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Sample records for psd synapse types

  1. Proteomic Studies of a Single CNS Synapse Type: The Parallel Fiber/Purkinje Cell Synapse

    Science.gov (United States)

    Selimi, Fekrije; Cristea, Ileana M; Heller, Elizabeth; Chait, Brian T; Heintz, Nathaniel

    2009-01-01

    Precise neuronal networks underlie normal brain function and require distinct classes of synaptic connections. Although it has been shown that certain individual proteins can localize to different classes of synapses, the biochemical composition of specific synapse types is not known. Here, we have used a combination of genetically engineered mice, affinity purification, and mass spectrometry to profile proteins at parallel fiber/Purkinje cell synapses. We identify approximately 60 candidate postsynaptic proteins that can be classified into 11 functional categories. Proteins involved in phospholipid metabolism and signaling, such as the protein kinase MRCKγ, are major unrecognized components of this synapse type. We demonstrate that MRCKγ can modulate maturation of dendritic spines in cultured cortical neurons, and that it is localized specifically to parallel fiber/Purkinje cell synapses in vivo. Our data identify a novel synapse-specific signaling pathway, and provide an approach for detailed investigations of the biochemical complexity of central nervous system synapse types. PMID:19402746

  2. The Biochemical Anatomy of Cortical Inhibitory Synapses

    Science.gov (United States)

    Heller, Elizabeth A.; Zhang, Wenzhu; Selimi, Fekrije; Earnheart, John C.; Ślimak, Marta A.; Santos-Torres, Julio; Ibañez-Tallon, Ines; Aoki, Chiye; Chait, Brian T.; Heintz, Nathaniel

    2012-01-01

    Classical electron microscopic studies of the mammalian brain revealed two major classes of synapses, distinguished by the presence of a large postsynaptic density (PSD) exclusively at type 1, excitatory synapses. Biochemical studies of the PSD have established the paradigm of the synapse as a complex signal-processing machine that controls synaptic plasticity. We report here the results of a proteomic analysis of type 2, inhibitory synaptic complexes isolated by affinity purification from the cerebral cortex. We show that these synaptic complexes contain a variety of neurotransmitter receptors, neural cell-scaffolding and adhesion molecules, but that they are entirely lacking in cell signaling proteins. This fundamental distinction between the functions of type 1 and type 2 synapses in the nervous system has far reaching implications for models of synaptic plasticity, rapid adaptations in neural circuits, and homeostatic mechanisms controlling the balance of excitation and inhibition in the mature brain. PMID:22768092

  3. Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence

    Directory of Open Access Journals (Sweden)

    Esperanza Fernández

    2017-10-01

    Full Text Available Arc is an activity-regulated neuronal protein, but little is known about its interactions, assembly into multiprotein complexes, and role in human disease and cognition. We applied an integrated proteomic and genetic strategy by targeting a tandem affinity purification (TAP tag and Venus fluorescent protein into the endogenous Arc gene in mice. This allowed biochemical and proteomic characterization of native complexes in wild-type and knockout mice. We identified many Arc-interacting proteins, of which PSD95 was the most abundant. PSD95 was essential for Arc assembly into 1.5-MDa complexes and activity-dependent recruitment to excitatory synapses. Integrating human genetic data with proteomic data showed that Arc-PSD95 complexes are enriched in schizophrenia, intellectual disability, autism, and epilepsy mutations and normal variants in intelligence. We propose that Arc-PSD95 postsynaptic complexes potentially affect human cognitive function.

  4. Prevention of Noise Damage to Cochlear Synapses

    Science.gov (United States)

    2015-10-01

    deafness still suffices to cause a significant hearing impairment by destroying synapses between hair cells and cochlear (spiral ganglion) neurons. This...localized PSD and ribbon. Synapses are counted in the confocal image stacks with an optical disector technique. The total number of synapses on IHCs in each

  5. Beta1-adrenergic receptor-mediated dilation of rat cerebral artery requires Shaker-type KV1 channels on PSD95 scaffold.

    Science.gov (United States)

    Moore, Christopher L; McClenahan, Samantha J; Hanvey, Hillary M; Jang, Dae-Song; Nelson, Piper L; Joseph, Biny K; Rhee, Sung W

    2015-09-01

    Postsynaptic density-95 (PSD95) is a scaffolding protein in cerebral vascular smooth muscle cells (cVSMCs), which binds to Shaker-type K(+) (KV1) channels and facilitates channel opening through phosphorylation by protein kinase A. β1-Adrenergic receptors (β1ARs) also have a binding motif for PSD95. Functional association of β1AR with KV1 channels through PSD95 may represent a novel vasodilator complex in cerebral arteries (CA). We explored whether a β1AR-PSD95-KV1 complex is a determinant of rat CA dilation. RT-PCR and western blots revealed expression of β1AR in CA. Isoproterenol induced a concentration-dependent dilation of isolated, pressurized rat CA that was blocked by the β1AR blocker CGP20712. Cranial window imaging of middle cerebral arterioles in situ showed isoproterenol- and norepinephrine-induced dilation that was blunted by β1AR blockade. Isoproterenol-induced hyperpolarization of cVSMCs in pressurized CA was blocked by CGP20712. Confocal images of cVSMCs immunostained with antibodies against β1AR and PSD95 indicated strong colocalization, and PSD95 co-immunoprecipitated with β1AR in CA lysate. Blockade of KV1 channels, β1AR or disruption of PSD95-KV1 interaction produced similar blunting of isoproterenol-induced dilation in pressurized CA. These findings suggest that PSD95 mediates a vasodilator complex with β1AR and KV1 channels in cVSMCs. This complex may be critical for proper vasodilation in rat CA.

  6. Posttranslational Modifications Regulate the Postsynaptic Localization of PSD-95.

    Science.gov (United States)

    Vallejo, Daniela; Codocedo, Juan F; Inestrosa, Nibaldo C

    2017-04-01

    The postsynaptic density (PSD) consists of a lattice-like array of interacting proteins that organizes and stabilizes synaptic receptors, ion channels, structural proteins, and signaling molecules required for normal synaptic transmission and synaptic function. The scaffolding and hub protein postsynaptic density protein-95 (PSD-95) is a major element of central chemical synapses and interacts with glutamate receptors, cell adhesion molecules, and cytoskeletal elements. In fact, PSD-95 can regulate basal synaptic stability as well as the activity-dependent structural plasticity of the PSD and, therefore, of the excitatory chemical synapse. Several studies have shown that PSD-95 is highly enriched at excitatory synapses and have identified multiple protein structural domains and protein-protein interactions that mediate PSD-95 function and trafficking to the postsynaptic region. PSD-95 is also a target of several signaling pathways that induce posttranslational modifications, including palmitoylation, phosphorylation, ubiquitination, nitrosylation, and neddylation; these modifications determine the synaptic stability and function of PSD-95 and thus regulate the fates of individual dendritic spines in the nervous system. In the present work, we review the posttranslational modifications that regulate the synaptic localization of PSD-95 and describe their functional consequences. We also explore the signaling pathways that induce such changes.

  7. Live imaging of endogenous PSD-95 using ENABLED: a conditional strategy to fluorescently label endogenous proteins.

    Science.gov (United States)

    Fortin, Dale A; Tillo, Shane E; Yang, Guang; Rah, Jong-Cheol; Melander, Joshua B; Bai, Suxia; Soler-Cedeño, Omar; Qin, Maozhen; Zemelman, Boris V; Guo, Caiying; Mao, Tianyi; Zhong, Haining

    2014-12-10

    Stoichiometric labeling of endogenous synaptic proteins for high-contrast live-cell imaging in brain tissue remains challenging. Here, we describe a conditional mouse genetic strategy termed endogenous labeling via exon duplication (ENABLED), which can be used to fluorescently label endogenous proteins with near ideal properties in all neurons, a sparse subset of neurons, or specific neuronal subtypes. We used this method to label the postsynaptic density protein PSD-95 with mVenus without overexpression side effects. We demonstrated that mVenus-tagged PSD-95 is functionally equivalent to wild-type PSD-95 and that PSD-95 is present in nearly all dendritic spines in CA1 neurons. Within spines, while PSD-95 exhibited low mobility under basal conditions, its levels could be regulated by chronic changes in neuronal activity. Notably, labeled PSD-95 also allowed us to visualize and unambiguously examine otherwise-unidentifiable excitatory shaft synapses in aspiny neurons, such as parvalbumin-positive interneurons and dopaminergic neurons. Our results demonstrate that the ENABLED strategy provides a valuable new approach to study the dynamics of endogenous synaptic proteins in vivo. Copyright © 2014 the authors 0270-6474/14/3416698-15$15.00/0.

  8. Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels.

    Science.gov (United States)

    Zhao, Yanjun; Sivaji, Sivaprakash; Chiang, Michael C; Ali, Haadi; Zukowski, Monica; Ali, Sareen; Kennedy, Bryan; Sklyar, Alex; Cheng, Alice; Guo, Zihan; Reed, Alexander K; Kodali, Ravindra; Borowski, Jennifer; Frost, Georgia; Beukema, Patrick; Wills, Zachary P

    2017-10-11

    Compelling evidence links amyloid beta (Aβ) peptide accumulation in the brains of Alzheimer's disease (AD) patients with the emergence of learning and memory deficits, yet a clear understanding of the events that drive this synaptic pathology are lacking. We present evidence that neurons exposed to Aβ are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) acts as Aβ receptors mediating an inhibition of synapse assembly, plasticity, and learning. Live imaging studies reveal Aβ activates NgRs on the dendritic shaft of neurons, triggering an inhibition of calcium signaling. We define T-type calcium channels as a target of Aβ-NgR signaling, mediating Aβ's inhibitory effects on calcium, synapse assembly, plasticity, and learning. These studies highlight deficits in new synapse assembly as a potential initiator of cognitive pathology in AD, and pinpoint calcium dysregulation mediated by NgRs and T-type channels as key components. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence.

    Science.gov (United States)

    Fernández, Esperanza; Collins, Mark O; Frank, René A W; Zhu, Fei; Kopanitsa, Maksym V; Nithianantharajah, Jess; Lemprière, Sarah A; Fricker, David; Elsegood, Kathryn A; McLaughlin, Catherine L; Croning, Mike D R; Mclean, Colin; Armstrong, J Douglas; Hill, W David; Deary, Ian J; Cencelli, Giulia; Bagni, Claudia; Fromer, Menachem; Purcell, Shaun M; Pocklington, Andrew J; Choudhary, Jyoti S; Komiyama, Noboru H; Grant, Seth G N

    2017-10-17

    Arc is an activity-regulated neuronal protein, but little is known about its interactions, assembly into multiprotein complexes, and role in human disease and cognition. We applied an integrated proteomic and genetic strategy by targeting a tandem affinity purification (TAP) tag and Venus fluorescent protein into the endogenous Arc gene in mice. This allowed biochemical and proteomic characterization of native complexes in wild-type and knockout mice. We identified many Arc-interacting proteins, of which PSD95 was the most abundant. PSD95 was essential for Arc assembly into 1.5-MDa complexes and activity-dependent recruitment to excitatory synapses. Integrating human genetic data with proteomic data showed that Arc-PSD95 complexes are enriched in schizophrenia, intellectual disability, autism, and epilepsy mutations and normal variants in intelligence. We propose that Arc-PSD95 postsynaptic complexes potentially affect human cognitive function. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. A Specific Nutrient Combination Attenuates the Reduced Expression of PSD-95 in the Proximal Dendrites of Hippocampal Cell Body Layers in a Mouse Model of Phenylketonuria

    Science.gov (United States)

    Bruinenberg, Vibeke M.; van Vliet, Danique; Attali, Amos; de Wilde, Martijn C.; Kuhn, Mirjam; van Spronsen, Francjan J.; van der Zee, Eddy A.

    2016-01-01

    The inherited metabolic disease phenylketonuria (PKU) is characterized by increased concentrations of phenylalanine in the blood and brain, and as a consequence neurotransmitter metabolism, white matter, and synapse functioning are affected. A specific nutrient combination (SNC) has been shown to improve synapse formation, morphology and function. This could become an interesting new nutritional approach for PKU. To assess whether treatment with SNC can affect synapses, we treated PKU mice with SNC or an isocaloric control diet and wild-type (WT) mice with an isocaloric control for 12 weeks, starting at postnatal day 31. Immunostaining for post-synaptic density protein 95 (PSD-95), a post-synaptic density marker, was carried out in the hippocampus, striatum and prefrontal cortex. Compared to WT mice on normal chow without SNC, PKU mice on the isocaloric control showed a significant reduction in PSD-95 expression in the hippocampus, specifically in the granular cell layer of the dentate gyrus, with a similar trend seen in the cornus ammonis 1 (CA1) and cornus ammonis 3 (CA3) pyramidal cell layer. No differences were found in the striatum or prefrontal cortex. PKU mice on a diet supplemented with SNC showed improved expression of PSD-95 in the hippocampus. This study gives the first indication that SNC supplementation has a positive effect on hippocampal synaptic deficits in PKU mice. PMID:27102170

  11. Chemosensory organs as models of neuronal synapses.

    Science.gov (United States)

    Shaham, Shai

    2010-03-01

    Neuronal synapses are important microstructures that underlie complex cognitive capacities. Recent studies, primarily in Caenorhabditis elegans and Drosophila melanogaster, have revealed surprising parallels between these synapses and the 'chemosensory synapses' that reside at the tips of chemosensory cells that respond to environmental stimuli. Similarities in the structures, mechanisms of action and specific molecules found at these sites extend to the presynaptic, postsynaptic and glial entities composing both synapse types. In this article I propose that chemosensory synapses may serve as useful models of neuronal synapses, and consider the possibility that the two synapse types derive from a common ancestral structure.

  12. Diversity of Spine Synapses in Animals

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    Wang, Ya-Xian; Mattson, Mark P.; Yao, Pamela J.

    2016-01-01

    Here we examine the structure of the various types of spine synapses throughout the animal kingdom. Based on available evidence, we suggest that there are two major categories of spine synapses: invaginating and non-invaginating, with distributions that vary among different groups of animals. In the simplest living animals with definitive nerve cells and synapses, the cnidarians and ctenophores, most chemical synapses do not form spine synapses. But some cnidarians have invaginating spine synapses, especially in photoreceptor terminals of motile cnidarians with highly complex visual organs, and also in some mainly sessile cnidarians with rapid prey capture reflexes. This association of invaginating spine synapses with complex sensory inputs is retained in the evolution of higher animals in photoreceptor terminals and some mechanoreceptor synapses. In contrast to invaginating spine synapse, non-invaginating spine synapses have been described only in animals with bilateral symmetry, heads and brains, associated with greater complexity in neural connections. This is apparent already in the simplest bilaterians, the flatworms, which can have well-developed non-invaginating spine synapses in some cases. Non-invaginating spine synapses diversify in higher animal groups. We also discuss the functional advantages of having synapses on spines and more specifically, on invaginating spines. And finally we discuss pathologies associated with spine synapses, concentrating on those systems and diseases where invaginating spine synapses are involved. PMID:27230661

  13. Splicing-Dependent Trans-synaptic SALM3–LAR-RPTP Interactions Regulate Excitatory Synapse Development and Locomotion

    Directory of Open Access Journals (Sweden)

    Yan Li

    2015-09-01

    Full Text Available Synaptic adhesion molecules regulate diverse aspects of synapse development and plasticity. SALM3 is a PSD-95-interacting synaptic adhesion molecule known to induce presynaptic differentiation in contacting axons, but little is known about its presynaptic receptors and in vivo functions. Here, we identify an interaction between SALM3 and LAR family receptor protein tyrosine phosphatases (LAR-RPTPs that requires the mini-exon B splice insert in LAR-RPTPs. In addition, SALM3-dependent presynaptic differentiation requires all three types of LAR-RPTPs. SALM3 mutant (Salm3−/− mice display markedly reduced excitatory synapse number but normal synaptic plasticity in the hippocampal CA1 region. Salm3−/− mice exhibit hypoactivity in both novel and familiar environments but perform normally in learning and memory tests administered. These results suggest that SALM3 regulates excitatory synapse development and locomotion behavior.

  14. PSD Increment Consumption Guidance

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    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  15. PSD Increment Consumption Question

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  16. Neuroligin-1 loss is associated with reduced tenacity of excitatory synapses.

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    Adel Zeidan

    Full Text Available Neuroligins (Nlgns are postsynaptic, integral membrane cell adhesion molecules that play important roles in the formation, validation, and maturation of synapses in the mammalian central nervous system. Given their prominent roles in the life cycle of synapses, it might be expected that the loss of neuroligin family members would affect the stability of synaptic organization, and ultimately, affect the tenacity and persistence of individual synaptic junctions. Here we examined whether and to what extent the loss of Nlgn-1 affects the dynamics of several key synaptic molecules and the constancy of their contents at individual synapses over time. Fluorescently tagged versions of the postsynaptic scaffold molecule PSD-95, the AMPA-type glutamate receptor subunit GluA2 and the presynaptic vesicle molecule SV2A were expressed in primary cortical cultures from Nlgn-1 KO mice and wild-type (WT littermates, and live imaging was used to follow the constancy of their contents at individual synapses over periods of 8-12 hours. We found that the loss of Nlgn-1 was associated with larger fluctuations in the synaptic contents of these molecules and a poorer preservation of their contents at individual synapses. Furthermore, rates of synaptic turnover were somewhat greater in neurons from Nlgn-1 knockout mice. Finally, the increased GluA2 redistribution rates observed in neurons from Nlgn-1 knockout mice were negated by suppressing spontaneous network activity. These findings suggest that the loss of Nlgn-1 is associated with some use-dependent destabilization of excitatory synapse organization, and indicate that in the absence of Nlgn-1, the tenacity of excitatory synapses might be somewhat impaired.

  17. New players tip the scales in the balance between excitatory and inhibitory synapses

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    El-Husseini Alaa

    2005-03-01

    Full Text Available Abstract Synaptogenesis is a highly controlled process, involving a vast array of players which include cell adhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteins associated with the synaptic vesicle machinery. These molecules cooperate in an intricate manner on both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts. This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputs but virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight control of a balance between the types of synapses formed regulates the overall neuronal excitability, and is thus critical for normal brain function and plasticity. However, little is known about how this balance is achieved. This review discusses recent findings which provide clues to how neurons may control excitatory and inhibitory synapse formation, with focus on the involvement of the neuroligin family and PSD-95 in this process.

  18. AII amacrine cells express L-type calcium channels at their output synapses.

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    Habermann, Christopher J; O'Brien, Brendan J; Wässle, Heinz; Protti, Dario A

    2003-07-30

    AII amacrine cells play a critical role in the high-fidelity signal transmission pathways involved with nighttime vision. The temporal properties of the light responses strongly depend on the transfer function at different synaptic stages and consequently on presynaptic calcium influx. AII light responses are complex waveforms generated by graded input, they comprise Na+-based spikes as well as a sustained component, and they are transferred to graded cone bipolar cells. It is, therefore, of interest to determine the properties of AII voltage-dependent calcium channels (VDCCs) to establish whether these cells express N-type and/or P/Q-type VDCCs, characteristic of spiking neurons, or whether they are more like graded neurons, which mostly use L-type VDCCs. We combined electrophysiological, molecular biological, and imaging techniques to characterize calcium currents and their sites of origin in mouse AII amacrine cells. Calcium currents activated at potentials more positive than -60 mV (maximally between -50 and -20 mV) and inactivated slowly. These currents were blocked by dihydropyridine (DHP) antagonists and were enhanced by the DHP agonist BayK 8644. Single-cell RT-PCR analysis of mRNA encoding for different calcium channel alpha subunits in AIIs revealed a consistent expression of the alpha1-D subunit. Calcium imaging of AII cells showed that the greatest change in intracellular calcium occurred in the lobular appendages, with minor changes being observed in the arboreal dendrites. Depolarization-induced calcium rises were also modulated by DHPs, suggesting that a particular kind of L-type VDCC, mainly localized to the lobular appendages, enables these spiking-capable neurons to release neurotransmitter in a sustained manner onto OFF-cone bipolar cells.

