jeremy J; Sweatt, J David

    2016-09-06

    Human haploinsufficiency of the transcription factor Tcf4 leads to a rare autism spectrum disorder called Pitt-Hopkins syndrome (PTHS), which is associated with severe language impairment and development delay. Here, we demonstrate that Tcf4 haploinsufficient mice have deficits in social interaction, ultrasonic vocalization, prepulse inhibition, and spatial and associative learning and memory. Despite learning deficits, Tcf4(+/-) mice have enhanced long-term potentiation in the CA1 area of the hippocampus. In translationally oriented studies, we found that small-molecule HDAC inhibitors normalized hippocampal LTP and memory recall. A comprehensive set of next-generation sequencing experiments of hippocampal mRNA and methylated DNA isolated from Tcf4-deficient and WT mice before or shortly after experiential learning, with or without administration of vorinostat, identified "memory-associated" genes modulated by HDAC inhibition and dysregulated by Tcf4 haploinsufficiency. Finally, we observed that Hdac2 isoform-selective knockdown was sufficient to rescue memory deficits in Tcf4(+/-) mice. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. Cryo?electron tomography reveals a critical role of RIM1? in synaptic vesicle tethering

    OpenAIRE

    Fern?ndez-Busnadiego, Rub?n; Asano, Shoh; Oprisoreanu, Ana-Maria; Sakata, Eri; Doengi, Michael; Kochovski, Zdravko; Z?rner, Magdalena; Stein, Valentin; Schoch, Susanne; Baumeister, Wolfgang; Lu?i?, Vladan

    2013-01-01

    Synaptic vesicles are embedded in a complex filamentous network at the presynaptic terminal. Before fusion, vesicles are linked to the active zone (AZ) by short filaments (tethers). The identity of the molecules that form and regulate tethers remains unknown, but Rab3-interacting molecule (RIM) is a prominent candidate, given its central role in AZ organization. In this paper, we analyzed presynaptic architecture of RIM1? knockout (KO) mice by cryo?electron tomography. In stark contrast to pr...

  7. Reversed synaptic effects of hypocretin and NPY mediated by excitatory GABA-dependent synaptic activity in developing MCH neurons.

    Science.gov (United States)

    Li, Ying; Xu, Youfen; van den Pol, Anthony N

    2013-03-01

    In mature neurons, GABA is the primary inhibitory neurotransmitter. In contrast, in developing neurons, GABA exerts excitatory actions, and in some neurons GABA-mediated excitatory synaptic activity is more prevalent than glutamate-mediated excitation. Hypothalamic neuropeptides that modulate cognitive arousal and energy homeostasis, hypocretin/orexin and neuropeptide Y (NPY), evoked reversed effects on synaptic actions that were dependent on presynaptic GABA release onto melanin-concentrating hormone (MCH) neurons. MCH neurons were identified by selective green fluorescent protein (GFP) expression in transgenic mice. In adults, hypocretin increased GABA release leading to reduced excitation. In contrast, in the developing brain as studied here with analysis of miniature excitatory postsynaptic currents, paired-pulse ratios, and evoked potentials, hypocretin acted presynaptically to enhance the excitatory actions of GABA. The ability of hypocretin to enhance GABA release increases inhibition in adult neurons but paradoxically enhances excitation in developing MCH neurons. In contrast, NPY attenuation of GABA release reduced inhibition in mature neurons but enhanced inhibition during development by attenuating GABA excitation. Both hypocretin and NPY also evoked direct actions on developing MCH neurons. Hypocretin excited MCH cells by activating a sodium-calcium exchanger and by reducing potassium currents; NPY reduced activity by increasing an inwardly rectifying potassium current. These data for the first time show that both hypocretin and NPY receptors are functional presynaptically during early postnatal hypothalamic development and that both neuropeptides modulate GABA actions during development with a valence of enhanced excitation or inhibition opposite to that of the adult state, potentially allowing neuropeptide modulation of use-dependent synapse stabilization.

  8. 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.