  19. VID22 is required for transcriptional activation of the PSD2 gene in the yeast Saccharomyces cerevisiae.

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    Miyata, Non; Miyoshi, Takuya; Yamaguchi, Takanori; Nakazono, Toshimitsu; Tani, Motohiro; Kuge, Osamu

    2015-12-15

    Phosphatidylethanolamine (PE) in the yeast Saccharomyces cerevisiae is synthesized through decarboxylation of phosphatidylserine (PS), catalysed by PS decarboxylase 1 (Psd1p) and 2 (Psd2p) and the cytidine 5'-diphosphate (CDP)-ethanolamine (CDP-Etn) pathway. PSD1 null (psd1Δ) and PSD2 null (psd2Δ) mutants are viable in a synthetic minimal medium, but a psdpsd2Δ double mutant exhibits Etn auxotrophy, which is incorporated into PE through the CDP-Etn pathway. We have previously shown that psd1Δ is synthetic lethal with deletion of VID22 (vid22Δ) [Kuroda et al. (2011) Mol. Microbiol. 80: , 248-265]. In the present study, we found that vid22Δ mutant exhibits Etn auxotrophy under PSD1-depressed conditions. Deletion of VID22 in wild-type and PSD1-depressed cells caused partial defects in PE formation through decarboxylation of PS. The enzyme activity of PS decarboxylase in an extract of vid22Δ cells was ∼70% of that in wild-type cells and similar to that in psd2Δ cells and the PS decarboxylase activity remaining in the PSD1-depressed cells became almost negligible with deletion of VID22. Thus, the vid22Δ mutation was suggested to cause a defect in the Psd2p activity. Furthermore, vid22Δ cells were shown to be defective in expression of the PSD2 gene tagged with 6×HA, the defect being ameliorated by replacement of the native promoter of the PSD2 gene with a CYC1 promoter. In addition, an α-galactosidase reporter assay revealed that the activity of the promoter of the PSD2 gene in vid22Δ cells was ∼5% of that in wild-type cells. These results showed that VID22 is required for transcriptional activation of the PSD2 gene. © 2015 Authors; published by Portland Press Limited.

  20. Type 7 adenylyl cyclase is involved in the ethanol and CRF sensitivity of GABAergic synapses in mouse central amygdala

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    Maureen T. Cruz

    2011-01-01

    Full Text Available AbstractThe GABAergic system in the central amygdala (CeA plays a major role in ethanol dependence and in the anxiogenic response to ethanol withdrawal. Previously, we found that both ethanol and corticotropin releasing factor (CRF increase GABAergic transmission in mouse and rat CeA neurons, in part by enhancing the release of GABA via activation of presynaptic CRF1 receptors. CRF1 receptors are coupled to the enzyme adenylyl cyclase (AC, which produces the second messenger cyclic AMP. There are nine isoforms of AC, but we recently found that CRF1 receptors in the pituitary were coupled to the Type 7 AC (AC7. Therefore, using an in vitro electrophysiological approach in brain slices, here we have investigated a possible role of the AC7 signaling pathway in ethanol and CRF effects on CeA GABAergic synapses of genetically modified mice with diminished brain Adcy7 activity (HET compared to their littermate male wild type (WT mice. We found no significant differences in basal membrane properties, mean baseline amplitude of evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs, or paired-pulse facilitation (PPF of GABAA-IPSPs between HET and WT mice. In CeA neurons of WT mice, ethanol superfusion significantly augmented (by 39% GABAA-IPSPs and decreased PPF (by 25%, suggesting increased presynaptic GABA release. However, these effects were absent in HET mice. CRF superfusion also significantly augmented IPSPs (by 38% and decreased PPF (by 23% in WT CeA neurons, and still elicited a significant but smaller (by 13% increase of IPSP amplitude, but no effect on PPF, in HET mice. These electrophysiological data suggest that AC7 plays an important role in ethanol and CRF modulation of presynaptic GABA release in CeA and thus may underlie ethanol-related behaviors such as anxiety and dependence.

  1. Diffusion barriers constrain receptors at synapses.

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    Marianne Renner

    Full Text Available The flux of neurotransmitter receptors in and out of synapses depends on receptor interaction with scaffolding molecules. However, the crowd of transmembrane proteins and the rich cytoskeletal environment may constitute obstacles to the diffusion of receptors within the synapse. To address this question, we studied the membrane diffusion of the γ-aminobutyric acid type A receptor (GABA(AR subunits clustered (γ2 or not (α5 at inhibitory synapses in rat hippocampal dissociated neurons. Relative to the extrasynaptic region, γ2 and α5 showed reduced diffusion and increased confinement at both inhibitory and excitatory synapses but they dwelled for a short time at excitatory synapses. In contrast, γ2 was ~3-fold more confined and dwelled ~3-fold longer in inhibitory synapses than α5, indicating faster synaptic escape of α5. Furthermore, using a gephyrin dominant-negative approach, we showed that the increased residency time of γ2 at inhibitory synapses was due to receptor-scaffold interactions. As shown for GABA(AR, the excitatory glutamate receptor 2 subunit (GluA2 of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR had lower mobility in both excitatory and inhibitory synapses but a higher residency time at excitatory synapses. Therefore barriers impose significant diffusion constraints onto receptors at synapses where they accumulate or not. Our data further reveal that the confinement and the dwell time but not the diffusion coefficient report on the synapse specific sorting, trapping and accumulation of receptors.

  2. Long-duration epilepsy affects cell morphology and glutamatergic synapses in type IIB focal cortical dysplasia.

    Science.gov (United States)

    Finardi, Adele; Colciaghi, Francesca; Castana, Laura; Locatelli, Denise; Marras, Carlo Efisio; Nobili, Paola; Fratelli, Maddalena; Bramerio, Manuela Adele; Lorusso, Giorgio; Battaglia, Giorgio Stefano

    2013-08-01

    To investigate hypothesized effects of severe epilepsy on malformed cortex, we analyzed surgical samples from eight patients with type IIB focal cortical dysplasia (FCD) in comparison with samples from nine non-dysplastic controls. We investigated, using stereological quantification methods, where appropriate, dysplastic neurons, neuronal density, balloon cells, glia, glutamatergic synaptic input, and the expression of N-methyl-D-aspartate (NMDA) receptor subunits and associated membrane-associated guanylate kinase (MAGUK). In all FCD patients, the dysplastic areas giving rise to epileptic discharges were characterized by larger dysmorphic neurons, reduced neuronal density, and increased glutamatergic inputs, compared to adjacent areas with normal cytology. The duration of epilepsy was found to correlate directly (a) with dysmorphic neuron size, (b) reduced neuronal cell density, and (c) extent of reactive gliosis in epileptogenic/dysplastic areas. Consistent with increased glutamatergic input, western blot revealed that NMDA regulatory subunits and related MAGUK proteins were up-regulated in epileptogenic/dysplastic areas of all FCD patients examined. Taken together, these results support the hypothesis that epilepsy itself alters morphology-and probably also function-in the malformed epileptic brain. They also suggest that glutamate/NMDA/MAGUK dysregulation might be the intracellular trigger that modifies brain morphology and induces cell death.

  3. The sticky synapse

    DEFF Research Database (Denmark)

    Owczarek, Sylwia Elzbieta; Kristiansen, Lars Villiam; Hortsch, Michael

    NCAM-type proteins modulate multiple neuronal functions, including the outgrowth and guidance of neurites, the formation, maturation, and plasticity of synapses, and the induction of both long-term potentiation and long-term depression. The ectodomains of NCAM proteins have a basic structure...... signal transduction. A central feature of the synaptic function of NCAM proteins is the regulation of their extracellular interactions by adhesion-modulating glycoepitopes, their removal from the cell surface by endocytosis, and the elimination of their adhesion-mediating interactions by the proteolytic...

  4. Remote Laser Diffraction PSD Analyzer

    Energy Technology Data Exchange (ETDEWEB)

    Batcheller, Thomas Aquinas; Huestis, Gary Michael; Bolton, Steven Michael

    2000-06-01

    Particle size distribution (PSD) analysis of radioactive slurry samples were obtained using a modified "off-the-shelf" classical laser light scattering particle size analyzer. A Horiba Instruments Inc. Model La-300 PSD analyzer, which has a 0.1 to 600 micron measurement range, was modified for remote application in a "hot cell" (gamma radiation) environment. The general details of the modifications to this analyzer are presented in this paper. This technology provides rapid and simple PSD analysis, especially down in the fine and microscopic particle size regime. Particle size analysis of these radioactive slurries down in this smaller range was not achievable - making this technology far superior than the traditional methods used previously. Remote deployment and utilization of this technology is in an exploratory stage. The risk of malfunction in this radiation environment is countered by gaining of this tremendously useful fundamental engineering data. Successful acquisition of this data, in conjunction with other characterization analyses, provides important information that can be used in the myriad of potential radioactive waste management alternatives.

  5. The regulated secretory pathway in CD4(+ T cells contributes to human immunodeficiency virus type-1 cell-to-cell spread at the virological synapse.

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    Clare Jolly

    2011-09-01

    Full Text Available Direct cell-cell spread of Human Immunodeficiency Virus type-1 (HIV-1 at the virological synapse (VS is an efficient mode of dissemination between CD4(+ T cells but the mechanisms by which HIV-1 proteins are directed towards intercellular contacts is unclear. We have used confocal microscopy and electron tomography coupled with functional virology and cell biology of primary CD4(+ T cells from normal individuals and patients with Chediak-Higashi Syndrome and report that the HIV-1 VS displays a regulated secretion phenotype that shares features with polarized secretion at the T cell immunological synapse (IS. Cell-cell contact at the VS re-orientates the microtubule organizing center (MTOC and organelles within the HIV-1-infected T cell towards the engaged target T cell, concomitant with polarization of viral proteins. Directed secretion of proteins at the T cell IS requires specialized organelles termed secretory lysosomes (SL and we show that the HIV-1 envelope glycoprotein (Env localizes with CTLA-4 and FasL in SL-related compartments and at the VS. Finally, CD4(+ T cells that are disabled for regulated secretion are less able to support productive cell-to-cell HIV-1 spread. We propose that HIV-1 hijacks the regulated secretory pathway of CD4(+ T cells to enhance its dissemination.

  6. PSD Determination, Portland Cement Plant

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    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  7. Effect of complex aerobic physical exercise on PSD-95 in the hippocampus and on cognitive function in juvenile mice

    Science.gov (United States)

    Satriani, W. H.; Redjeki, S.; Kartinah, N. T.

    2017-08-01

    Increased neuroplasticity induced by complex aerobic physical exercise is associated with improved cognitive function in adult mice. Increased cognitive function is assumed to be based on increased synapse formation. One of the regions of the brain that is important in cognitive function is the hippocampus, which plays a role in memory formation. Post synaptic density-95 (PSD-95) is an adhesion protein of the post-synaptic density scaffolding that is essential to synaptic stabilization. As we age, the PSD-95 molecule matures the synapses needed for the formation of the basic circuitry of the nervous system in the brain. However, during the growth period, synapse elimination is higher than its formation. This study aims to determine whether complex aerobic exercise can improve cognitive function and PSD-95 levels in the hippocampus of juvenile mice during their growth stage. The mice performed complex aerobic exercise starting at five weeks of age and continuing for seven weeks with a gradual increase of 8 m/min. At eight weeks it was increased to 10 m/min. The exercise was done for five days of each week. The subjects of the study were tested for cognition one week before being sacrificed (at 12 weeks). The PSD-95 in the hippocampus was measured with ELISA. The results showed that there was a significant difference in cognitive function, where p exercise and a control group that did not. However, the PSD-95 levels did not differ significantly between the two groups. The results of this study indicate that early complex aerobic exercise can improve cognitive ability in adulthood but does not increase the levels of PSD-95 in adults.

  8. Calcium channel-dependent molecular maturation of photoreceptor synapses.

    Directory of Open Access Journals (Sweden)

    Nawal Zabouri

    Full Text Available Several studies have shown the importance of calcium channels in the development and/or maturation of synapses. The Ca(V1.4(α(1F knockout mouse is a unique model to study the role of calcium channels in photoreceptor synapse formation. It features abnormal ribbon synapses and aberrant cone morphology. We investigated the expression and targeting of several key elements of ribbon synapses and analyzed the cone morphology in the Ca(V1.4(α(1F knockout retina. Our data demonstrate that most abnormalities occur after eye opening. Indeed, scaffolding proteins such as Bassoon and RIM2 are properly targeted at first, but their expression and localization are not maintained in adulthood. This indicates that either calcium or the Ca(V1.4 channel, or both are necessary for the maintenance of their normal expression and distribution in photoreceptors. Other proteins, such as Veli3 and PSD-95, also display abnormal expression in rods prior to eye opening. Conversely, vesicle related proteins appear normal. Our data demonstrate that the Ca(V1.4 channel is important for maintaining scaffolding proteins in the ribbon synapse but less vital for proteins related to vesicular release. This study also confirms that in adult retinae, cones show developmental features such as sprouting and synaptogenesis. Overall we present evidence that in the absence of the Ca(V1.4 channel, photoreceptor synapses remain immature and are unable to stabilize.

  9. Comparative anatomy of phagocytic and immunological synapses

    Directory of Open Access Journals (Sweden)

    Florence eNiedergang

    2016-01-01

    Full Text Available The generation of phagocytic cups and immunological synapses are crucial events of the innate and adaptive immune responses, respectively. They are triggered by distinct immune receptors and performed by different cell types. However, growing experimental evidence shows that a very close series of molecular and cellular events control these two processes. Thus, the tight and dynamic interplay between receptor signaling, actin and microtubule cytoskeleton, and targeted vesicle traffic are all critical features to build functional phagosomes and immunological synapses. Interestingly, both phagocytic cups and immunological synapses display particular spatial and temporal patterns of receptors and signaling molecules, leading to the notion of phagocytic synapse. Here we discuss both types of structures, their organization and the mechanisms by which they are generated and regulated.

  10. Differences in the multiple step process of inhibition of neurotransmitter release induced by tetanus toxin and botulinum neurotoxins type A and B at Aplysia synapses.

    Science.gov (United States)

    Poulain, B; De Paiva, A; Deloye, F; Doussau, F; Tauc, L; Weller, U; Dolly, J O

    1996-01-01

    In order to gain insights into the steps (binding, uptake, intracellular effect) which differ in the inhibitory actions of tetanus toxin and botulinum neurotoxins types A or B, their temperature dependencies were investigated at identified cholinergic and non-cholinergic synapses in Aplysia. Upon lowering the temperature from 22 degrees C to 10 degrees C, extracellularly applied botulinum neurotoxin type A and B appeared unable to inhibit transmitter release whilst tetanus toxin exhibited a residual activity. Binding of each toxin to the neuronal membrane appeared virtually unaltered following this temperature change. By contrast, the intracellular effects of botulinum neurotoxin type B and tetanus toxin were strongly attenuated by temperature reduction whereas the inhibitory action of botulinum neurotoxin type A was only moderately reduced. Importantly, this discrepancy relates to the known proteolytic cleavage of different synaptic proteins by these two toxin groups. Since both the binding and intracellular activity of botulinum neurotoxin type A are minimally affected at 10 degrees C, its inability to inhibit neurotransmission at this low temperature when applied extracellularly indicated attenuation of its uptake. Due to the strict temperature dependence of the intracellular action of tetanus toxin and botulinum neurotoxin type B, but not A, an examination of the effects of changes in temperature on the internalization step was facilitated by the use of heterologous mixtures of the toxins' heavy and light chains. At 10 degrees C, heavy chain from tetanus toxin but not from botulinum neurotoxin type B mediated uptake of botulinum neurotoxin type A light chain. Collectively, these results provide evidence that, at least in Aplysia, the uptake mechanism for botulinum neurotoxin types A and B differs from that of tetanus toxin.

  11. Synapses and Memory Storage

    OpenAIRE

    Mayford, Mark; Siegelbaum, Steven A.; Kandel, Eric R.

    2012-01-01

    The synapse is the functional unit of the brain. During the last several decades we have acquired a great deal of information on its structure, molecular components, and physiological function. It is clear that synapses are morphologically and molecularly diverse and that this diversity is recruited to different functions. One of the most intriguing findings is that the size of the synaptic response in not invariant, but can be altered by a variety of homo- and heterosynaptic factors such as ...

  12. Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses.

    Directory of Open Access Journals (Sweden)

    Laurent Ladepeche

    Full Text Available Dopamine receptor potently modulates glutamate signalling, synaptic plasticity and neuronal network adaptations in various pathophysiological processes. Although key intracellular signalling cascades have been identified, the cellular mechanism by which dopamine and glutamate receptor-mediated signalling interplay at glutamate synapse remain poorly understood. Among the cellular mechanisms proposed to aggregate D1R in glutamate synapses, the direct interaction between D1R and the scaffold protein PSD95 or the direct interaction with the glutamate NMDA receptor (NMDAR have been proposed. To tackle this question we here used high-resolution single nanoparticle imaging since it provides a powerful way to investigate at the sub-micron resolution the dynamic interaction between these partners in live synapses. We demonstrate in hippocampal neuronal networks that dopamine D1 receptors (D1R laterally diffuse within glutamate synapses, in which their diffusion is reduced. Disrupting the interaction between D1R and PSD95, through genetical manipulation and competing peptide, did not affect D1R dynamics in glutamatergic synapses. However, preventing the physical interaction between D1R and the GluN1 subunit of NMDAR abolished the synaptic stabilization of diffusing D1R. Together, these data provide direct evidence that the interaction between D1R and NMDAR in synapses participate in the building of the dopamine-receptor-mediated signalling, and most likely to the glutamate-dopamine cross-talk.

  13. Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca2+ Channels at Mammalian Hippocampal Synapses

    Directory of Open Access Journals (Sweden)

    Alexander F. Jeans

    2017-10-01

    Full Text Available Voltage-dependent Ca2+ channels (VGCC represent the principal source of Ca2+ ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca2+ influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP in mammalian hippocampal neurons using optical techniques. We find that changes in evoked Ca2+ currents specifically through P/Q-type, but not N-type, VGCC mediate bidirectional homeostatic regulation of both neurotransmitter release efficacy and the size of the major synaptic vesicle pools. Selective dependence of HSP on P/Q-type VGCC in mammalian terminals has important implications for phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.

  14. Short-Term Facilitation at a Detonator Synapse Requires the Distinct Contribution of Multiple Types of Voltage-Gated Calcium Channels.

    Science.gov (United States)

    Chamberland, Simon; Evstratova, Alesya; Tóth, Katalin

    2017-05-10

    Neuronal calcium elevations are shaped by several key parameters, including the properties, density, and the spatial location of voltage-gated calcium channels (VGCCs). These features allow presynaptic terminals to translate complex firing frequencies and tune the amount of neurotransmitter released. Although synchronous neurotransmitter release relies on both P/Q- and N-type VGCCs at hippocampal mossy fiber-CA3 synapses, the specific contribution of VGCCs to calcium dynamics, neurotransmitter release, and short-term facilitation remains unknown. Here, we used random-access two-photon calcium imaging together with electrophysiology in acute mouse hippocampal slices to dissect the roles of P/Q- and N-type VGCCs. Our results show that N-type VGCCs control glutamate release at a limited number of release sites through highly localized Ca 2+ elevations and support short-term facilitation by enhancing multivesicular release. In contrast, Ca 2+ entry via P/Q-type VGCCs promotes the recruitment of additional release sites through spatially homogeneous Ca 2+ elevations. Altogether, our results highlight the specialized contribution of P/Q- and N-types VGCCs to neurotransmitter release. SIGNIFICANCE STATEMENT In presynaptic terminals, neurotransmitter release is dynamically regulated by the transient opening of different types of voltage-gated calcium channels. Hippocampal giant mossy fiber terminals display extensive short-term facilitation during repetitive activity, with a large several fold postsynaptic response increase. Though, how giant mossy fiber terminals leverage distinct types of voltage-gated calcium channels to mediate short-term facilitation remains unexplored. Here, we find that P/Q- and N-type VGCCs generate different spatial patterns of calcium elevations in giant mossy fiber terminals and support short-term facilitation through specific participation in two mechanisms. Whereas N-type VGCCs contribute only to the synchronization of multivesicular release

  15. Impairment of TrkB-PSD-95 signaling in Angelman syndrome.

    Directory of Open Access Journals (Sweden)

    Cong Cao

    Full Text Available Angelman syndrome (AS is a neurodevelopment disorder characterized by severe cognitive impairment and a high rate of autism. AS is caused by disrupted neuronal expression of the maternally inherited Ube3A ubiquitin protein ligase, required for the proteasomal degradation of proteins implicated in synaptic plasticity, such as the activity-regulated cytoskeletal-associated protein (Arc/Arg3.1. Mice deficient in maternal Ube3A express elevated levels of Arc in response to synaptic activity, which coincides with severely impaired long-term potentiation (LTP in the hippocampus and deficits in learning behaviors. In this study, we sought to test whether elevated levels of Arc interfere with brain-derived neurotrophic factor (BDNF TrkB receptor signaling, which is known to be essential for both the induction and maintenance of LTP. We report that TrkB signaling in the AS mouse is defective, and show that reduction of Arc expression to control levels rescues the signaling deficits. Moreover, the association of the postsynaptic density protein PSD-95 with TrkB is critical for intact BDNF signaling, and elevated levels of Arc were found to impede PSD-95/TrkB association. In Ube3A deficient mice, the BDNF-induced recruitment of PSD-95, as well as PLCγ and Grb2-associated binder 1 (Gab1 with TrkB receptors was attenuated, resulting in reduced activation of PLCγ-α-calcium/calmodulin-dependent protein kinase II (CaMKII and PI3K-Akt, but leaving the extracellular signal-regulated kinase (Erk pathway intact. A bridged cyclic peptide (CN2097, shown by nuclear magnetic resonance (NMR studies to uniquely bind the PDZ1 domain of PSD-95 with high affinity, decreased the interaction of Arc with PSD-95 to restore BDNF-induced TrkB/PSD-95 complex formation, signaling, and facilitate the induction of LTP in AS mice. We propose that the failure of TrkB receptor signaling at synapses in AS is directly linked to elevated levels of Arc associated with PSD-95 and PSD-95

  16. A bionics chemical synapse.

    Science.gov (United States)

    Thanapitak, Surachoke; Toumazou, Christofer

    2013-06-01

    Implementation of the current mode CMOS circuit for chemical synapses (AMPA and NMDA receptors) with dynamic change of glutamate as the neurotransmitter input is presented in this paper. Additionally, circuit realisation for receptor GABA(A) and GABA(B) with an electrical signal which symbolises γ-Aminobutyric Acid (GABA) perturbation is introduced. The chemical sensor for glutamate sensing is the modified ISFET with enzyme (glutamate oxidase) immobilisation. The measured results from these biomimetics chemical synapse circuits closely match with the simulation result from the mathematical model. The total power consumption of the whole chip (four chemical synapse circuits and all auxiliary circuits) is 168.3 μW. The total chip area is 3 mm(2) in 0.35-μm AMS CMOS technology.

  17. Size and receptor density of glutamatergic synapses: a viewpoint from left-right asymmetry of CA3-CA1 connections

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    Yoshiaki Shinohara

    2009-07-01

    Full Text Available Synaptic plasticity is considered to be the main mechanism for learning and memory. Excitatory synapses in the cerebral cortex and hippocampus undergo plastic changes during development and in response to electric stimulation. It is widely accepted that this process is mediated by insertion and elimination of various glutamate receptors. In a series of recent investigations on left-right asymmetry of hippocampal CA3-CA1 synapses, glutamate receptor subunits have been found to have distinctive expression patterns that depend on the postsynaptic density (PSD area. Particularly notable are the GluR1 AMPA receptor subunit and NR2B NMDA receptor subunit, where receptor density has either a supra-linear (GluR1 AMPA or inverse (NR2B NMDAR relationship to the PSD area. We review current understanding of structural and physiological synaptic plasticity and propose a scheme to classify receptor subtypes by their expression pattern with respect to PSD area.

  18. Small RNAs regulate the biocontrol property of fluorescent Pseudomonas strain Psd.

    Science.gov (United States)

    Upadhyay, Anamika; Kochar, Mandira; Upadhyay, Ashutosh; Tripathy, Soumya; Rajam, Manchikatla Venkat; Srivastava, Sheela

    2017-03-01

    The production of biocontrol factors by Pseudomonads is reported to be controlled at the post-transcriptional level by the GacS/GacA signal transduction pathway. This involves RNA-binding translational repressor proteins, RsmA and RsmE, and the small regulatory RNAs (sRNAs) RsmX, RsmY, and RsmZ. While the former represses genes involved in secondary metabolite production, the latter relieves this repression at the end of exponential growth. We have studied the fluorescent Pseudomonas strain Psd, possessing good biocontrol potential, and confirmed the presence of rsmY and rsmZ by PCR amplification. Gene constructs for all the three small RNAs (RsmX, RsmY and RsmZ) carried on broad host-range plasmid, pME6032 were mobilized into strain Psd. Expression analysis of gacA in the recombinant strains over-expressing rsmX (Psd-pME7320), rsmY (Psd-pME6359) and rsmZ (Psd-pME6918) revealed a significant upregulation of the response regulator. Besides, a remarkable down-regulation of rsmA was also reported in all the strains. The variant strains were found to produce comparatively higher levels of phenazines. Indole acetic acid levels were higher to some extent, and strain Psd-pME6918 also showed elevated production of HCN. The tomato seedlings infected with Fusarium oxysporum and Verticillium dahliae in the presence of culture filtrate of the recombinant strains showed better plant protection response in comparison to the wild-type strain Psd. These results suggest that small RNAs are important determinants in regulation of the biocontrol property of strain Psd. Copyright © 2016 Elsevier GmbH. All rights reserved.

  19. Synapses and memory storage.

    Science.gov (United States)

    Mayford, Mark; Siegelbaum, Steven A; Kandel, Eric R

    2012-06-01

    The synapse is the functional unit of the brain. During the last several decades we have acquired a great deal of information on its structure, molecular components, and physiological function. It is clear that synapses are morphologically and molecularly diverse and that this diversity is recruited to different functions. One of the most intriguing findings is that the size of the synaptic response in not invariant, but can be altered by a variety of homo- and heterosynaptic factors such as past patterns of use or modulatory neurotransmitters. Perhaps the most difficult challenge in neuroscience is to design experiments that reveal how these basic building blocks of the brain are put together and how they are regulated to mediate the information flow through neural circuits that is necessary to produce complex behaviors and store memories. In this review we will focus on studies that attempt to uncover the role of synaptic plasticity in the regulation of whole-animal behavior by learning and memory.

  20. Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development.

    Science.gov (United States)

    Huang, Huiqian; Lin, Xiaochen; Liang, Zhuoyi; Zhao, Teng; Du, Shengwang; Loy, Michael M T; Lai, Kwok-On; Fu, Amy K Y; Ip, Nancy Y

    2017-08-15

    The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.

  1. Structure of the first PDZ domain of human PSD-93

    DEFF Research Database (Denmark)

    Fiorentini, Monica; Nielsen, Ann Kallehauge; Kristensen, Ole

    2009-01-01

    the PDZ1-PDZ2 linker region at the extreme C-terminus of PDZ1, implying that the oligomerization that is observed is not of biological significance in full-length PSD-93. Comparison of the structures of the binding cleft of PSD-93 PDZ1 with the previously reported structures of PSD-93 PDZ2 and PDZ3...

  2. Some upper and lower bounds on PSD-rank

    NARCIS (Netherlands)

    T. J. Lee (Troy); Z. Wei (Zhaohui); R. M. de Wolf (Ronald)

    2014-01-01

    textabstractPositive semidefinite rank (PSD-rank) is a relatively new quantity with applications to combinatorial optimization and communication complexity. We first study several basic properties of PSD-rank, and then develop new techniques for showing lower bounds on the PSD-rank. All of these

  3. Some upper and lower bounds on PSD-rank

    NARCIS (Netherlands)

    Lee, T.; Wei, Z.; de Wolf, R.

    Positive semidefinite rank (PSD-rank) is a relatively new complexity measure on matrices, with applications to combinatorial optimization and communication complexity. We first study several basic properties of PSD-rank, and then develop new techniques for showing lower bounds on the PSD-rank. All

  4. The secretory synapse: the secrets of a serial killer.

    Science.gov (United States)

    Bossi, Giovanna; Trambas, Christina; Booth, Sarah; Clark, Richard; Stinchcombe, Jane; Griffiths, Gillian M

    2002-11-01

    Cytotoxic T lymphocytes (CTLs) destroy their targets by a process involving secretion of specialized granules. The interactions between CTLs and target can be very brief; nevertheless, adhesion and signaling proteins segregate into an immunological synapse. Secretion occurs in a specialized secretory domain. Use of live and fixed cell microscopy allows this secretory synapse to be visualized both temporally and spatially. The combined use of confocal and electron microscopy has produced some surprising findings, which suggest that the secretory synapse may be important both in delivering the lethal hit and in facilitating membrane transfer from target to CTL. Studies on the secretory synapse in wild-type and mutant CTLs have been used to identify proteins involved in secretion. Further clues as to the signals required for secretion are emerging from comparisons of inhibitory and activating synapses formed by natural killer cells.

  5. Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses

    Science.gov (United States)

    Turecek, Josef; Jackman, Skyler L.; Regehr, Wade G.

    2017-11-01

    At most synapses in the brain, short-term plasticity dynamically modulates synaptic strength. Rapid frequency-dependent changes in synaptic strength have key roles in sensory adaptation, gain control and many other neural computations. However, some auditory, vestibular and cerebellar synapses maintain constant strength over a wide range of firing frequencies, and as a result efficiently encode firing rates. Despite its apparent simplicity, frequency-invariant transmission is difficult to achieve because of inherent synaptic nonlinearities. Here we study frequency-invariant transmission at synapses from Purkinje cells to deep cerebellar nuclei and at vestibular synapses in mice. Prolonged activation of these synapses leads to initial depression, which is followed by steady-state responses that are frequency invariant for their physiological activity range. We find that synaptotagmin 7 (Syt7), a calcium sensor for short-term facilitation, is present at both synapses. It was unclear why a sensor for facilitation would be present at these and other depressing synapses. We find that at Purkinje cell and vestibular synapses, Syt7 supports facilitation that is normally masked by depression, which can be revealed in wild-type mice but is absent in Syt7 knockout mice. In wild-type mice, facilitation increases with firing frequency and counteracts depression to produce frequency-invariant transmission. In Syt7-knockout mice, Purkinje cell and vestibular synapses exhibit conventional use-dependent depression, weakening to a greater extent as the firing frequency is increased. Presynaptic rescue of Syt7 expression restores both facilitation and frequency-invariant transmission. Our results identify a function for Syt7 at synapses that exhibit overall depression, and demonstrate that facilitation has an unexpected and important function in producing frequency-invariant transmission.

  6. NeuroD2 regulates the development of hippocampal mossy fiber synapses

    Directory of Open Access Journals (Sweden)

    Wilke Scott A

    2012-02-01

    Full Text Available Abstract Background The assembly of neural circuits requires the concerted action of both genetically determined and activity-dependent mechanisms. Calcium-regulated transcription may link these processes, but the influence of specific transcription factors on the differentiation of synapse-specific properties is poorly understood. Here we characterize the influence of NeuroD2, a calcium-dependent transcription factor, in regulating the structural and functional maturation of the hippocampal mossy fiber (MF synapse. Results Using NeuroD2 null mice and in vivo lentivirus-mediated gene knockdown, we demonstrate a critical role for NeuroD2 in the formation of CA3 dendritic spines receiving MF inputs. We also use electrophysiological recordings from CA3 neurons while stimulating MF axons to show that NeuroD2 regulates the differentiation of functional properties at the MF synapse. Finally, we find that NeuroD2 regulates PSD95 expression in hippocampal neurons and that PSD95 loss of function in vivo reproduces CA3 neuron spine defects observed in NeuroD2 null mice. Conclusion These experiments identify NeuroD2 as a key transcription factor that regulates the structural and functional differentiation of MF synapses in vivo.

  7. Axonal synapses utilize multiple synaptic ribbons in the mammalian retina.

    Directory of Open Access Journals (Sweden)

    Hong-Lim Kim

    Full Text Available In the mammalian retina, bipolar cells and ganglion cells which stratify in sublamina a of the inner plexiform layer (IPL show OFF responses to light stimuli while those that stratify in sublamina b show ON responses. This functional relationship between anatomy and physiology is a key principle of retinal organization. However, there are at least three types of retinal neurons, including intrinsically photosensitive retinal ganglion cells (ipRGCs and dopaminergic amacrine cells, which violate this principle. These cell types have light-driven ON responses, but their dendrites mainly stratify in sublamina a of the IPL, the OFF sublayer. Recent anatomical studies suggested that certain ON cone bipolar cells make axonal or ectopic synapses as they descend through sublamina a, thus providing ON input to cells which stratify in the OFF sublayer. Using immunoelectron microscopy with 3-dimensional reconstruction, we have identified axonal synapses of ON cone bipolar cells in the rabbit retina. Ten calbindin ON cone bipolar axons made en passant ribbon synapses onto amacrine or ganglion dendrites in sublamina a of the IPL. Compared to the ribbon synapses made by bipolar terminals, these axonal ribbon synapses were characterized by a broad postsynaptic element that appeared as a monad and by the presence of multiple short synaptic ribbons. These findings confirm that certain ON cone bipolar cells can provide ON input to amacrine and ganglion cells whose dendrites stratify in the OFF sublayer via axonal synapses. The monadic synapse with multiple ribbons may be a diagnostic feature of the ON cone bipolar axonal synapse in sublamina a. The presence of multiple ribbons and a broad postsynaptic density suggest these structures may be very efficient synapses. We also identified axonal inputs to ipRGCs with the architecture described above.

  8. Inhibition potentiates the synchronizing action of electrical synapses

    Directory of Open Access Journals (Sweden)

    Benjamin Pfeuty

    2007-11-01

    Full Text Available In vivo and in vitro experimental studies have found that blocking electrical interactions connecting GABAergic interneurons reduces oscillatory activity in the µ range in cortex. However, recent theoretical works have shown that the ability of electrical synapses to promote or impede synchrony, when alone, depends on their location on the dendritic tree of the neurons, the intrinsic properties of the neurons and the connectivity of the network. The goal of the present paper is to show that this versatility in the synchronizing ability of electrical synapses is greatly reduced when the neurons also interact via inhibition. To this end, we study a model network comprising two-compartment conductance-based neurons interacting with both types of synapses. We investigate the effect of electrical synapses on the dynamical state of the network as a function of the strength of the inhibition. We find that for weak inhibition, electrical synapses reinforce inhibition-generated synchrony only if they promote synchrony when they are alone. In contrast, when inhibition is sufficiently strong, electrical synapses improve synchrony even if when acting alone they would stabilize asynchronous firing. We clarify the mechanism underlying this cooperative interplay between electrical and inhibitory synapses. We show that it is relevant in two physiologically observed regimes: spike-to-spike synchrony, where neurons fire at almost every cycle of the population oscillations, and stochastic synchrony, where neurons fire irregularly and at a rate which is substantially lower than the frequency of the global population rhythm.

  9. Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments.

    Science.gov (United States)

    Nicholson, Daniel A; Yoshida, Rie; Berry, Robert W; Gallagher, Michela; Geinisman, Yuri

    2004-09-01

    A central problem in the neurobiology of normal aging is why learning is preserved in some aged individuals yet impaired in others. To investigate this issue, we examined whether age-related deficits in spatial learning are associated with a reduction in postsynaptic density (PSD) area in hippocampal excitatory synapses (i.e., with a structural modification that is likely to have a deleterious effect on synaptic function). A hippocampus-dependent version of the Morris water maze task was used to separate Long-Evans male rats into young adult, aged learning-unimpaired, and equally aged learning-impaired groups. Axospinous synapses from the CA1 stratum radiatum were analyzed using systematic random sampling and serial section analyses. We report that aged learning-impaired rats exhibit a marked ( approximately 30%) and significant reduction in PSD area, whereas aged learning-unimpaired rats do not. The observed structural alteration involves a substantial proportion of perforated synapses but is not observed in nonperforated synapses. These findings support the notion that many hippocampal perforated synapses become less efficient in aged learning-impaired rats, which may contribute to cognitive decline during normal aging.

  10. Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons

    Directory of Open Access Journals (Sweden)

    Mitchell D’Rozario

    2016-04-01

    Full Text Available Proneural proteins of the class I/II basic-helix-loop-helix (bHLH family are highly conserved transcription factors. Class I bHLH proteins are expressed in a broad number of tissues during development, whereas class II bHLH protein expression is more tissue restricted. Our understanding of the function of class I/II bHLH transcription factors in both invertebrate and vertebrate neurobiology is largely focused on their function as regulators of neurogenesis. Here, we show that the class I bHLH proteins Daughterless and Tcf4 are expressed in postmitotic neurons in Drosophila melanogaster and mice, respectively, where they function to restrict neurite branching and synapse formation. Our data indicate that Daughterless performs this function in part by restricting the expression of the cell adhesion molecule Neurexin. This suggests a role for these proteins outside of their established roles in neurogenesis.

  11. Cell-type specific short-term plasticity at auditory nerve synapses controls feed-forward inhibition in the dorsal cochlear nucleus.

    Science.gov (United States)

    Sedlacek, Miloslav; Brenowitz, Stephan D

    2014-01-01

    Feed-forward inhibition (FFI) represents a powerful mechanism by which control of the timing and fidelity of action potentials in local synaptic circuits of various brain regions is achieved. In the cochlear nucleus, the auditory nerve provides excitation to both principal neurons and inhibitory interneurons. Here, we investigated the synaptic circuit associated with fusiform cells (FCs), principal neurons of the dorsal cochlear nucleus (DCN) that receive excitation from auditory nerve fibers and inhibition from tuberculoventral cells (TVCs) on their basal dendrites in the deep layer of DCN. Despite the importance of these inputs in regulating fusiform cell firing behavior, the mechanisms determining the balance of excitation and FFI in this circuit are not well understood. Therefore, we examined the timing and plasticity of auditory nerve driven FFI onto FCs. We find that in some FCs, excitatory and inhibitory components of FFI had the same stimulation thresholds indicating they could be triggered by activation of the same fibers. In other FCs, excitation and inhibition exhibit different stimulus thresholds, suggesting FCs and TVCs might be activated by different sets of fibers. In addition, we find that during repetitive activation, synapses formed by the auditory nerve onto TVCs and FCs exhibit distinct modes of short-term plasticity. Feed-forward inhibitory post-synaptic currents (IPSCs) in FCs exhibit short-term depression because of prominent synaptic depression at the auditory nerve-TVC synapse. Depression of this feedforward inhibitory input causes a shift in the balance of fusiform cell synaptic input towards greater excitation and suggests that fusiform cell spike output will be enhanced by physiological patterns of auditory nerve activity.

  12. Cell-type specific short-term plasticity at auditory nerve synapses controls feed-forward inhibition in the dorsal cochlear nucleus

    Directory of Open Access Journals (Sweden)

    Miloslav eSedlacek

    2014-07-01

    Full Text Available Feedforward inhibition represents a powerful mechanism by which control of the timing and fidelity of action potentials in local synaptic circuits of various brain regions is achieved. In the cochlear nucleus, the auditory nerve provides excitation to both principal neurons and inhibitory interneurons. Here, we investigated the synaptic circuit associated with fusiform cells (FCs, principal neurons of the dorsal cochlear nucleus (DCN that receive excitation from auditory nerve fibers and inhibition from tuberculoventral cells (TVCs on their basal dendrites in the deep layer of DCN. Despite the importance of these inputs in regulating fusiform cell firing behavior, the mechanisms determining the balance of excitation and feed-forward inhibition in this circuit are not well understood. Therefore, we examined the timing and plasticity of auditory nerve driven feed-forward inhibition (FFI onto FCs. We find that in some FCs, excitatory and inhibitory components of feed-forward inhibition had the same stimulation thresholds indicating they could be triggered by activation of the same fibers. In other FCs, excitation and inhibition exhibit different stimulus thresholds, suggesting FCs and TVCs might be activated by different sets of fibers. In addition we find that during repetitive activation, synapses formed by the auditory nerve onto TVCs and FCs exhibit distinct modes of short-term plasticity. Feed-forward inhibitory post-synaptic currents (IPSCs in FCs exhibit short-term depression because of prominent synaptic depression at the auditory nerve-TVC synapse. Depression of this feedforward inhibitory input causes a shift in the balance of fusiform cell synaptic input towards greater excitation and suggests that fusiform cell spike output will be enhanced by physiological patterns of auditory nerve activity.