  9. Multistate Resistive Switching Memory for Synaptic Memory Applications

    KAUST Repository

    Hota, Mrinal Kanti

    2016-07-12

    Reproducible low bias bipolar resistive switching memory in HfZnOx based memristors is reported. The modification of the concentration of oxygen vacancies in the ternary oxide film, which is facilitated by adding ZnO into HfO2, results in improved memory operation by the ternary oxide compared to the single binary oxides. A controlled multistate memory operation is achieved by controlling current compliance and RESET stop voltages. A high DC cyclic stability up to 400 cycles in the multistate memory performance is observed. Conventional synaptic operation in terms of potentiation, depression plasticity, and Ebbinghaus forgetting process are also studied. The memory mechanism is shown to originate from the migration of the oxygen vacancies and modulation of the interfacial layers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

  10. Memristor-based neural networks: Synaptic versus neuronal stochasticity

    KAUST Repository

    Naous, Rawan

    2016-11-02

    In neuromorphic circuits, stochasticity in the cortex can be mapped into the synaptic or neuronal components. The hardware emulation of these stochastic neural networks are currently being extensively studied using resistive memories or memristors. The ionic process involved in the underlying switching behavior of the memristive elements is considered as the main source of stochasticity of its operation. Building on its inherent variability, the memristor is incorporated into abstract models of stochastic neurons and synapses. Two approaches of stochastic neural networks are investigated. Aside from the size and area perspective, the impact on the system performance, in terms of accuracy, recognition rates, and learning, among these two approaches and where the memristor would fall into place are the main comparison points to be considered.

  11. LTD-like molecular pathways in developmental synaptic pruning

    Science.gov (United States)

    Piochon, Claire; Kano, Masanobu; Hansel, Christian

    2016-01-01

    In long-term depression (LTD) at synapses in the adult brain, synaptic strength is reduced in an experience-dependent manner. LTD thus provides a cellular mechanism for information storage in some forms of learning. A similar activity-dependent reduction in synaptic strength also occurs in the developing brain and there provides an essential step in synaptic pruning and the postnatal development of neural circuits. Here we review evidence suggesting that LTD and synaptic pruning share components of their underlying molecular machinery and may thus represent two developmental stages of the same type of synaptic modulation that serve different, but related, functions in neural circuit plasticity. We also assess the relationship between LTD and synaptic pruning in the context of recent findings of LTD dysregulation in several mouse models of autism spectrum disorder (ASD) and discuss whether LTD deficits can indicate impaired pruning processes that are required for proper brain development. PMID:27669991

  12. Electrophysiological Techniques for Studying Synaptic Activity In Vivo.

    Science.gov (United States)

    Jeggo, Ross; Zhao, Fei-Yue; Spanswick, David

    2014-03-03

    Understanding the physiology, pharmacology, and plasticity associated with synaptic function is a key goal of neuroscience research and is fundamental to identifying the processes involved in the development and manifestation of neurological disease. A diverse range of electrophysiological methodologies are used to study synaptic function. Described in this unit is a technique for recording electrical activity from a single component of the central nervous system that is used to investigate pre- and post-synaptic elements of synaptic function. A strength of this technique is that it can be used on live animals, although the effect of anesthesia must be taken into consideration when interpreting the results. This methodology can be employed not only in naïve animals for studying normal physiological synaptic function, but also in a variety of disease models, including transgenic animals, to examine dysfunctional synaptic plasticity associated with neurological pathologies. Copyright © 2013 John Wiley & Sons, Inc. All rights reserved.

  13. [Astrocytes and microglia: active players in synaptic plasticity].

    Science.gov (United States)

    Ronzano, Rémi

    2017-12-01

    Synaptic plasticity consists in a change in structure and composition of presynaptic and postsynaptic compartments. For a long time, synaptic plasticity had been thought as a neuronal mechanism only under the control of neural network activity. However, recently, with the growing knowledge about glial physiology, plasticity has been reviewed as a mechanism influenced by the synaptic environment. Thus, it appears that astrocytes and microglia modulate these mechanisms modifying neural environment by clearance of neurotransmitters, releasing essential factors and modulating inflammation. Moreover, glia can change its own activity and the expression pattern of many factors that modulate synaptic plasticity according to the environment. Hence, these populations of "non-neuronal" cells in the central nervous system seem to be active players in synaptic plasticity. This review discusses how glia modulates synaptic plasticity focusing on long-term potentiation and depression, and questions the role of the signaling processes between astrocytes and microglia in these mechanisms. © 2017 médecine/sciences – Inserm.

  14. Alteration of AMPA Receptor-Mediated Synaptic Transmission by Alexa Fluor 488 and 594 in Cerebellar Stellate Cells123

    Science.gov (United States)

    2016-01-01

    Abstract The fluorescent dyes, Alexa Fluor 488 and 594 are commonly used to visualize dendritic structures and the localization of synapses, both of which are critical for the spatial and temporal integration of synaptic inputs. However, the effect of the dyes on synaptic transmission is not known. Here we investigated whether Alexa Fluor dyes alter the properties of synaptic currents mediated by two subtypes of AMPA receptors (AMPARs) at cerebellar stellate cell synapses. In naive mice, GluA2-lacking AMPAR-mediated synaptic currents displayed an inwardly rectifying current–voltage (I–V) relationship due to blockade by cytoplasmic spermine at depolarized potentials. We found that the inclusion of 100 µm Alexa Fluor dye, but not 10 µm, in the pipette solution led to a gradual increase in the amplitude of EPSCs at +40 mV and a change in the I–V relationship from inwardly rectifying to more linear. In mice exposed to an acute stress, AMPARs switched to GluA2-containing receptors, and 100 µm Alexa Fluor 594 did not alter the I–V relationship of synaptic currents. Therefore, a high concentration of Alexa Fluor dye changed the I–V relationship of EPSCs at GluA2-lacking AMPAR synapses. PMID:27280156

  15. Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants

    OpenAIRE

    Hirata, Hiromi; Carta, Eloisa; Yamanaka, Iori; Harvey, Robert J.; Kuwada, John Y.

    2010-01-01

    Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo) mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR) β subunit genes. These mutants exhibit a loss of glycinergic synaptic ...

  16. Two Mutations Preventing PDZ-Protein Interactions of GluR1 Have Opposite Effects on Synaptic Plasticity

    Science.gov (United States)

    Boehm, Jannic; Ehrlich, Ingrid; Hsieh, Helen; Malinow, Roberto

    2006-01-01

    The regulated trafficking of GluR1 contributes significantly to synaptic plasticity, but studies addressing the function of the GluR1 C-terminal PDZ-ligand domain in this process have produced conflicting results. Here, we resolve this conflict by showing that apparently similar C-terminal mutations of the GluR1 PDZ-ligand domain result in…

  17. Biphasic response of action potential duration to metabolic inhibition in rabbit and human ventricular myocytes: role of transient outward current and ATP-regulated potassium current

    NARCIS (Netherlands)

    Verkerk, A. O.; Veldkamp, M. W.; van Ginneken, A. C.; Bouman, L. N.

    1996-01-01

    Inhibition of cell metabolism is associated with significant changes in action potential duration. The aim of this study was to investigate the time course of the changes in action potential duration during metabolic inhibition and to determine what changes in membrane currents are responsible. The

  18. 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.

  19. Mild hypoxia affects synaptic connectivity in cultured neuronal networks.

    Science.gov (United States)

    Hofmeijer, Jeannette; Mulder, Alex T B; Farinha, Ana C; van Putten, Michel J A M; le Feber, Joost

    2014-04-04

    Eighty percent of patients with chronic mild cerebral ischemia/hypoxia resulting from chronic heart failure or pulmonary disease have cognitive impairment. Overt structural neuronal damage is lacking and the precise cause of neuronal damage is unclear. As almost half of the cerebral energy consumption is used for synaptic transmission, and synaptic failure is the first abrupt consequence of acute complete anoxia, synaptic dysfunction is a candidate mechanism for the cognitive deterioration in chronic mild ischemia/hypoxia. Because measurement of synaptic functioning in patients is problematic, we use cultured networks of cortical neurons from new born rats, grown over a multi-electrode array, as a model system. These were exposed to partial hypoxia (partial oxygen pressure of 150Torr lowered to 40-50Torr) during 3 (n=14) or 6 (n=8) hours. Synaptic functioning was assessed before, during, and after hypoxia by assessment of spontaneous network activity, functional connectivity, and synaptically driven network responses to electrical stimulation. Action potential heights and shapes and non-synaptic stimulus responses were used as measures of individual neuronal integrity. During hypoxia of 3 and 6h, there was a statistically significant decrease of spontaneous network activity, functional connectivity, and synaptically driven network responses, whereas direct responses and action potentials remained unchanged. These changes were largely reversible. Our results indicate that in cultured neuronal networks, partial hypoxia during 3 or 6h causes isolated disturbances of synaptic connectivity. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Statistical mechanics of attractor neural network models with synaptic depression