  13. PSD Applicability: Industrial Scrap Processing Company

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  14. Baseline Value for PSD Increment Consumption

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  15. PSD Applicability Determination - Southwestern Public Service Company

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  16. PSD Determination - Consolidated Edison of New York

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  17. PSD Determination Cabot Corporation - Fuel Conversion

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  18. PSD Applicability Pulp and Paper Mill

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  19. Turbine Enhancements and PSD Applicability -- Holcomb Station

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  20. Alzheimer's disease: synapses gone cold

    Directory of Open Access Journals (Sweden)

    Hyman Bradley T

    2011-08-01

    Full Text Available Abstract Alzheimer's disease (AD is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (Aβ, the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. Aβ oligomers inhibit long-term potentiation (LTP and facilitate long-term depression (LTD, electrophysiological correlates of memory formation. Furthermore, oligomeric Aβ has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these observations are now being elucidated, and may provide clear therapeutic targets for effectively treating the disease. Here, we review recent findings concerning AD pathogenesis with a particular focus on how Aβ impacts synapses.

  1. LRRTM3 Regulates Excitatory Synapse Development through Alternative Splicing and Neurexin Binding

    Directory of Open Access Journals (Sweden)

    Ji Won Um

    2016-02-01

    Full Text Available The four members of the LRRTM family (LRRTM1-4 are postsynaptic adhesion molecules essential for excitatory synapse development. They have also been implicated in neuropsychiatric diseases. Here, we focus on LRRTM3, showing that two distinct LRRTM3 variants generated by alternative splicing regulate LRRTM3 interaction with PSD-95, but not its excitatory synapse-promoting activity. Overexpression of either LRRTM3 variant increased excitatory synapse density in dentate gyrus (DG granule neurons, whereas LRRTM3 knockdown decreased it. LRRTM3 also controlled activity-regulated AMPA receptor surface expression in an alternative splicing-dependent manner. Furthermore, Lrrtm3-knockout mice displayed specific alterations in excitatory synapse density, excitatory synaptic transmission and excitability in DG granule neurons but not in CA1 pyramidal neurons. Lastly, LRRTM3 required only specific splice variants of presynaptic neurexins for their synaptogenic activity. Collectively, our data highlight alternative splicing and differential presynaptic ligand utilization in the regulation of LRRTMs, revealing key regulatory mechanisms for excitatory synapse development.

  2. Positioning of AMPA Receptor-Containing Endosomes Regulates Synapse Architecture

    Directory of Open Access Journals (Sweden)

    Marta Esteves da Silva

    2015-11-01

    Full Text Available Lateral diffusion in the membrane and endosomal trafficking both contribute to the addition and removal of AMPA receptors (AMPARs at postsynaptic sites. However, the spatial coordination between these mechanisms has remained unclear, because little is known about the dynamics of AMPAR-containing endosomes. In addition, how the positioning of AMPAR-containing endosomes affects synapse organization and functioning has never been directly explored. Here, we used live-cell imaging in hippocampal neuron cultures to show that intracellular AMPARs are transported in Rab11-positive recycling endosomes, which frequently enter dendritic spines and depend on the microtubule and actin cytoskeleton. By using chemically induced dimerization systems to recruit kinesin (KIF1C or myosin (MyosinV/VI motors to Rab11-positive recycling endosomes, we controlled their trafficking and found that induced removal of recycling endosomes from spines decreases surface AMPAR expression and PSD-95 clusters at synapses. Our data suggest a mechanistic link between endosome positioning and postsynaptic structure and composition.

  3. [Effect of diallyl disulfide on learning and memory abilities and hippocampal synapses in mouse models of Alzheimer's disease].

    Science.gov (United States)

    Chai, Ji-Xia; Li, Hui-Hui; Wang, Yuan-Yuan; Chai, Qiang; He, Wen-Xin; Zhou, Yan-Mei; Hu, Xiao-Dong; Wang, Zhen-Huan

    2016-10-20

    To explore the effect of diallyl disulfide (DADS) on hippocampal synapses and learning and memory abilities in a mouse model of A1zheimer's disease (AD). Mouse models of AD established by agglutinated Aβ1-42 injection in the lateral cerebral ventricle were randomized into 4 groups and treated with DADS at the daily doses of 0, 10, 50 and 100 mg/kg by gavage for 30 consecutive days. The learning and memory abilities of the mice were assessed with Morris water maze test; the structures of the dendritic spines and synapses in CA1 region of the hippocampus were observed under transmission electron microscope with silver staining; PSD95 and SYP protein and mRNA expressions in the hippocampus were detected with Western blotting and RT-PCR. Compared with the AD model mice, the mice treated with 50 and 100 mg/kg DADS showed enhanced learning and memory abilities in Morris water maze test. The dendritic spines and synapses in CA1 region of the hippocampus increased obviously and hippocampal expressions of PSD95 and SYP were enhanced in mice treated with 50 and 100 mg/kg DADS. DADS at the daily doses of 50 and 100 mg/kg can improve the learning and memory abilities and increase the number of dendritic spines and synapses in the hippocampus in mouse models of AD.

  4. FRET-FLIM investigation of PSD95-NMDA receptor interaction in dendritic spines; control by calpain, CaMKII and Src family kinase.

    Directory of Open Access Journals (Sweden)

    Kim Doré

    Full Text Available Little is known about the changes in protein interactions inside synapses during synaptic remodeling, as their live monitoring in spines has been limited. We used a FRET-FLIM approach in developing cultured rat hippocampal neurons expressing fluorescently tagged NMDA receptor (NMDAR and PSD95, two essential proteins in synaptic plasticity, to examine the regulation of their interaction. NMDAR stimulation caused a transient decrease in FRET between the NMDAR and PSD95 in spines of young and mature neurons. The activity of both CaMKII and calpain were essential for this effect in both developmental stages. Meanwhile, inhibition of Src family kinase (SFK had opposing impacts on this decrease in FRET in young versus mature neurons. Our data suggest concerted roles for CaMKII, SFK and calpain activity in regulating activity-dependent separation of PSD95 from GluN2A or GluN2B. Finally, we found that calpain inhibition reduced spine growth that was caused by NMDAR activity, supporting the hypothesis that PSD95-NMDAR separation is implicated in synaptic remodeling.

  5. Synapse Pathology in Psychiatric and Neurologic Disease

    NARCIS (Netherlands)

    M. van Spronsen (Myrrhe); C.C. Hoogenraad (Casper)

    2010-01-01

    textabstractInhibitory and excitatory synapses play a fundamental role in information processing in the brain. Excitatory synapses usually are situated on dendritic spines, small membrane protrusions that harbor glutamate receptors and postsynaptic density components and help transmit electrical

  6. Optimal learning rules for discrete synapses.

    Directory of Open Access Journals (Sweden)

    Adam B Barrett

    2008-11-01

    Full Text Available There is evidence that biological synapses have a limited number of discrete weight states. Memory storage with such synapses behaves quite differently from synapses with unbounded, continuous weights, as old memories are automatically overwritten by new memories. Consequently, there has been substantial discussion about how this affects learning and storage capacity. In this paper, we calculate the storage capacity of discrete, bounded synapses in terms of Shannon information. We use this to optimize the learning rules and investigate how the maximum information capacity depends on the number of synapses, the number of synaptic states, and the coding sparseness. Below a certain critical number of synapses per neuron (comparable to numbers found in biology, we find that storage is similar to unbounded, continuous synapses. Hence, discrete synapses do not necessarily have lower storage capacity.

  7. Ephaptic interactions within a chemical synapse: hemichannel-mediated ephaptic inhibition in the retina

    NARCIS (Netherlands)

    Kamermans, Maarten; Fahrenfort, Iris

    2004-01-01

    The two best-known types of cell-cell communication are chemical synapses and electrical synapses, which are formed by gap junctions. A third, less well known, form of communication is ephaptic transmission, in which electric fields generated by a specific neuron alter the excitability of

  8. North Coast Unified Air Quality Management District: PSD Delegation Agreements

    Science.gov (United States)

    Agreements for Partial Delegation of the Federal Prevention of Significant Deterioration (PSD) Program Set Forth in 40 CPR 52.21 by the United States Environmental Protection Agency, Region 9 to the North Coast Unified Air Quality Management District.

  9. Psd1 Effects on Candida albicans Planktonic Cells and Biofilms

    Directory of Open Access Journals (Sweden)

    Sónia Gonçalves

    2017-06-01

    Full Text Available Candida albicans is an important human pathogen, causing opportunistic infections. The adhesion of planktonic cells to a substrate is the first step for biofilm development. The antimicrobial peptide (AMP Psd1 is a defensin isolated from Pisum sativum seeds. We tested the effects of this AMP on C. albicans biofilms and planktonic cells, comparing its activity with amphotericin B and fluconazole. Three C. albicans variants were studied, one of them a mutant deficient in glucosylceramide synthase, conferring resistance to Psd1 antifungal action. Atomic force microscopy (AFM was used to assess morphological and biomechanical changes on fungal cells. Surface alterations, with membrane disruption and leakage of cellular contents, were observed. Cytometry assays and confocal microscopy imaging showed that Psd1 causes cell death, in a time and concentration-dependent manner. These results demonstrate Psd1 pleiotropic action against a relevant fungal human pathogen, suggesting its use as natural antimycotic agent.

  10. Meet the players: local translation at the synapse

    Directory of Open Access Journals (Sweden)

    Sandra eFernandez Moya

    2014-11-01

    Full Text Available It is widely believed that activity-dependent synaptic plasticity is the basis for learning and memory. Both processes are dependent on new protein synthesis at the synapse. Here, we describe a mechanism how dendritic mRNAs are transported and subsequently translated at activated synapses. Furthermore, we present the players involved in the regulation of local dendritic translation upon neuronal stimulation and their molecular interplay that maintain local proteome homeostasis. Any dysregulation causes several types of neurological disorders including muscular atrophies, cancers, neuropathies, neurodegenerative and cognitive disorders.

  11. An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development

    Directory of Open Access Journals (Sweden)

    Xinglong Gu

    2016-01-01

    Full Text Available In the mammalian brain, GABAergic synaptic transmission provides inhibitory balance to glutamatergic excitatory drive and controls neuronal output. The molecular mechanisms underlying the development of GABAergic synapses remain largely unclear. Here, we report that NMDA-type ionotropic glutamate receptors (NMDARs in individual immature neurons are the upstream signaling molecules essential for GABAergic synapse development, which requires signaling via Calmodulin binding motif in the C0 domain of the NMDAR GluN1 subunit. Interestingly, in neurons lacking NMDARs, whereas GABAergic synaptic transmission is strongly reduced, the tonic inhibition mediated by extrasynaptic GABAA receptors is increased, suggesting a compensatory mechanism for the lack of synaptic inhibition. These results demonstrate a crucial role for NMDARs in specifying the development of inhibitory synapses, and suggest an important mechanism for controlling the establishment of the balance between synaptic excitation and inhibition in the developing brain.

  12. Protein tyrosine phosphatase PTP1B is involved in hippocampal synapse formation and learning.

    Directory of Open Access Journals (Sweden)

    Federico Fuentes

    Full Text Available ER-bound PTP1B is expressed in hippocampal neurons, and accumulates among neurite contacts. PTP1B dephosphorylates ß-catenin in N-cadherin complexes ensuring cell-cell adhesion. Here we show that endogenous PTP1B, as well as expressed GFP-PTP1B, are present in dendritic spines of hippocampal neurons in culture. GFP-PTP1B overexpression does not affect filopodial density or length. In contrast, impairment of PTP1B function or genetic PTP1B-deficiency leads to increased filopodia-like dendritic spines and a reduction in mushroom-like spines, while spine density is unaffected. These morphological alterations are accompanied by a disorganization of pre- and post-synapses, as judged by decreased clustering of synapsin-1 and PSD-95, and suggest a dynamic synaptic phenotype. Notably, levels of ß-catenin-Tyr-654 phosphorylation increased ∼5-fold in the hippocampus of adult PTP1B(-/- (KO mice compared to wild type (WT mice and this was accompanied by a reduction in the amount of ß-catenin associated with N-cadherin. To determine whether PTP1B-deficiency alters learning and memory, we generated mice lacking PTP1B in the hippocampus and cortex (PTP1B(fl/fl-Emx1-Cre. PTP1B(fl/fl-Emx1-Cre mice displayed improved performance in the Barnes maze (decreased time to find and enter target hole, utilized a more efficient strategy (cued, and had better recall compared to WT controls. Our results implicate PTP1B in structural plasticity within the hippocampus, likely through modulation of N-cadherin function by ensuring dephosphorylation of ß-catenin on Tyr-654. Disruption of hippocampal PTP1B function or expression leads to elongation of dendritic filopodia and improved learning and memory, demonstrating an exciting novel role for this phosphatase.

  13. Climbing fiber synapse elimination in cerebellar Purkinje cells.

    Science.gov (United States)

    Watanabe, Masahiko; Kano, Masanobu

    2011-11-01

    Innervation of Purkinje cells (PCs) by multiple climbing fibers (CFs) is refined into mono-innervation during the first three postnatal weeks of rodents' lives. In this review article, we will integrate the current knowledge on developmental process and mechanisms of CF synapse elimination. In the 'creeper' stage of CF innervation (postnatal day 0 (P0)∼), CFs creep among PC somata to form transient synapses on immature dendrites. In the 'pericellular nest' stage (P5∼), CFs densely surround and innervate PC somata. CF innervation is then displaced to the apical portion of PC somata in the 'capuchon' stage (P9∼), and translocate to dendrites in the 'dendritic' (P12∼) stage. Along with the developmental changes in CF wiring, functional and morphological distinctions become larger among CF inputs. PCs are initially innervated by more than five CFs with similar strengths (∼P3). During P3-7 only a single CF is selectively strengthened (functional differentiation), and it undergoes dendritic translocation from P9 on (dendritic translocation). Following the functional differentiation, perisomatic CF synapses are eliminated nonselectively; this proceeds in two distinct phases. The early phase (P7-11) is conducted independently of parallel fiber (PF)-PC synapse formation, while the late phase (P12-17) critically depends on it. The P/Q-type voltage-dependent Ca(2+) channel in PCs triggers selective strengthening of single CF inputs, promotes dendritic translocation of the strengthened CFs, and drives the early phase of CF synapse elimination. In contrast, the late phase is mediated by the mGluR1-Gαq-PLCβ4-PKCγ signaling cascade in PCs driven at PF-PC synapses, whose structural connectivity is stabilized and maintained by the GluRδ2-Cbln1-neurexin system. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  14. Tank Farm WM-182 and WM 183 Heel Slurry Samples PSD Results

    Energy Technology Data Exchange (ETDEWEB)

    Batcheller, Thomas Aquinas

    2000-09-01

    Particle size distribution (PSD) analysis of INTEC Tank Farm WM-182 and WM-183 heel slurry samples were performed using a modified Horiba LA-300 PSD analyzer at the RAL facility. There were two types of testing performed: typical PSD analysis, and setting rate testing. Although the heel slurry samples were obtained from two separate vessels, the particle size distribution results were quite similar. The slurry solids were from approximately a minimum particle size of 0.5 mm to a maximum of 230 mm-with about 90% of the material between 2-to-133 mm, and the cumulative 50% value at approximately 20 mm. This testing also revealed that high frequency sonication with an ultrasonic element may break-up larger particles in the WM-182 and WM-183 tank from heel slurries. This finding represents useful information regarding ultimate tank heel waste processing. Settling rate testing results were also fairly consistent with material from both vessels in that it appears that most of the mass of solids settle to an agglomerated, yet easily redispersed layer at the bottom. A dispersed and suspended material remained in the "clear" layer above the settled layer after about one-half an hour of settling time. This material had a statistical mode of approximately 5 mm and a maximum particle size of 30 mm.

  15. NKp46 clusters at the immune synapse and regulates NK cell polarization

    Directory of Open Access Journals (Sweden)

    Uzi eHadad

    2015-09-01

    Full Text Available Natural killer cells play an important role in first-line defense against tumor and virus-infected cells. The activity of NK cells is tightly regulated by a repertoire of cell-surface expressed inhibitory and activating receptors. NKp46 is a major NK cell activating receptor that is involved in the elimination of target cells. NK cells form different types of synapses that result in distinct functional outcomes: cytotoxic, inhibitory, and regulatory. Recent studies revealed that complex integration of NK receptor signaling controls cytoskeletal rearrangement and other immune synapse-related events. However the distinct nature by which NKp46 participates in NK immunological synapse formation and function remains unknown. In this study we determined that NKp46 forms microclusters structures at the immune synapse between NK cells and target cells. Over-expression of human NKp46 is correlated with increased accumulation of F-actin mesh at the immune synapse. Concordantly, knock-down of NKp46 in primary human NK cells decreased recruitment of F-actin to the synapse. Live cell imaging experiments showed a linear correlation between NKp46 expression and lytic granules polarization to the immune synapse. Taken together, our data suggest that NKp46 signaling directly regulates the NK lytic immune synapse from early formation to late function.

  16. Tunnel junction based memristors as artificial synapses.

    Science.gov (United States)

    Thomas, Andy; Niehörster, Stefan; Fabretti, Savio; Shepheard, Norman; Kuschel, Olga; Küpper, Karsten; Wollschläger, Joachim; Krzysteczko, Patryk; Chicca, Elisabetta

    2015-01-01

    We prepared magnesia, tantalum oxide, and barium titanate based tunnel junction structures and investigated their memristive properties. The low amplitudes of the resistance change in these types of junctions are the major obstacle for their use. Here, we increased the amplitude of the resistance change from 10% up to 100%. Utilizing the memristive properties, we looked into the use of the junction structures as artificial synapses. We observed analogs of long-term potentiation, long-term depression and spike-time dependent plasticity in these simple two terminal devices. Finally, we suggest a possible pathway of these devices toward their integration in neuromorphic systems for storing analog synaptic weights and supporting the implementation of biologically plausible learning mechanisms.

  17. Three-dimensional distribution of cortical synapses: a replicated point pattern-based analysis

    Science.gov (United States)

    Anton-Sanchez, Laura; Bielza, Concha; Merchán-Pérez, Angel; Rodríguez, José-Rodrigo; DeFelipe, Javier; Larrañaga, Pedro

    2014-01-01

    The biggest problem when analyzing the brain is that its synaptic connections are extremely complex. Generally, the billions of neurons making up the brain exchange information through two types of highly specialized structures: chemical synapses (the vast majority) and so-called gap junctions (a substrate of one class of electrical synapse). Here we are interested in exploring the three-dimensional spatial distribution of chemical synapses in the cerebral cortex. Recent research has showed that the three-dimensional spatial distribution of synapses in layer III of the neocortex can be modeled by a random sequential adsorption (RSA) point process, i.e., synapses are distributed in space almost randomly, with the only constraint that they cannot overlap. In this study we hypothesize that RSA processes can also explain the distribution of synapses in all cortical layers. We also investigate whether there are differences in both the synaptic density and spatial distribution of synapses between layers. Using combined focused ion beam milling and scanning electron microscopy (FIB/SEM), we obtained three-dimensional samples from the six layers of the rat somatosensory cortex and identified and reconstructed the synaptic junctions. A total volume of tissue of approximately 4500μm3 and around 4000 synapses from three different animals were analyzed. Different samples, layers and/or animals were aggregated and compared using RSA replicated spatial point processes. The results showed no significant differences in the synaptic distribution across the different rats used in the study. We found that RSA processes described the spatial distribution of synapses in all samples of each layer. We also found that the synaptic distribution in layers II to VI conforms to a common underlying RSA process with different densities per layer. Interestingly, the results showed that synapses in layer I had a slightly different spatial distribution from the other layers. PMID:25206325

  18. Motor axon synapses on renshaw cells contain higher levels of aspartate than glutamate.

    Directory of Open Access Journals (Sweden)

    Dannette S Richards

    Full Text Available Motoneuron synapses on spinal cord interneurons known as Renshaw cells activate nicotinic, AMPA and NMDA receptors consistent with co-release of acetylcholine and excitatory amino acids (EAA. However, whether these synapses express vesicular glutamate transporters (VGLUTs capable of accumulating glutamate into synaptic vesicles is controversial. An alternative possibility is that these synapses release other EAAs, like aspartate, not dependent on VGLUTs. To clarify the exact EAA concentrated at motor axon synapses we performed a quantitative postembedding colloidal gold immunoelectron analysis for aspartate and glutamate on motor axon synapses (identified by immunoreactivity to the vesicular acetylcholine transporter; VAChT contacting calbindin-immunoreactive (-IR Renshaw cell dendrites. The results show that 71% to 80% of motor axon synaptic boutons on Renshaw cells contained aspartate immunolabeling two standard deviations above average neuropil labeling. Moreover, VAChT-IR synapses on Renshaw cells contained, on average, aspartate immunolabeling at 2.5 to 2.8 times above the average neuropil level. In contrast, glutamate enrichment was lower; 21% to 44% of VAChT-IR synapses showed glutamate-IR two standard deviations above average neuropil labeling and average glutamate immunogold density was 1.7 to 2.0 times the neuropil level. The results were not influenced by antibody affinities because glutamate antibodies detected glutamate-enriched brain homogenates more efficiently than aspartate antibodies detecting aspartate-enriched brain homogenates. Furthermore, synaptic boutons with ultrastructural features of Type I excitatory synapses were always labeled by glutamate antibodies at higher density than motor axon synapses. We conclude that motor axon synapses co-express aspartate and glutamate, but aspartate is concentrated at higher levels than glutamate.

  19. Immunogold electron microscopic evidence of differential regulation of GluN1, GluN2A, and GluN2B, NMDA-type glutamate receptor subunits in rat hippocampal CA1 synapses during benzodiazepine withdrawal.

    Science.gov (United States)

    Das, Paromita; Zerda, Ricardo; Alvarez, Francisco J; Tietz, Elizabeth I

    2010-11-01

    Benzodiazepine withdrawal-anxiety is associated with enhanced α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR)-mediated glutamatergic transmission in rat hippocampal CA1 synapses due to enhanced synaptic insertion and phosphorylation of GluA1 homomers. Interestingly, attenuation of withdrawal-anxiety is associated with a reduction in N-methyl-D-aspartate receptor (NMDAR)-mediated currents and subunit expression, secondary to AMPA receptor potentiation. Therefore, in this study ultrastructural evidence for possible reductions in NMDAR GluN1, GluN2A, and GluN2B subunits was sought at CA1 stratum radiatum synapses in proximal dendrites using postembedding immunogold labeling of tissues from rats withdrawn for 2 days from 1-week daily oral administration of the benzodiazepine, flurazepam (FZP). GluN1-immunogold density and the percentage of immunopositive synapses were significantly decreased in tissues from FZP-withdrawn rats. Similar decreases were observed for GluN2B subunits; however, the relative lateral distribution of GluN2B-immunolabeling within the postsynaptic density did not change after BZ withdrawal. In contrast to the GluN2B subunit, the percentage of synapses labeled with the GluN2A subunit antibody and the density of immunogold labeling for this subunit was unchanged. The spatial localization of immunogold particles associated with each NMDAR subunit was consistent with a predominantly postsynaptic localization. The data therefore provide direct evidence for reduced synaptic GluN1/GluN2B receptors and preservation of GluN1/GluN2A receptors in the CA1 stratum radiatum region during BZ withdrawal. Based on collective findings in this benzodiazepine withdrawal-anxiety model, we propose a functional model illustrating the changes in glutamate receptor populations at excitatory synapses during benzodiazepine withdrawal. © 2010 Wiley-Liss, Inc.

  20. Comparing the response of PSD-capable plastic scintillator to standard liquid scintillator

    Science.gov (United States)

    Woolf, Richard S.; Hutcheson, Anthony L.; Gwon, Chul; Phlips, Bernard F.; Wulf, Eric A.

    2015-06-01

    This work discusses a test campaign to characterize the response of the recently developed plastic scintillator with pulse shape discrimination (PSD) capabilities (EJ-299-33). PSD is a property exhibited by certain types of scintillating material in which incident stimuli (fast neutrons or γ rays) can be separated by exploiting differences in the scintillation light pulse tail. Detector geometries used were: a 10 cm×10 cm×10 cm cube and a 10-cm diameter×10-cm long cylinder. EJ-301 and EJ-309 liquid scintillators with well-known responses were also tested. The work was conducted at the University of Massachusetts Lowell Van De Graaff accelerator. The facility accelerated protons on a thin Li target to yield quasi-monoenergetic neutrons from the 7Li(p,n)7Be reaction (Q-value: -1.644 MeV). Collimated fast neutrons were obtained by placing detectors behind a neutron spectrometer. Rotating the spectrometer, and thus changing the neutron energy, allowed us to achieve 0.5-3.2 MeV neutrons in 200-300 keV steps. Data were acquired through a flash analog-to-digital converter (ADC) capable of performing digital PSD measurements. By using the PSD technique to separate the neutron events from unwanted γ background, we constructed a pulse height spectrum at each energy. Obtaining a relationship of the relative light output versus energy allowed us to construct the response function for the EJ-299-33 and liquid scintillator. The EJ-299-33 response in terms of electron equivalent energy (Ee.e.) vs. proton equivalent energy (Ep.e.), how it compared with the standard xylene-based EJ-301 (or, NE-213/BC-501 A equivalent) and EJ-309 liquid scintillator response, and how the EJ-301 and EJ-309 compared, are presented. We find that the EJ-299-33 demonstrated a lower light output by up to 40% for environment affected the detector response. We find relatively good agreement between our results and the modeling; however, the observed response could not be fully accounted for due to

  1. Developmental refinement of hair cell synapses tightens the coupling of Ca2+ influx to exocytosis

    Science.gov (United States)

    Wong, Aaron B; Rutherford, Mark A; Gabrielaitis, Mantas; Pangršič, Tina; Göttfert, Fabian; Frank, Thomas; Michanski, Susann; Hell, Stefan; Wolf, Fred; Wichmann, Carolin; Moser, Tobias

    2014-01-01

    Cochlear inner hair cells (IHCs) develop from pre-sensory pacemaker to sound transducer. Here, we report that this involves changes in structure and function of the ribbon synapses between IHCs and spiral ganglion neurons (SGNs) around hearing onset in mice. As synapses matured they changed from holding several small presynaptic active zones (AZs) and apposed postsynaptic densities (PSDs) to one large AZ/PSD complex per SGN bouton. After the onset of hearing (i) IHCs had fewer and larger ribbons; (ii) CaV1.3 channels formed stripe-like clusters rather than the smaller and round clusters at immature AZs; (iii) extrasynaptic CaV1.3-channels were selectively reduced, (iv) the intrinsic Ca2+ dependence of fast exocytosis probed by Ca2+ uncaging remained unchanged but (v) the apparent Ca2+ dependence of exocytosis linearized, when assessed by progressive dihydropyridine block of Ca2+ influx. Biophysical modeling of exocytosis at mature and immature AZ topographies suggests that Ca2+ influx through an individual channel dominates the [Ca2+] driving exocytosis at each mature release site. We conclude that IHC synapses undergo major developmental refinements, resulting in tighter spatial coupling between Ca2+ influx and exocytosis. PMID:24442635

  2. Face classification using electronic synapses

    Science.gov (United States)

    Yao, Peng; Wu, Huaqiang; Gao, Bin; Eryilmaz, Sukru Burc; Huang, Xueyao; Zhang, Wenqiang; Zhang, Qingtian; Deng, Ning; Shi, Luping; Wong, H.-S. Philip; Qian, He

    2017-05-01

    Conventional hardware platforms consume huge amount of energy for cognitive learning due to the data movement between the processor and the off-chip memory. Brain-inspired device technologies using analogue weight storage allow to complete cognitive tasks more efficiently. Here we present an analogue non-volatile resistive memory (an electronic synapse) with foundry friendly materials. The device shows bidirectional continuous weight modulation behaviour. Grey-scale face classification is experimentally demonstrated using an integrated 1024-cell array with parallel online training. The energy consumption within the analogue synapses for each iteration is 1,000 × (20 ×) lower compared to an implementation using Intel Xeon Phi processor with off-chip memory (with hypothetical on-chip digital resistive random access memory). The accuracy on test sets is close to the result using a central processing unit. These experimental results consolidate the feasibility of analogue synaptic array and pave the way toward building an energy efficient and large-scale neuromorphic system.

  3. BRP-170 and BRP190 Isoforms of Bruchpilot Protein Differentially Contribute to the Frequency of Synapses and Synaptic Circadian Plasticity in the Visual System of Drosophila

    Directory of Open Access Journals (Sweden)

    Olga eWoznicka

    2015-06-01

    Full Text Available In the first optic neuropil (lamina of the optic lobe of Drosophila melanogaster, two classes of synapses, tetrad and feedback, show daily rhythms in the number and size of presynaptic profiles examined at the level of transmission electron microscopy (TEM. Number of tetrad presynaptic profiles increases twice a day, once in the morning and again in the evening, and their presynaptic ribbons are largest in the evening. In contrast, feedback synapses peak at night. The frequency of synapses is correlated with size of the presynaptic element measured as the platform size of so-called T-bars, with T-bar platforms being largest with increasing synapse frequency. The large scaffold protein Bruchpilot (BRP is a major essential constituent of T-bars, with two major isoforms of 190 and 170 kD forming T-bars of the peripheral NMJ synapses and in the brain. In addition to the analysis of cyclic plasticity of tetrad and feedback synapses in wild-type flies, we used TEM to examine daily changes in the size and distribution of synapses within isoform-specific BRP mutants, expressing BRP-190 (BRP170 or BRP-170 (BRP190 only. We found that the number and circadian plasticity of synapses depends on both isoforms. In the BRP190 lacking BRP-190 there was almost 50% less tetrad synapses demonstrable than when both isoforms were present. The lack of BRP-170 and BRP-190 increased and decreased, respectively the number of feedback synapses, indicating that BRP-190 forms most of the feedback synapses. In both mutants, the daily plasticity of tetrad and feedback presynaptic profiles was abolished, except for feedback synapses in BRP190. The oscillations in the number and size of presynaptic elements seem to depend on a different contribution of BRP isoforms in a presynaptic element at different time during the day and night and at various synapse types. The participation of both BRP isoforms may vary in different classes of synapses.

  4. Marshall Space Flight Center Propulsion Systems Department (PSD) KM Initiative

    Science.gov (United States)

    Caraccioli, Paul; Varnadoe, Tom; McCarter, Mike

    2006-01-01

    NASA Marshall Space Flight Center s Propulsion Systems Department (PSD) is four months into a fifteen month Knowledge Management (KM) initiative to support enhanced engineering decision making and analyses, faster resolution of anomalies (near-term) and effective, efficient knowledge infused engineering processes, reduced knowledge attrition, and reduced anomaly occurrences (long-term). The near-term objective of this initiative is developing a KM Pilot project, within the context of a 3-5 year KM strategy, to introduce and evaluate the use of KM within PSD. An internal NASA/MSFC PSD KM team was established early in project formulation to maintain a practitioner, user-centric focus throughout the conceptual development, planning and deployment of KM technologies and capabilities with in the PSD. The PSD internal team is supported by the University of Alabama's Aging Infrastructure Systems Center Of Excellence (AISCE), Intergraph Corporation, and The Knowledge Institute. The principle product of the initial four month effort has been strategic planning of PSD KM implementation by first determining the "as is" state of KM capabilities and developing, planning and documenting the roadmap to achieve the desired "to be" state. Activities undertaken to support the planning phase have included data gathering; cultural surveys, group work-sessions, interviews, documentation review, and independent research. Assessments and analyses have been performed including industry benchmarking, related local and Agency initiatives, specific tools and techniques used and strategies for leveraging existing resources, people and technology to achieve common KM goals. Key findings captured in the PSD KM Strategic Plan include the system vision, purpose, stakeholders, prioritized strategic objectives mapped to the top ten practitioner needs and analysis of current resource usage. Opportunities identified from research, analyses, cultural/KM surveys and practitioner interviews include

  5. A Comparison of PSD Enveloping Methods for Nonstationary Vibration

    Science.gov (United States)

    Irvine, Tom

    2015-01-01

    There is a need to derive a power spectral density (PSD) envelope for nonstationary acceleration time histories, including launch vehicle data, so that components can be designed and tested accordingly. This paper presents the results of the three methods for an actual flight accelerometer record. Guidelines are given for the application of each method to nonstationary data. The method can be extended to other scenarios, including transportation vibration.

  6. Actin is crucial for all kinetically distinguishable forms of endocytosis at synapses

    Science.gov (United States)

    Wu, Xin-Sheng; Lee, Sunghoon; Sheng, Jiansong; Zhang, Zhen; Zhao, Weidong; Wang, Dongsheng; Jin, Yinghui; Charnay, Patrick; Ervasti, James M.; Wu, Ling-Gang

    2016-01-01

    Summary Mechanical force is needed to mediate endocytosis. Whether actin, the most abundant force-generating molecule, is essential for endocytosis is highly controversial in mammalian cells, particularly synapses, likely due to the use of actin blockers, the efficiency and specificity of which are often unclear in the studied cell. Here we addressed this issue using knockout approach combined with measurements of membrane capacitance and fission pore conductance, imaging of vesicular protein endocytosis, and electron microscopy. We found that two actin isoforms, β- and γ-actin, are crucial for slow, rapid, bulk, and overshoot endocytosis at large calyx-type synapses, and for slow endocytosis and bulk endocytosis at small hippocampal synapses. Polymerized actin provides mechanical force to form endocytic pits. Actin also facilitates replenishment of the readily releasable vesicle pool, likely via endocytic clearance of active zones. We conclude that polymerized actin provides mechanical force essential for all kinetically distinguishable forms of endocytosis at synapses. PMID:27840001

  7. Actin Is Crucial for All Kinetically Distinguishable Forms of Endocytosis at Synapses.

    Science.gov (United States)

    Wu, Xin-Sheng; Lee, Sung Hoon; Sheng, Jiansong; Zhang, Zhen; Zhao, Wei-Dong; Wang, Dongsheng; Jin, Yinghui; Charnay, Patrick; Ervasti, James M; Wu, Ling-Gang

    2016-12-07

    Mechanical force is needed to mediate endocytosis. Whether actin, the most abundant force-generating molecule, is essential for endocytosis is highly controversial in mammalian cells, particularly synapses, likely due to the use of actin blockers, the efficiency and specificity of which are often unclear in the studied cell. Here we addressed this issue using a knockout approach combined with measurements of membrane capacitance and fission pore conductance, imaging of vesicular protein endocytosis, and electron microscopy. We found that two actin isoforms, β- and γ-actin, are crucial for slow, rapid, bulk, and overshoot endocytosis at large calyx-type synapses, and for slow endocytosis and bulk endocytosis at small hippocampal synapses. Polymerized actin provides mechanical force to form endocytic pits. Actin also facilitates replenishment of the readily releasable vesicle pool, likely via endocytic clearance of active zones. We conclude that polymerized actin provides mechanical force essential for all kinetically distinguishable forms of endocytosis at synapses. Published by Elsevier Inc.

  8. Neural circuit rewiring: insights from DD synapse remodeling.

    Science.gov (United States)

    Kurup, Naina; Jin, Yishi

    2016-01-01

    Nervous systems exhibit many forms of neuronal plasticity during growth, learning and memory consolidation, as well as in response to injury. Such plasticity can occur across entire nervous systems as with the case of insect metamorphosis, in individual classes of neurons, or even at the level of a single neuron. A striking example of neuronal plasticity in C. elegans is the synaptic rewiring of the GABAergic Dorsal D-type motor neurons during larval development, termed DD remodeling. DD remodeling entails multi-step coordination to concurrently eliminate pre-existing synapses and form new synapses on different neurites, without changing the overall morphology of the neuron. This mini-review focuses on recent advances in understanding the cellular and molecular mechanisms driving DD remodeling.

  9. A new measure for the strength of electrical synapses

    Directory of Open Access Journals (Sweden)

    Julie S Haas

    2015-09-01

    Full Text Available Electrical synapses, like chemical synapses, mediate intraneuronal communication. Electrical synapses are typically quantified by subthreshold measurements of coupling, which fall short in describing their impact on spiking activity in coupled neighbors. Here we describe a novel measurement for electrical synapse strength that directly evaluates the effect of synaptically transmitted activity on spike timing. This method, also applicable to neurotransmitter-based synapses, communicates the considerable strength of electrical synapses. For electrical synapses measured in rodent slices of the thalamic reticular nucleus, spike timing is modulated by tens of ms by activity in a coupled neighbor.

  10. Synapse proteomics: current status and quantitative applications

    NARCIS (Netherlands)

    Li, K.W.; Jimenez, C.R.

    2008-01-01

    Chemical synapses are key organelles for neurotransmission. The coordinated actions of protein networks in diverse synaptic subdomains drive the sequential molecular events of transmitter release from the presynaptic bouton, activation of transmitter receptors located in the postsynaptic density and

  11. The Synapse : volume 14 : issue 5

    OpenAIRE

    Galea, Wilfred; Ellul, Ian C.

    2015-01-01

    Apart from the normal articles regarding medicine, this issue contains also the following: The Synapse eLearning Videos; Editor’s pick for bookworms; Heard in the Grapevine - swabbing of newborns with vaginas effluvia and smelling tuberculosis

  12. The Diversity of Cortical Inhibitory Synapses

    Directory of Open Access Journals (Sweden)

    Yoshiyuki eKubota

    2016-04-01

    Full Text Available The most typical and well known inhibitory action in the cortical microcircuit is a strong inhibition on the target neuron by axo-somatic synapses. However, it has become clear that synaptic inhibition in the cortex is much more diverse and complicated. Firstly, at least ten or more inhibitory non-pyramidal cell subtypes engage in diverse inhibitory functions to produce the elaborate activity characteristic of the different cortical states. Each distinct non-pyramidal cell subtype has its own independent inhibitory function. Secondly, the inhibitory synapses innervate different neuronal domains, such as axons, spines, dendrites and soma, and their IPSP size is not uniform. Thus cortical inhibition is highly complex, with a wide variety of anatomical and physiological modes. Moreover, the functional significance of the various inhibitory synapse innervation styles and their unique structural dynamic behaviors differ from those of excitatory synapses. In this review, we summarize our current understanding of the inhibitory mechanisms of the cortical microcircuit.

  13. Organic electronics: Battery-like artificial synapses

    Science.gov (United States)

    Yang, J. Joshua; Xia, Qiangfei

    2017-04-01

    Borrowing the operating principles of a battery, a three-terminal organic switch has been developed on a flexible plastic substrate. The device consumes very little power and can be used as an artificial synapse for brain-inspired computing.