    International Nuclear Information System (INIS)

    Igarashi, Yasuhiko; Oizumi, Masafumi; Otsubo, Yosuke; Nagata, Kenji; Okada, Masato

    2009-01-01

    Synaptic depression is known to control gain for presynaptic inputs. Since cortical neurons receive thousands of presynaptic inputs, and their outputs are fed into thousands of other neurons, the synaptic depression should influence macroscopic properties of neural networks. We employ simple neural network models to explore the macroscopic effects of synaptic depression. Systems with the synaptic depression cannot be analyzed due to asymmetry of connections with the conventional equilibrium statistical-mechanical approach. Thus, we first propose a microscopic dynamical mean field theory. Next, we derive macroscopic steady state equations and discuss the stabilities of steady states for various types of neural network models.

  1. Autophagy mediates the degradation of synaptic vesicles: A potential mechanism of synaptic plasticity injury induced by microwave exposure in rats.

    Science.gov (United States)

    Hao, Yanhui; Li, Wenchao; Wang, Hui; Zhang, Jing; Yu, Chao; Tan, Shengzhi; Wang, Haoyu; Xu, Xinping; Dong, Ji; Yao, Binwei; Zhou, Hongmei; Zhao, Li; Peng, Ruiyun

    2018-02-03

    To explore how autophagy changes and whether autophagy is involved in the pathophysiological process of synaptic plasticity injury caused by microwave radiation, we established a 30 mW/cm 2 microwave-exposure in vivo model, which caused reversible injuries in rat neurons. Microwave radiation induced cognitive impairment in rats and synaptic plasticity injury in rat hippocampal neurons. Autophagy in rat hippocampal neurons was activated following microwave exposure. Additionally, we observed that synaptic vesicles were encapsulated by autophagosomes, a phenomenon more evident in the microwave-exposed group. Colocation of autophagosomes and synaptic vesicles in rat hippocampal neurons increased following microwave exposure. microwave exposure led to the activation of autophagy in rat hippocampal neurons, and excessive activation of autophagy might damage synaptic plasticity by mediating synaptic vesicle degradation. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

    Directory of Open Access Journals (Sweden)

    Sung-Soo Jang

    2016-01-01

    Full Text Available Alzheimer’s disease (AD is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β (Aβ peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβ oligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβ levels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets.

  3. Demonstration of Synaptic Behaviors and Resistive Switching Characterizations by Proton Exchange Reactions in Silicon Oxide

    Science.gov (United States)

    Chang, Yao-Feng; Fowler, Burt; Chen, Ying-Chen; Zhou, Fei; Pan, Chih-Hung; Chang, Ting-Chang; Lee, Jack C.

    2016-02-01

    We realize a device with biological synaptic behaviors by integrating silicon oxide (SiOx) resistive switching memory with Si diodes. Minimal synaptic power consumption due to sneak-path current is achieved and the capability for spike-induced synaptic behaviors is demonstrated, representing critical milestones for the use of SiO2-based materials in future neuromorphic computing applications. Biological synaptic behaviors such as long-term potentiation (LTP), long-term depression (LTD) and spike-timing dependent plasticity (STDP) are demonstrated systematically using a comprehensive analysis of spike-induced waveforms, and represent interesting potential applications for SiOx-based resistive switching materials. The resistive switching SET transition is modeled as hydrogen (proton) release from (SiH)2 to generate the hydrogen bridge defect, and the RESET transition is modeled as an electrochemical reaction (proton capture) that re-forms (SiH)2. The experimental results suggest a simple, robust approach to realize programmable neuromorphic chips compatible with large-scale CMOS manufacturing technology.

  4. Synaptic conductances during interictal discharges in pyramidal neurons of rat entorhinal cortex

    Directory of Open Access Journals (Sweden)

    Dmitry V. Amakhin

    2016-10-01

    Full Text Available In epilepsy, the balance of excitation and inhibition underlying the basis of neural network activity shifts, resulting in neuronal network hyperexcitability and recurrent seizure-associated discharges. Mechanisms involved in ictal and