  14. Synapse Formation in Monosynaptic Sensory–Motor Connections Is Regulated by Presynaptic Rho GTPase Cdc42

    Science.gov (United States)

    Imai, Fumiyasu; Ladle, David R.; Leslie, Jennifer R.; Duan, Xin; Rizvi, Tilat A.; Ciraolo, Georgianne M.; Zheng, Yi

    2016-01-01

    Spinal reflex circuit development requires the precise regulation of axon trajectories, synaptic specificity, and synapse formation. Of these three crucial steps, the molecular mechanisms underlying synapse formation between group Ia proprioceptive sensory neurons and motor neurons is the least understood. Here, we show that the Rho GTPase Cdc42 controls synapse formation in monosynaptic sensory–motor connections in presynaptic, but not postsynaptic, neurons. In mice lacking Cdc42 in presynaptic sensory neurons, proprioceptive sensory axons appropriately reach the ventral spinal cord, but significantly fewer synapses are formed with motor neurons compared with wild-type mice. Concordantly, electrophysiological analyses show diminished EPSP amplitudes in monosynaptic sensory–motor circuits in these mutants. Temporally targeted deletion of Cdc42 in sensory neurons after sensory–motor circuit establishment reveals that Cdc42 does not affect synaptic transmission. Furthermore, addition of the synaptic organizers, neuroligins, induces presynaptic differentiation of wild-type, but not Cdc42-deficient, proprioceptive sensory neurons in vitro. Together, our findings demonstrate that Cdc42 in presynaptic neurons is required for synapse formation in monosynaptic sensory–motor circuits. SIGNIFICANCE STATEMENT Group Ia proprioceptive sensory neurons form direct synapses with motor neurons, but the molecular mechanisms underlying synapse formation in these monosynaptic sensory–motor connections are unknown. We show that deleting Cdc42 in sensory neurons does not affect proprioceptive sensory axon targeting because axons reach the ventral spinal cord appropriately, but these neurons form significantly fewer presynaptic terminals on motor neurons. Electrophysiological analysis further shows that EPSPs are decreased in these mice. Finally, we demonstrate that Cdc42 is involved in neuroligin-dependent presynaptic differentiation of proprioceptive sensory neurons in vitro

  15. Prevention of Noise Damage to Cochlear Synapses

    Science.gov (United States)

    2016-10-01

    neurotrophic factor CNTF in promoting synapse regeneration. KEYWORDS Anandamide Auditory Brainstem Response Calcium Ion Calcium-Permeable AMPA Receptors...excitotoxic trauma (kainic acid) in vitro? f) Does CNTF promote synapse regeneration in vitro as does NT-3? W81XWH-14-1-0494 Annual Progress Report 29... CNTF ) is expressed in the organ of Corti at high levels, comparable to NT-3. We have also found that CNTF is approximately as effective as NT-3 in

  16. Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington’s disease model

    KAUST Repository

    Giralt, Albert

    2017-05-30

    The structure and function of spines and excitatory synapses are under the dynamic control of multiple signalling networks. Although tyrosine phosphorylation is involved, its regulation and importance are not well understood. Here we study the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the hippocampus. Hippocampal-related learning and CA1 long-term potentiation are severely impaired in Pyk2-deficient mice and are associated with alterations in NMDA receptors, PSD-95 and dendritic spines. In cultured hippocampal neurons, Pyk2 has autophosphorylation-dependent and -independent roles in determining PSD-95 enrichment and spines density. Pyk2 levels are decreased in the hippocampus of individuals with Huntington and in the R6/1 mouse model of the disease. Normalizing Pyk2 levels in the hippocampus of R6/1 mice rescues memory deficits, spines pathology and PSD-95 localization. Our results reveal a role for Pyk2 in spine structure and synaptic function, and suggest that its deficit contributes to Huntington’s disease cognitive impairments.

  17. ESPINA: a tool for the automated segmentation and counting of synapses in large stacks of electron microscopy images

    Directory of Open Access Journals (Sweden)

    Juan eMorales

    2011-03-01

    Full Text Available The synapses in the cerebral cortex can be classified into two main types, Gray’s type I and type II, which correspond to asymmetric (mostly glutamatergic excitatory and symmetric (inhibitory GABAergic synapses, respectively. Hence, the quantification and identification of their different types and the proportions in which they are found, is extraordinarily important in terms of brain function. The ideal approach to calculate the number of synapses per unit volume is to analyze three-dimensional samples reconstructed from serial sections. However, obtaining serial sections by transmission electron microscopy is an extremely time consuming and technically demanding task. Using FIB/SEM microscopy, we recently showed that virtually all synapses can be accurately identified as asymmetric or symmetric synapses when they are visualized, reconstructed and quantified from large three-dimensional tissue samples obtained in an automated manner. Nevertheless, the analysis, segmentation and quantification of synapses is still a labor intensive procedure. Thus, novel solutions are currently necessary to deal with the large volume of data that is being generated by automated 3D electron microscopy. Accordingly, we have developed ESPINA, a software tool that performs the automated segmentation and counting of synapses in a reconstructed 3D volume of the cerebral cortex, and that greatly facilitates and accelerates these processes.

  18. Espina: A Tool for the Automated Segmentation and Counting of Synapses in Large Stacks of Electron Microscopy Images

    Science.gov (United States)

    Morales, Juan; Alonso-Nanclares, Lidia; Rodríguez, José-Rodrigo; DeFelipe, Javier; Rodríguez, Ángel; Merchán-Pérez, Ángel

    2011-01-01

    The synapses in the cerebral cortex can be classified into two main types, Gray's type I and type II, which correspond to asymmetric (mostly glutamatergic excitatory) and symmetric (inhibitory GABAergic) synapses, respectively. Hence, the quantification and identification of their different types and the proportions in which they are found, is extraordinarily important in terms of brain function. The ideal approach to calculate the number of synapses per unit volume is to analyze 3D samples reconstructed from serial sections. However, obtaining serial sections by transmission electron microscopy is an extremely time consuming and technically demanding task. Using focused ion beam/scanning electron microscope microscopy, we recently showed that virtually all synapses can be accurately identified as asymmetric or symmetric synapses when they are visualized, reconstructed, and quantified from large 3D tissue samples obtained in an automated manner. Nevertheless, the analysis, segmentation, and quantification of synapses is still a labor intensive procedure. Thus, novel solutions are currently necessary to deal with the large volume of data that is being generated by automated 3D electron microscopy. Accordingly, we have developed ESPINA, a software tool that performs the automated segmentation and counting of synapses in a reconstructed 3D volume of the cerebral cortex, and that greatly facilitates and accelerates these processes. PMID:21633491

  19. The dendritic cell synapse: a life dedicated to T cell activation

    Directory of Open Access Journals (Sweden)

    Federica eBenvenuti

    2016-03-01

    Full Text Available T cell activation within immunological synapses is a complex process whereby different types of signals are transmitted from antigen presenting cells to T cells. The molecular strategies developed by T cells to interpret and integrate these signals have been systematically dissected in recent years and are now in large part understood. On the other side of the immune synapse dendritic cells (DCs participate actively to synapse formation and maintenance by remodeling of membrane receptors and intracellular content. However the details of such changes have been only partially characterized. The DCs actin cytoskeleton has been one of the first systems to be identified as playing an important role in T cell priming and some of the underlying mechanisms have been elucidated. Similarly, the DCs microtubule cytoskeleton undergoes major spatial changes during synapse formation that favor polarization of the DCs subcellular space toward the interacting T cell. Recently we have begun to investigate the trafficking machinery that controls polarized delivery of endosomal vesicles at the DC-T immune synapse with the aim of understanding the functional relevance of polarized secretion of soluble factors during T cell priming. Here we will review the current knowledge of events occurring in DCs during synapse formation and discuss the open questions that still remains unanswered.

  20. Prevention of Significant Deterioration (PSD) Emission Thresholds for Fountain Foundry

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  1. Memo on PSD Applicability Determination for an Ethanol Plant

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  2. National Asphalt Pavement Association Questions and Answers on PSD

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  3. Request for Guidance on PSD Applicability Determinations for Boiler Emissions

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  4. Applicability of PSD to Pennsylvania Power and Light Auxiliary Boiler

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  5. Valero Hydrocarbons BACT Analysis, PSD-TX-746

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  6. USDA Forest Service, Rocky Mountain Region PSD Permit Completeness Determination

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  7. PSD Applicability - Public Service Electric and Gas Company

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  8. Applicability of EPA's PSD Regulations to Floating Seafood Processors

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  9. Applicability of PSD to the Consolidated Edison Company

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  10. Appeal Procedures for PSD Permits Under The Consolidated Permit Regulations

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  11. PSD Determination of Applicability - UMD Coal Gasification Plant

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  12. Determining PSD Applicability Thresholds for Gas Turbine Based Facilities

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  13. Applicability of PSD to Carter Oil Company Pilot Plant

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  14. Union Carbide Chemicals and Plastics Company, Inc PSD Applicability

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  15. Synaptic Interactome Mining Reveals p140Cap as a New Hub for PSD Proteins Involved in Psychiatric and Neurological Disorders

    Directory of Open Access Journals (Sweden)

    Annalisa Alfieri

    2017-06-01

    Full Text Available Altered synaptic function has been associated with neurological and psychiatric conditions including intellectual disability, schizophrenia and autism spectrum disorder (ASD. Amongst the recently discovered synaptic proteins is p140Cap, an adaptor that localizes at dendritic spines and regulates their maturation and physiology. We recently showed that p140Cap knockout mice have cognitive deficits, impaired long-term potentiation (LTP and long-term depression (LTD, and immature, filopodia-like dendritic spines. Only a few p140Cap interacting proteins have been identified in the brain and the molecular complexes and pathways underlying p140Cap synaptic function are largely unknown. Here, we isolated and characterized the p140Cap synaptic interactome by co-immunoprecipitation from crude mouse synaptosomes, followed by mass spectrometry-based proteomics. We identified 351 p140Cap interactors and found that they cluster to sub complexes mostly located in the postsynaptic density (PSD. p140Cap interactors converge on key synaptic processes, including transmission across chemical synapses, actin cytoskeleton remodeling and cell-cell junction organization. Gene co-expression data further support convergent functions: the p140Cap interactors are tightly co-expressed with each other and with p140Cap. Importantly, the p140Cap interactome and its co-expression network show strong enrichment in genes associated with schizophrenia, autism, bipolar disorder, intellectual disability and epilepsy, supporting synaptic dysfunction as a shared biological feature in brain diseases. Overall, our data provide novel insights into the molecular organization of the synapse and indicate that p140Cap acts as a hub for postsynaptic complexes relevant to psychiatric and neurological disorders.

  16. Active Well Counting Using New PSD Plastic Detectors

    Energy Technology Data Exchange (ETDEWEB)

    Hausladen, Paul [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Newby, Jason [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); McElroy, Robert Dennis [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-11-01

    This report presents results and analysis from a series of proof-of-concept measurements to assess the suitability of segmented detectors constructed from Eljen EJ-299-34 PSD-plastic scintillator with pulse-shape discrimination capability for the purposes of quantifying uranium via active neutron coincidence counting. Present quantification of bulk uranium materials for international safeguards and domestic materials control and accounting relies on active neutron coincidence counting systems, such as the Active Well Coincidence Counter (AWCC) and the Uranium Neutron Coincidence Collar (UNCL), that use moderated He-3 proportional counters along with necessarily low-intensity 241Am(Li) neutron sources. Scintillation-based fast-neutron detectors are a potentially superior technology to the existing AWCC and UNCL designs due to their spectroscopic capability and their inherently short neutron coincidence times that largely eliminate random coincidences and enable interrogation by stronger sources. One of the past impediments to the investigation and adoption of scintillation counters for the purpose of quantifying bulk uranium was the commercial availability of scintillators having the necessary neutron-gamma pulse-shape discrimination properties only as flammable liquids. Recently, Eljen EJ-299-34 PSD-plastic scintillator became commercially available. The present work is the first assessment of an array of PSD-plastic detectors for the purposes of quantifying bulk uranium. The detector panel used in the present work was originally built as the focal plane for a fast-neutron imager, but it was repurposed for the present investigation by construction of a stand to support the inner well of an AWCC immediately in front of the detector panel. The detector panel and data acquisition of this system are particularly well suited for performing active-well fast-neutron counting of LEU and HEU samples because the active detector volume is solid, the 241Am(Li) interrogating

  17. 75 FR 70254 - PSD and Title V Permitting Guidance for Greenhouse Gases

    Science.gov (United States)

    2010-11-17

    ... AGENCY PSD and Title V Permitting Guidance for Greenhouse Gases AGENCY: Environmental Protection Agency... the EPA has posted its guidance titled, ``PSD and Title V Permitting Guidance for Greenhouse Gases... for Greenhouse Gases.'' This document has been determined to be an EPA Significant Guidance Document...

  18. 76 FR 23489 - Prevention of Significant Deterioration (PSD) and Nonattainment New Source Review (NSR...

    Science.gov (United States)

    2011-04-27

    ..., ``Prevention of Significant Deterioration (PSD) and Nonattainment New Source Review (NSR): Reconsideration of... AGENCY 40 CFR Parts 51 and 52 RIN 2060-AQ73 Prevention of Significant Deterioration (PSD) and Nonattainment New Source Review (NSR): Reconsideration of Inclusion of Fugitive Emissions; Interim Rule; Stay...

  19. 75 FR 6823 - Prevention of Significant Deterioration (PSD) and Nonattainment New Source Review (NSR...

    Science.gov (United States)

    2010-02-11

    ... AGENCY 40 CFR Parts 51 and 52 RIN 2060-AP73 Prevention of Significant Deterioration (PSD) and Nonattainment New Source Review (NSR): Reconsideration of Inclusion of Fugitive Emissions; Proposal for... emissions requirements in the federal Prevention of Significant Deterioration (PSD) program published in the...

  20. 75 FR 27191 - Prevention of Significant Deterioration (PSD) and Nonattainment New Source Review (NSR): Aggregation

    Science.gov (United States)

    2010-05-14

    ... AGENCY 40 CFR Parts 51 and 52 RIN 2060-AP80 Prevention of Significant Deterioration (PSD) and Nonattainment New Source Review (NSR): Aggregation AGENCY: Environmental Protection Agency (EPA). ACTION: Notice... period on our proposed reconsideration of the Prevention of Significant Deterioration (PSD) and...

  1. Thermodynamics of TMPC/PSd/Fullerene Nanocomposites: SANS Study

    KAUST Repository

    Chua, Yang-Choo

    2010-11-23

    Wereport a small angle neutron scattering study of the thermodynamics of a polymer mixture in the presence of nanoparticles, both in equilibrium and during phase separation. Neutron cloud point measurements and random phase approximation (RPA) analysis demonstrate that 1-2 mass % of C60 fullerenes destabilizes a highly interacting mixture of poly(tetramethyl bisphenol A polycarbonate) and deuterated polystyrene (TMPC/PSd). We unequivocally corroborate these findings with time-resolved temperature jump experiments that, in identical conditions, result in phase separation for the nanocomposite and stability for the neat polymer mixture. At lower C 60 loadings (viz. 0.2-0.5 mass %), stabilization of the mixture is observed. The nonmonotonic variation of the spinodal temperature with fullerene addition suggests a competitive interplay of asymmetric component interactions and nanoparticle dispersion. The stability line shift depends critically on particle dispersion and vanishes upon nanoparticle agglomeration. © 2010 American Chemical Society.

  2. Reduced Synapse and Axon Numbers in the Prefrontal Cortex of Rats Subjected to a Chronic Stress Model for Depression.

    Science.gov (United States)

    Csabai, Dávid; Wiborg, Ove; Czéh, Boldizsár

    2018-01-01

    Stressful experiences can induce structural changes in neurons of the limbic system. These cellular changes contribute to the development of stress-induced psychopathologies like depressive disorders. In the prefrontal cortex of chronically stressed animals, reduced dendritic length and spine loss have been reported. This loss of dendritic material should consequently result in synapse loss as well, because of the reduced dendritic surface. But so far, no one studied synapse numbers in the prefrontal cortex of chronically stressed animals. Here, we examined synaptic contacts in rats subjected to an animal model for depression, where animals are exposed to a chronic stress protocol. Our hypothesis was that long term stress should reduce the number of axo-spinous synapses in the medial prefrontal cortex. Adult male rats were exposed to daily stress for 9 weeks and afterward we did a post mortem quantitative electron microscopic analysis to quantify the number and morphology of synapses in the infralimbic cortex. We analyzed asymmetric (Type I) and symmetric (Type II) synapses in all cortical layers in control and stressed rats. We also quantified axon numbers and measured the volume of the infralimbic cortex. In our systematic unbiased analysis, we examined 21,000 axon terminals in total. We found the following numbers in the infralimbic cortex of control rats: 1.15 × 10 9 asymmetric synapses, 1.06 × 10 8 symmetric synapses and 1.00 × 10 8 myelinated axons. The density of asymmetric synapses was 5.5/μm 3 and the density of symmetric synapses was 0.5/μm 3 . Average synapse membrane length was 207 nm and the average axon terminal membrane length was 489 nm. Stress reduced the number of synapses and myelinated axons in the deeper cortical layers, while synapse membrane lengths were increased. These stress-induced ultrastructural changes indicate that neurons of the infralimbic cortex have reduced cortical network connectivity. Such reduced network connectivity is

  3. Reduced Synapse and Axon Numbers in the Prefrontal Cortex of Rats Subjected to a Chronic Stress Model for Depression

    Science.gov (United States)

    Csabai, Dávid; Wiborg, Ove; Czéh, Boldizsár

    2018-01-01

    Stressful experiences can induce structural changes in neurons of the limbic system. These cellular changes contribute to the development of stress-induced psychopathologies like depressive disorders. In the prefrontal cortex of chronically stressed animals, reduced dendritic length and spine loss have been reported. This loss of dendritic material should consequently result in synapse loss as well, because of the reduced dendritic surface. But so far, no one studied synapse numbers in the prefrontal cortex of chronically stressed animals. Here, we examined synaptic contacts in rats subjected to an animal model for depression, where animals are exposed to a chronic stress protocol. Our hypothesis was that long term stress should reduce the number of axo-spinous synapses in the medial prefrontal cortex. Adult male rats were exposed to daily stress for 9 weeks and afterward we did a post mortem quantitative electron microscopic analysis to quantify the number and morphology of synapses in the infralimbic cortex. We analyzed asymmetric (Type I) and symmetric (Type II) synapses in all cortical layers in control and stressed rats. We also quantified axon numbers and measured the volume of the infralimbic cortex. In our systematic unbiased analysis, we examined 21,000 axon terminals in total. We found the following numbers in the infralimbic cortex of control rats: 1.15 × 109 asymmetric synapses, 1.06 × 108 symmetric synapses and 1.00 × 108 myelinated axons. The density of asymmetric synapses was 5.5/μm3 and the density of symmetric synapses was 0.5/μm3. Average synapse membrane length was 207 nm and the average axon terminal membrane length was 489 nm. Stress reduced the number of synapses and myelinated axons in the deeper cortical layers, while synapse membrane lengths were increased. These stress-induced ultrastructural changes indicate that neurons of the infralimbic cortex have reduced cortical network connectivity. Such reduced network connectivity is likely

  4. Final PSD Permit Extension Letter - Energy Answers Arecibo, LLC/Energy Answers Arecibo Puerto Rico Renewable Energy Project, PR

    Science.gov (United States)

    This page contains the Final PSD Permit Extension Letter for Energy Answers Arecibo Puerto Rico Renewable Energy Project, issued on April 10, 2017 and the EPA Public Announcement for Final PSD Permit Extension for Energy Answers Arecibo, PR.

  5. Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors

    Directory of Open Access Journals (Sweden)

    Gesche eBorn

    2015-02-01

    Full Text Available Human genetics has identified rare copy number variations and deleterious mutations for all neurexin genes (NRXN1-3 in patients with neurodevelopmental diseases, and electrophysiological recordings in animal brains have shown that Nrxns are important for synaptic transmission. While several mouse models for Nrxn1α inactivation have previously been studied for behavioral changes, very little information is available for other variants. Here, we validate that mice lacking Nrxn2α exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior, which partially overlap, partially differ from Nrxn1α mutant behaviors. Using patch-clamp recordings in Nrxn2α knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. We also analyse at this cellular level a novel NRXN2 mouse model that carries a combined deletion of Nrxn2α and Nrxn2β. Electrophysiological analysis of this Nrxn2-mutant mouse shows surprisingly similar defects of excitatory release to Nrxn2α, indicating that the β-variant of Nrxn2 has no strong function in basic transmission at these synapses. Inhibitory transmission as well as synapse densities and ultrastructure remain unchanged in the neocortex of both models. Furthermore, at Nrxn2α and Nrxn2-mutant excitatory synapses we find an altered facilitation and N-methyl-D-aspartate receptor (NMDAR function because NMDAR-dependent decay time and NMDAR-mediated responses are reduced. As Nrxn can indirectly be linked to NMDAR via neuroligin and PSD-95, the trans-synaptic nature of this complex may help to explain occurrence of presynaptic and postsynaptic effects. Since excitatory/inhibitory imbalances and impairment of NMDAR function are alledged to have a role in autism and schizophrenia, our results support the idea of a related pathomechanism in these disorders.

  6. Stochastic resonance enhancement of small-world neural networks by hybrid synapses and time delay

    Science.gov (United States)

    Yu, Haitao; Guo, Xinmeng; Wang, Jiang

    2017-01-01

    The synergistic effect of hybrid electrical-chemical synapses and information transmission delay on the stochastic response behavior in small-world neuronal networks is investigated. Numerical results show that, the stochastic response behavior can be regulated by moderate noise intensity to track the rhythm of subthreshold pacemaker, indicating the occurrence of stochastic resonance (SR) in the considered neural system. Inheriting the characteristics of two types of synapses-electrical and chemical ones, neural networks with hybrid electrical-chemical synapses are of great improvement in neuron communication. Particularly, chemical synapses are conducive to increase the network detectability by lowering the resonance noise intensity, while the information is better transmitted through the networks via electrical coupling. Moreover, time delay is able to enhance or destroy the periodic stochastic response behavior intermittently. In the time-delayed small-world neuronal networks, the introduction of electrical synapses can significantly improve the signal detection capability by widening the range of optimal noise intensity for the subthreshold signal, and the efficiency of SR is largely amplified in the case of pure chemical couplings. In addition, the stochastic response behavior is also profoundly influenced by the network topology. Increasing the rewiring probability in pure chemically coupled networks can always enhance the effect of SR, which is slightly influenced by information transmission delay. On the other hand, the capacity of information communication is robust to the network topology within the time-delayed neuronal systems including electrical couplings.

  7. Endocannabinoid-dependent plasticity at spinal nociceptor synapses

    Science.gov (United States)

    Kato, Ako; Punnakkal, Pradeep; Pernía-Andrade, Alejandro Javier; von Schoultz, Carolin; Sharopov, Salim; Nyilas, Rita; Katona, István; Zeilhofer, Hanns Ulrich

    2012-01-01

    Neuroplastic changes at the spinal synapses between primary nociceptors and second order dorsal horn neurons play key roles in pain and analgesia. NMDA receptor-dependent forms of long-term plasticity have been studied extensively at these synapses, but little is known about possible contributions of the endocannabinoid system. Here, we addressed the role of cannabinoid (CB)1 receptors in activity-dependent plasticity at these synapses. We report that conditional low-frequency stimulation of high-threshold primary sensory nerve fibres paired with depolarisation of the postsynaptic neuron evoked robust long-term depression (LTD) of excitatory synaptic transmission by about 40% in the vast majority (90%) of recordings made in wild-type mice. When recordings were made from global or nociceptor-specific CB1 receptor-deficient mice (CB1−/− mice and sns-CB1−/− mice), the portion of neurons exhibiting LTD was strongly reduced to about 25%. Accordingly, LTD was prevented to a similar extent by the CB1 receptor antagonist AM 251 and mimicked by pharmacological activation of CB1 receptors. In a subset of neurons with EPSCs of particularly high stimulation thresholds, we furthermore found that the absence of CB1 receptors in CB1−/− and sns-CB1−/− mice converted the response to the paired conditioning stimulation protocol from LTD to long-term potentiation (LTP). Our results identify CB1 receptor-dependent LTD as a form of synaptic plasticity previously unknown in spinal nociceptors. They furthermore suggest that prevention of LTP may be a second hitherto unknown function of CB1 receptors in primary nociceptors. Both findings may have important implications for our understanding of endogenous pain control mechanisms and of analgesia evoked by cannabinoid receptor agonists. PMID:22826132

  8. Changes in rat hippocampal CA1 synapses following imipramine treatment

    DEFF Research Database (Denmark)

    Chen, Fenghua; Madsen, Torsten M; Wegener, Gregers

    2008-01-01

    of synapses) in subregions of the hippocampus by quantifying number of neurons and synapses. Adult male Sprague-Dawley rats were injected with imipramine or saline (i.p.) daily for 14 days. Unbiased stereological methods were used to quantify the number of neurons and synapses. No differences in the volume...... and number of neurons of hippocampal subregions following imipramine treatment were found. However, the number and percentage of CA1 asymmetric spine synapses increased significantly and, conversely, the percentage of asymmetric shaft synapses significantly decreased in the imipramine treated group. Our...... results indicate that administration of imipramine for 14 days in normal rats could significantly increase the excitatory spine synapses, and change the relative distribution of spine and shaft synapses. We speculate that the present findings may be explained by the establishment of new synaptic...

  9. PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2

    DEFF Research Database (Denmark)

    Zheng, Sika; Gray, Erin E; Chawla, Geetanjali

    2012-01-01

    Postsynaptic density protein 95 (PSD-95) is essential for synaptic maturation and plasticity. Although its synaptic regulation has been widely studied, the control of PSD-95 cellular expression is not understood. We found that Psd-95 was controlled post-transcriptionally during neural development...

  10. Cerebellar Shank2 Regulates Excitatory Synapse Density, Motor Coordination, and Specific Repetitive and Anxiety-Like Behaviors.

    Science.gov (United States)

    Ha, Seungmin; Lee, Dongwon; Cho, Yi Sul; Chung, Changuk; Yoo, Ye-Eun; Kim, Jihye; Lee, Jiseok; Kim, Woohyun; Kim, Hyosang; Bae, Yong Chul; Tanaka-Yamamoto, Keiko; Kim, Eunjoon

    2016-11-30

    Shank2 is a multidomain scaffolding protein implicated in the structural and functional coordination of multiprotein complexes at excitatory postsynaptic sites as well as in psychiatric disorders, including autism spectrum disorders. While Shank2 is strongly expressed in the cerebellum, whether Shank2 regulates cerebellar excitatory synapses, or contributes to the behavioral abnormalities observed in Shank2-/- mice, remains unexplored. Here we show that Shank2-/- mice show reduced excitatory synapse density in cerebellar Purkinje cells in association with reduced levels of excitatory postsynaptic proteins, including GluD2 and PSD-93, and impaired motor coordination in the Erasmus test. Shank2 deletion restricted to Purkinje cells (Pcp2-Cre;Shank2fl/fl mice) leads to similar reductions in excitatory synapse density, synaptic protein levels, and motor coordination. Pcp2-Cre;Shank2fl/fl mice do not recapitulate autistic-like behaviors observed in Shank2-/- mice, such as social interaction deficits, altered ultrasonic vocalizations, repetitive behaviors, and hyperactivity. However, Pcp2-Cre;Shank2fl/fl mice display enhanced repetitive behavior in the hole-board test and anxiety-like behavior in the light-dark test, which are not observed in Shank2-/- mice. These results implicate Shank2 in the regulation of cerebellar excitatory synapse density, motor coordination, and specific repetitive and anxiety-like behaviors. The postsynaptic side of excitatory synapses contains multiprotein complexes, termed the postsynaptic density, which contains receptors, scaffolding/adaptor proteins, and signaling molecules. Shank2 is an excitatory postsynaptic scaffolding protein implicated in the formation and functional coordination of the postsynaptic density and has been linked to autism spectrum disorders. Using Shank2-null mice and Shank2-conditional knock-out mice with a gene deletion restricted to cerebellar Purkinje cells, we explored functions of Shank2 in the cerebellum. We

  11. Morphological changes associated with the genesis and development of an excitatory glutemergic synapse: An integrated framework model

    Directory of Open Access Journals (Sweden)

    Venkateswaran Nagarajan

    2014-04-01

    Full Text Available The genesis of an excitatory synapse has its inception when a dendritic filopodium makes a tactile contact with a presynaptic specialisation (bouton. The subsequent maturation of the synapse takes place via a series of interrelated biochemical and biophysical signalling pathways which controls the actin polymerisation in the presynaptic and the postsynaptic sites. Although individual models of many of these signalling transductions have been proposed, a holistic model integrating the various signalling pathways to the morphological plasticity associated with the genesis and development of synapses has not. In this poster an attempt has been made towards establishing a framework for an integrated model such as the one aforementioned, encompassing several signalling pathways which control the morphology and the efficacy of the synapse. Predominant pathways include those triggered by NMDA and AMPA receptors, Trkb-BDNF, Integrin and Epherin. Also, steps towards a model that elucidates the change in shape of the synapse carried out by zonal actin polymerisation (ZAP governed by the "wastage" of neurotransmitters during exo cum endocytosis processes and the assimilation of the postsynaptic density (PSD and cell adhesion molecules with emphasis on Neurexin-Neuriligin, have been explored. The cannabinoid receptors in the PAZ have extracellular lipophilic domains. Endocannabinoid receptors are triggered by the retrograde signalling cues which negatively affect the cAMP dependent mechanisms. Apart from this, autoreceptors also pilot a feedback mechanism via secondary messengers with Ca 2+ ion concentration and neurotransmitter concentration in the synaptic cleft as its stakeholders. Feedback signals of autoreceptors which functions in accordance to “Lock and Key Mechanism” plays a vital role in fine-tuning the plasticity of the synapse and in controlling the presynaptic release probability by invoking PKA dependent pathways. In a future continuation

  12. Double inverse stochastic resonance with dynamic synapses

    Science.gov (United States)

    Uzuntarla, Muhammet; Torres, Joaquin J.; So, Paul; Ozer, Mahmut; Barreto, Ernest

    2017-01-01

    We investigate the behavior of a model neuron that receives a biophysically realistic noisy postsynaptic current based on uncorrelated spiking activity from a large number of afferents. We show that, with static synapses, such noise can give rise to inverse stochastic resonance (ISR) as a function of the presynaptic firing rate. We compare this to the case with dynamic synapses that feature short-term synaptic plasticity and show that the interval of presynaptic firing rate over which ISR exists can be extended or diminished. We consider both short-term depression and facilitation. Interestingly, we find that a double inverse stochastic resonance (DISR), with two distinct wells centered at different presynaptic firing rates, can appear.

  13. Mitochondrial synapses: intracellular communication and signal integration.

    Science.gov (United States)

    Picard, Martin

    2015-08-01

    Communication is a central theme in biology. Consequently, specialized structures have evolved to permit rapid communication among cells, tissues, organs, and physiological systems, thus enhancing the overall function and adaptation of the organism. A prime example is the neuronal synapse. In the brain, synaptic communication establishes neuronal networks with the capacity to integrate, process, and store information, giving rise to complex output signals capable of orchestrating functions across the organism. At the intracellular level, discoveries now reveal the existence of 'mitochondrial synapses' establishing mitochondrial networks, with defined chromatin-modifying mitochondrial output signals capable of orchestrating gene expression across the genome. These discoveries raise the possibility that in addition to their role as powerhouses and neuromodulators, mitochondria behave as intracellular signal-processing networks. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Analysis of synapse assembly in Drosophila melanogaster

    OpenAIRE

    Fouquet, Wernher

    2009-01-01

    The majority of rapid cell-to-cell communication mechanisms and information processing within the nervous system makes use of chemical synapses. Fast neurotransmission on these sites not only requires very close apposition of pre- and postsynaptic partners, but also depends on an effective structural arrangement of cellular components on both sides of the synaptic cleft. Synaptic vesicles fuse at active zones (AZs), characterized by an electron-dense protein mesh of insufficiently characteriz...

  15. Maximum Likelihood PSD Estimation for Speech Enhancement in Reverberation and Noise

    DEFF Research Database (Denmark)

    Kuklasinski, Adam; Doclo, Simon; Jensen, Søren Holdt

    2016-01-01

    In this contribution we focus on the problem of power spectral density (PSD) estimation from multiple microphone signals in reverberant and noisy environments. The PSD estimation method proposed in this paper is based on the maximum likelihood (ML) methodology. In particular, we derive a novel ML...... instrumental measures and is shown to be higher than when the competing estimator is used. Moreover, we perform a speech intelligibility test where we demonstrate that both the proposed and the competing PSD estimators lead to similar intelligibility improvements....

  16. POWER SPECTRUM DENSITY (PSD ANALYSIS OF AUTOMOTIVE PEDAL-PAD

    Directory of Open Access Journals (Sweden)

    AHMED RITHAUDDEEN YUSOFF

    2016-04-01

    Full Text Available Vibration at the pedal-pad may contribute to discomfort of foot plantar fascia during driving. This is due to transmission of vibration to the mount, chassis, pedal, and then to the foot plantar fascia. This experimental study is conducted to determine the estimation of peak value using the power spectral density of the vertical vibration input at the foot. The power spectral density value is calculated based on the frequency range between 13 Hz to 18 Hz. This experiment was conducted using 12 subjects testing on three size of pedal-pads; small, medium and large. The result shows that peak value occurs at resonance frequency of 15 Hz. The PSD values at that resonance frequency are 0.251 (m/s2 2/Hz for small pedal-pad, followed by the medium pedal-pad is at 0.387 (m/s2 2/Hz and lastly for the large pedal-pad is at 0.483 (m/s22/Hz. The resultsindicate that during driving, the foot vibration when interact with the large pedal-pad contributed higher stimulus compared with the small and medium pedal-pad. The pedal-pad size plays an important role in the pedal element designs in terms of vibration-transfer from pedal-pads on the feet, particularly to provide comfort to the driver while driving.

  17. Coordinated Feeding Behavior in Trichoplax, an Animal without Synapses.

    Directory of Open Access Journals (Sweden)

    Carolyn L Smith

    Full Text Available Trichoplax is a small disk-shaped marine metazoan that adheres to substrates and locomotes by ciliary gliding. Despite having only six cell types and lacking synapses Trichoplax coordinates a complex sequence of behaviors culminating in external digestion of algae. We combine live cell imaging with electron microscopy to show how this is accomplished. When Trichoplax glides over a patch of algae, its cilia stop beating so it ceases moving. A subset of one of the cell types, lipophils, simultaneously secretes granules whose content rapidly lyses algae. This secretion is accurately targeted, as only lipophils located near algae release granules. The animal pauses while the algal content is ingested, and then resumes gliding. Global control of gliding is coordinated with precise local control of lipophil secretion suggesting the presence of mechanisms for cellular communication and integration.

  18. Diurnal rhythms in neurexins transcripts and inhibitory/excitatory synapse scaffold proteins in the biological clock.

    Science.gov (United States)

    Shapiro-Reznik, Mika; Jilg, Anje; Lerner, Hadas; Earnest, David J; Zisapel, Nava

    2012-01-01

    The neurexin genes (NRXN1/2/3) encode two families (α and β) of highly polymorphic presynaptic proteins that are involved in excitatory/inhibitory synaptic balance. Recent studies indicate that neuronal activation and memory formation affect NRXN1/2/3α expression and alternative splicing at splice sites 3 and 4 (SS#3/SS#4). Neurons in the biological clock residing in the suprachiasmatic nuclei of the hypothalamus (SCN) act as self-sustained oscillators, generating rhythms in gene expression and electrical activity, to entrain circadian bodily rhythms to the 24 hours day/night cycles. Cell autonomous oscillations in NRXN1/2/3α expression and SS#3/SS#4 exons splicing and their links to rhythms in excitatory/inhibitory synaptic balance in the circadian clock were explored. NRXN1/2/3α expression and SS#3/SS#4 splicing, levels of neurexin-2α and the synaptic scaffolding proteins PSD-95 and gephyrin (representing excitatory and inhibitory synapses, respectively) were studied in mRNA and protein extracts obtained from SCN of C3H/J mice at different times of the 24 hours day/night cycle. Further studies explored the circadian oscillations in these components and causality relationships in immortalized rat SCN2.2 cells. Diurnal rhythms in mNRXN1α and mNRXN2α transcription, SS#3/SS#4 exon-inclusion and PSD-95 gephyrin and neurexin-2α levels were found in the SCN in vivo. No such rhythms were found with mNRXN3α. SCN2.2 cells also exhibited autonomous circadian rhythms in rNRXN1/2 expression SS#3/SS#4 exon inclusion and PSD-95, gephyrin and neurexin-2α levels. rNRXN3α and rNRXN1/2β were not expressed. Causal relationships were demonstrated, by use of specific siRNAs, between rNRXN2α SS#3 exon included transcripts and gephyrin levels in the SCN2.2 cells. These results show for the first time dynamic, cell autonomous, diurnal rhythms in expression and splicing of NRXN1/2 and subsequent effects on the expression of neurexin-2α and postsynaptic scaffolding proteins

  19. Interaction partners of PSD-93 studied by X-ray crystallography and fluorescence polarization spectroscopy

    DEFF Research Database (Denmark)

    Fiorentini, Monica; Bach, Anders; Strømgaard, Kristian

    2013-01-01

    the extreme C-terminus of GluD2 with PSD-93 PDZ1 have been investigated in the crystalline phase. Two different binding modes of these residues were observed, suggesting that the peptide is not tightly bound to PSD-93 PDZ1. In accordance, the two N-terminal PSD-93 PDZ domains show no appreciable binding...... affinity for a GluD2-derived C-terminal octapeptide, whereas micromolar affinity was observed for a GluN2B-derived C-terminal octapeptide. This indicates that if present, the interactions between GluD2 and PSD-93 involve more than the extreme terminus of the receptor. In contrast, the tumour...

  20. The number and distribution of AMPA receptor channels containing fast kinetic GluA3 and GluA4 subunits at auditory nerve synapses depend on the target cells.

    Science.gov (United States)

    Rubio, María E; Matsui, Ko; Fukazawa, Yugo; Kamasawa, Naomi; Harada, Harumi; Itakura, Makoto; Molnár, Elek; Abe, Manabu; Sakimura, Kenji; Shigemoto, Ryuichi

    2017-11-01

    The neurotransmitter receptor subtype, number, density, and distribution relative to the location of transmitter release sites are key determinants of signal transmission. AMPA-type ionotropic glutamate receptors (AMPARs) containing GluA3 and GluA4 subunits are prominently expressed in subsets of neurons capable of firing action potentials at high frequencies, such as auditory relay neurons. The auditory nerve (AN) forms glutamatergic synapses on two types of relay neurons, bushy cells (BCs) and fusiform cells (FCs) of the cochlear nucleus. AN-BC and AN-FC synapses have distinct kinetics; thus, we investigated whether the number, density, and localization of GluA3 and GluA4 subunits in these synapses are differentially organized using quantitative freeze-fracture replica immunogold labeling. We identify a positive correlation between the number of AMPARs and the size of AN-BC and AN-FC synapses. Both types of AN synapses have similar numbers of AMPARs; however, the AN-BC have a higher density of AMPARs than AN-FC synapses, because the AN-BC synapses are smaller. A higher number and density of GluA3 subunits are observed at AN-BC synapses, whereas a higher number and density of GluA4 subunits are observed at AN-FC synapses. The intrasynaptic distribution of immunogold labeling revealed that AMPAR subunits, particularly GluA3, are concentrated at the center of the AN-BC synapses. The central distribution of AMPARs is absent in GluA3-knockout mice, and gold particles are evenly distributed along the postsynaptic density. GluA4 gold labeling was homogenously distributed along both synapse types. Thus, GluA3 and GluA4 subunits are distributed at AN synapses in a target-cell-dependent manner.

  1. PSD microscopy: a new technique for adaptive local scanning of microscale objects.

    Science.gov (United States)

    Rahimi, Mehdi; Shen, Yantao

    2017-01-01

    A position-sensitive detector/device (PSD) is a sensor that is capable of tracking the location of a laser beam on its surface. PSDs are used in many scientific instruments and technical applications including but not limited to atomic force microscopy, human eye movement monitoring, mirrors or machine tool alignment, vibration analysis, beam position control and so on. This work intends to propose a new application using the PSD. That is a new microscopy system called scanning PSD microscopy. The working mechanism is about putting an object on the surface of the PSD and fast scanning its area with a laser beam. To achieve a high degree of accuracy and precision, a reliable framework was designed using the PSD. In this work, we first tried to improve the PSD reading and its measurement performance. This was done by minimizing the effects of noise, distortion and other disturbing parameters. After achieving a high degree of confidence, the microscopy system can be implemented based on the improved PSD measurement performance. Later to improve the scanning efficiency, we developed an adaptive local scanning system to scan the whole area of the PSD in a short matter of time. It was validated that our comprehensive and adaptive local scanning method can shorten the scanning time in order of hundreds of times in comparison with the traditional raster scanning without losing any important information about the scanned 2D objects. Methods are also introduced to scan very complicated objects with bifurcations and crossings. By incorporating all these methods, the new microscopy system is capable of scanning very complicated objects in the matter of a few seconds with a resolution that is in order of a few micrometers.

  2. Energy-efficient neuron, synapse and STDP integrated circuits.

    Science.gov (United States)

    Cruz-Albrecht, Jose M; Yung, Michael W; Srinivasa, Narayan

    2012-06-01

    Ultra-low energy biologically-inspired neuron and synapse integrated circuits are presented. The synapse includes a spike timing dependent plasticity (STDP) learning rule circuit. These circuits have been designed, fabricated and tested using a 90 nm CMOS process. Experimental measurements demonstrate proper operation. The neuron and the synapse with STDP circuits have an energy consumption of around 0.4 pJ per spike and synaptic operation respectively.

  3. Stabilization of the angiotensin-(1-7) receptor Mas through interaction with PSD95.

    Science.gov (United States)

    Bian, Weihua; Sun, Licui; Yang, Longyan; Li, Ji-Feng; Hu, Jia; Zheng, Shuai; Guo, Ruihan; Feng, Duiping; Ma, Qian; Shi, Xiaocui; Xiong, Ying; Yang, Xiaomei; Song, Ran; Xu, Jianguo; Wang, Songlin; He, Junqi

    2013-08-01

    The functions and signalling mechanisms of the Ang-(1-7) [angiotensin-(1-7)] receptor Mas have been studied extensively. However, less attention has been paid to the intracellular regulation of Mas protein. In the present study, PSD95 (postsynaptic density 95), a novel binding protein of Mas receptor, was identified, and their association was characterized further. Mas specifically interacts with PDZ1-2, but not the PDZ3, domain of PSD95 via Mas-CT (Mas C-terminus), and the last four amino acids [ETVV (Glu-Thr-Val-Val)] of Mas-CT were determined to be essential for this interaction, as shown by GST pull-down, co-immunoprecipitation and confocal co-localization experiments. Gain-of-function and loss-of-function studies indicated that PSD95 enhanced Mas protein expression by increasing the stabilization of the receptor. Mas degradation was robustly inhibited by the proteasome inhibitor MG132 in time- and dose-dependent manners, and the expression of PSD95 impaired Mas ubiquitination, indicating that the PSD95-Mas association inhibits Mas receptor degradation via the ubiquitin-proteasome proteolytic pathway. These findings reveal a novel mechanism of Mas receptor regulation by which its expression is modulated at the post-translational level by ubiquitination, and clarify the role of PSD95, which binds directly to Mas, blocking the ubiquitination and subsequent degradation of the receptor via the ubiquitin-proteasome proteolytic pathway.

  4. How synapses can enhance sensibility of a neural network

    Science.gov (United States)

    Protachevicz, P. R.; Borges, F. S.; Iarosz, K. C.; Caldas, I. L.; Baptista, M. S.; Viana, R. L.; Lameu, E. L.; Macau, E. E. N.; Batista, A. M.

    2018-02-01

    In this work, we study the dynamic range in a neural network modelled by cellular automaton. We consider deterministic and non-deterministic rules to simulate electrical and chemical synapses. Chemical synapses have an intrinsic time-delay and are susceptible to parameter variations guided by learning Hebbian rules of behaviour. The learning rules are related to neuroplasticity that describes change to the neural connections in the brain. Our results show that chemical synapses can abruptly enhance sensibility of the neural network, a manifestation that can become even more predominant if learning rules of evolution are applied to the chemical synapses.

  5. GLIA: listening and talking to the synapse.

    Science.gov (United States)

    Haydon, P G

    2001-03-01

    Glial cells are emerging from the background to become more prominent in our thinking about integration in the nervous system. Given that glial cells associated with synapses integrate neuronal inputs and can release transmitters that modulate synaptic activity, it is time to rethink our understanding of the wiring diagram of the nervous system. It is no longer appropriate to consider solely neuron-neuron connections; we also need to develop a view of the intricate web of active connections among glial cells, and between glia and neurons. Without such a view, it might be impossible to decode the language of the brain.

  6. Conductive Hearing Loss Has Long-Lasting Structural and Molecular Effects on Presynaptic and Postsynaptic Structures of Auditory Nerve Synapses in the Cochlear Nucleus.

    Science.gov (United States)

    Clarkson, Cheryl; Antunes, Flora M; Rubio, Maria E

    2016-09-28

    Sound deprivation by conductive hearing loss increases hearing thresholds, but little is known about the response of the auditory brainstem during and after conductive hearing loss. Here, we show in young adult rats that 10 d of monaural conductive hearing loss (i.e., earplugging) leads to hearing deficits that persist after sound levels are restored. Hearing thresholds in response to clicks and frequencies higher than 8 kHz remain increased after a 10 d recovery period. Neural output from the cochlear nucleus measured at 10 dB above threshold is reduced and followed by an overcompensation at the level of the lateral lemniscus. We assessed whether structural and molecular substrates at auditory nerve (endbulb of Held) synapses in the cochlear nucleus could explain these long-lasting changes in hearing processing. During earplugging, vGluT1 expression in the presynaptic terminal decreased and synaptic vesicles were smaller. Together, there was an increase in postsynaptic density (PSD) thickness and an upregulation of GluA3 AMPA receptor subunits on bushy cells. After earplug removal and a 10 d recovery period, the density of synaptic vesicles increased, vesicles were also larger, and the PSD of endbulb synapses was larger and thicker. The upregulation of the GluA3 AMPAR subunit observed during earplugging was maintained after the recovery period. This suggests that GluA3 plays a role in plasticity in the cochlear nucleus. Our study demonstrates that sound deprivation has long-lasting alterations on structural and molecular presynaptic and postsynaptic components at the level of the first auditory nerve synapse in the auditory brainstem. Despite being the second most prevalent form of hearing loss, conductive hearing loss and its effects on central synapses have received relatively little attention. Here, we show that 10 d of monaural conductive hearing loss leads to an increase in hearing thresholds, to an increased central gain upstream of the cochlear nucleus at

  7. Double-tract reconstruction after laparoscopic proximal gastrectomy using detachable ENDO-PSD.

    Science.gov (United States)

    Aburatani, Tomoki; Kojima, Kazuyuki; Otsuki, Sho; Murase, Hideaki; Okuno, Keisuke; Gokita, Kentaro; Tomii, Chiharu; Tanioka, Toshiro; Inokuchi, Mikito

    2017-04-07

    Proximal gastrectomy (PG) is widely performed in Japan as a function-preserving surgical approach. Since esophagogastrostomy (EG) was associated with increased reflux symptoms and anastomotic strictures, we have chosen double-tract reconstruction (DTR) as the standard reconstruction method since March 2013. In this study, we described a novel method of laparoscopic DTR using detachable ENDO-PSD and compared its 1-year outcome with EG performed formerly in our institution. Patients who underwent laparoscopic PG between May 2005 and July 2014 were retrospectively divided into two groups based on the type of reconstruction and were subsequently analyzed (19 patients in the DTR group and 22 in the EG group). All of them underwent a laparoscopic PG with regional lymph node dissection. In the DTR group, the lower left port site was extended to 4 cm, and an intracorporeal purse-string suture was performed using the detachable ENDO-PSD. The jejunogastrostomy was fashioned on the anterior side of the remnant stomach parallel to the transection line, 2 cm from the cut end. The EG group used the conventional purse-string suture instrument through the 6 cm upper midline mini-laparotomy incision. Patient characteristics, operative data, early operative complications and 1-year postoperative follow-up findings were compared between the two groups. The frequencies of reflux symptoms (10.5 vs. 54.5%, P = 0.003), usage of proton pump inhibitors (31.6 vs. 72.7%, P = 0.008), and anastomotic strictures (0 vs. 27%, P = 0.014) were significantly lower in the DTR group as compared to the EG group. There were no significant differences between the two groups with regard to operation time, blood loss, postoperative hospital stay, postoperative complications, average postoperative/preoperative weight loss ratio, and postoperative/preoperative ratio of biochemical markers (hemoglobin, total protein, albumin, cholesterol). Our results indicate that DTR is a useful reconstruction

  8. Generation of functional inhibitory synapses incorporating defined combinations of GABA(A or glycine receptor subunits

    Directory of Open Access Journals (Sweden)

    Christine Laura Dixon

    2015-12-01

    Full Text Available Fast inhibitory neurotransmission in the brain is mediated by wide range of GABAA receptor (GABAAR and glycine receptor (GlyR isoforms, each with different physiological and pharmacological properties. Because multiple isoforms are expressed simultaneously in most neurons, it is difficult to define the properties of inhibitory postsynaptic currents mediated by individual isoforms in vivo. Although recombinant expression systems permit the expression of individual isoforms in isolation, they require exogenous agonist application which cannot mimic the dynamic neurotransmitter profile characteristic of native synapses. We describe a neuron-HEK293 cell co-culture technique for generating inhibitory synapses incorporating defined combinations of GABAAR or GlyR subunits. Primary neuronal cultures, prepared from embryonic rat cerebral cortex or spinal cord, are used to provide presynaptic GABAergic and glycinergic terminals, respectively. When the cultures are mature, HEK293 cells expressing the subunits of interest plus neuroligin 2A are plated onto the neurons, which rapidly form synapses onto HEK293 cells. Patch clamp electrophysiology is then used to analyze the physiological and pharmacological properties of the inhibitory postsynaptic currents mediated by the recombinant receptors. The method is suitable for investigating the kinetic properties or the effects of drugs on inhibitory postsynaptic currents mediated by defined GABAAR or GlyR isoforms of interest, the effects of hereditary disease mutations on the formation and function of both types of synapses, and synaptogenesis and synaptic clustering mechanisms. The entire cell preparation procedure takes 2 – 5 weeks.

  9. Role of perisynaptic parameters in neurotransmitter homeostasis - computational study of a general synapse

    Science.gov (United States)

    Pendyam, Sandeep; Mohan, Ashwin; Kalivas, Peter W.; Nair, Satish S.

    2015-01-01

    Extracellular neurotransmitter concentrations vary over a wide range depending on the type of neurotransmitter and location in the brain. Neurotransmitter homeostasis near a synapse is achieved by a balance of several mechanisms including vesicular release from the presynapse, diffusion, uptake by transporters, non-synaptic production, and regulation of release by autoreceptors. These mechanisms are also affected by the glia surrounding the synapse. However, the role of these mechanisms in achieving neurotransmitter homeostasis is not well understood. A biophysical modeling framework was proposed to reverse engineer glial configurations and parameters related to homeostasis for synapses that support a range of neurotransmitter gradients. Model experiments reveal that synapses with extracellular neurotransmitter concentrations in the micromolar range require non-synaptic neurotransmitter sources and tight synaptic isolation by extracellular glial formations. The model was used to identify the role of perisynaptic parameters on neurotransmitter homeostasis, and to propose glial configurations that could support different levels of extracellular neurotransmitter concentrations. Ranking the parameters based on their effect on neurotransmitter homeostasis, non-synaptic sources were found to be the most important followed by transporter concentration and diffusion coefficient. PMID:22460547

  10. Thrombospondins 1 and 2 are important for afferent synapse formation and function in the inner ear

    Science.gov (United States)

    Mendus, Diana; Sundaresan, Srividya; Grillet, Nicolas; Wangsawihardja, Felix; Leu, Rose; Müller, Ulrich; Jones, Sherri M.; Mustapha, Mirna

    2014-01-01

    Thrombospondins (TSPs) are a family of secreted extracellular matrix proteins that have been shown to be involved in the formation of synapses in the central nervous system. In this study, we show that TSP1 and TSP2 are expressed in the cochlea, and offer the first description of their putative roles in afferent synapse development and function in the inner ear. We examined mice with deletions of TSP1, TSP2, and both (TSP1/2), for inner ear development and function. Immunostaining for synaptic markers indicated a significant decrease in the number of formed afferent synapses in the cochlea of TSP2 and TSP1/2 knockout (KO) mice at P29. In functional studies, TSP2 and TSP1/2 KO mice showed elevated auditory brainstem response (ABR) thresholds compared to wild type littermates starting at postnatal (P) day 15 with the most severe phenotype for the TSP1/2 KO mice. TSP1/2 KO mice also showed reduced wave I amplitudes of ABR and vestibular evoked potential suggesting a synaptic dysfunction in both the auditory and vestibular systems. While ABR thresholds in TSP1 KO mice were relatively unaffected at early ages, TSP1/2 double mutants exhibited the most severe phenotype among all the genotypes tested, suggesting functional redundancy between these two genes. Based on the above results, we propose that TSPs play an important role in afferent synapse development and function of the inner ear. PMID:24460873

  11. Persistent posttetanic depression at cerebellar parallel fiber to Purkinje cell synapses.

    Science.gov (United States)

    Bergerot, Astrid; Rigby, Mark; Bouvier, Guy; Marcaggi, Païkan

    2013-01-01

    Plasticity at the cerebellar parallel fiber to Purkinje cell synapse may underlie information processing and motor learning. In vivo, parallel fibers appear to fire in short high frequency bursts likely to activate sparsely distributed synapses over the Purkinje cell dendritic tree. Here, we report that short parallel fiber tetanic stimulation evokes a ∼7-15% depression which develops over 2 min and lasts for at least 20 min. In contrast to the concomitantly evoked short-term endocannabinoid-mediated depression, this persistent posttetanic depression (PTD) does not exhibit a dependency on the spatial pattern of synapse activation and is not caused by any detectable change in presynaptic calcium signaling. This persistent PTD is however associated with increased paired-pulse facilitation and coefficient of variation of synaptic responses, suggesting that its expression is presynaptic. The chelation of postsynaptic calcium prevents its induction, suggesting that post- to presynaptic (retrograde) signaling is required. We rule out endocannabinoid signaling since the inhibition of type 1 cannabinoid receptors, monoacylglycerol lipase or vanilloid receptor 1, or incubation with anandamide had no detectable effect. The persistent PTD is maximal in pre-adolescent mice, abolished by adrenergic and dopaminergic receptors block, but unaffected by adrenergic and dopaminergic agonists. Our data unveils a novel form of plasticity at parallel fiber synapses: a persistent PTD induced by physiologically relevant input patterns, age-dependent, and strongly modulated by the monoaminergic system. We further provide evidence supporting that the plasticity mechanism involves retrograde signaling and presynaptic diacylglycerol.

  12. Short-term plasticity and long-term potentiation mimicked in single inorganic synapses

    Science.gov (United States)

    Ohno, Takeo; Hasegawa, Tsuyoshi; Tsuruoka, Tohru; Terabe, Kazuya; Gimzewski, James K.; Aono, Masakazu

    2011-08-01

    Memory is believed to occur in the human brain as a result of two types of synaptic plasticity: short-term plasticity (STP) and long-term potentiation (LTP; refs , , , ). In neuromorphic engineering, emulation of known neural behaviour has proven to be difficult to implement in software because of the highly complex interconnected nature of thought processes. Here we report the discovery of a Ag2S inorganic synapse, which emulates the synaptic functions of both STP and LTP characteristics through the use of input pulse repetition time. The structure known as an atomic switch, operating at critical voltages, stores information as STP with a spontaneous decay of conductance level in response to intermittent input stimuli, whereas frequent stimulation results in a transition to LTP. The Ag2S inorganic synapse has interesting characteristics with analogies to an individual biological synapse, and achieves dynamic memorization in a single device without the need of external preprogramming. A psychological model related to the process of memorizing and forgetting is also demonstrated using the inorganic synapses. Our Ag2S element indicates a breakthrough in mimicking synaptic behaviour essential for the further creation of artificial neural systems that emulate characteristics of human memory.

  13. Development of polyhouse type solar dryer for Kashmir valley.

    Science.gov (United States)

    Shahi, Navin Chandra; Khan, Junaid N; Lohani, Umesh C; Singh, Anupama; Kumar, Anil

    2011-06-01

    Polyhouse type solar dryer (PSD) consist of drying chamber, drying trays and exhaust fan was developed for drying fruits and vegetables. The relative humidity (RH) inside the PSD varied in between 21 to 74% as compared to outside RH which ranged from 40 to 75%. The performance was found suitable and resulted in efficient drying at low RH. The thermal performance test for PSD under full and no load testing conditions were calculated. The temperature inside the dryer was 62 to 76% higher than the ambient conditions. PSD was helpful in reducing the drying ranging from 33 to 53%. The capacity of PSD was 100-150 kg per batch. The economic cost of solar dryer was compared with mechanical drying for beneficial to local producer. The cost of PSD Rs 80,000 could recover within the period of 1.5 years by adopting solar drying technology.

  14. ARHGAP12 functions as a developmental brake on excitatory synapse function

    NARCIS (Netherlands)

    Ba, W.; Selten, M.M.; van der Raadt, J.; van Veen, H.; Li, L.L.; Benevento, M.; Oudakker, A.R.; Lasabuda, R.S.E.; Letteboer, S.J.; Roepman, R.; van Wezel, Richard Jack Anton; Courtney, M.J.; van Bokhoven, H.; Nadif Kasri, N.

    2016-01-01

    The molecular mechanisms that promote excitatory synapse development have been extensively studied. However, the molecular events preventing precocious excitatory synapse development so that synapses form at the correct time and place are less well understood. Here, we report the functional

  15. Cadmium action in synapses in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Minami, Akira; Takeda, Atsushi; Nishibaba, Daisuke; Tekefuta, Sachiyo; Oku, Naoto [Department of Radiobiochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka (Japan)

    2001-05-01

    Chronic exposure to cadmium causes central nervous system disorders, e.g., olfactory dysfunction. To clarify cadmium toxicity in synaptic neurotransmission in the brain, the movement and action of cadmium in the synapses was examined using in vivo microdialysis. One and 24 h after injection of {sup 109}CdCl{sub 2} into the amygdala of rats, {sup 109}Cd release into the extracellular space was facilitated by stimulation with high K{sup +}, suggesting that cadmium taken up in amygdalar neurons is released into the synaptic clefts in a calcium- and impulse-dependent manner. To examine the action of cadmium in the synapses, the amygdala was perfused with artificial cerebrospinal fluid containing 10-30 {mu}M CdCl{sub 2}. The release of excitatory neurotransmitters, i.e., glutamate and aspartate, into the extracellular space was decreased during perfusion with cadmium, while the release of inhibitory neurotransmitters, i.e., glycine and {gamma}-amino butyric acid (GABA), into the extracellular space was increased during the period. These results suggest that cadmium released from the amygdalar neuron terminals affects the degree and balance of excitation-inhibition in synaptic neurotransmission. (author)

  16. Contact time periods in immunological synapse

    Science.gov (United States)

    Bush, Daniel R.; Chattopadhyay, Amit K.

    2014-10-01

    This paper resolves the long standing debate as to the proper time scale of the onset of the immunological synapse bond, the noncovalent chemical bond defining the immune pathways involving T cells and antigen presenting cells. Results from our model calculations show to be of the order of seconds instead of minutes. Close to the linearly stable regime, we show that in between the two critical spatial thresholds defined by the integrin:ligand pair (Δ2˜ 40-45 nm) and the T-cell receptor TCR:peptide-major-histocompatibility-complex pMHC bond (Δ1˜ 14-15 nm), grows monotonically with increasing coreceptor bond length separation δ (= Δ2-Δ1˜ 26-30 nm) while decays with Δ1 for fixed Δ2. The nonuniversal δ-dependent power-law structure of the probability density function further explains why only the TCR:pMHC bond is a likely candidate to form a stable synapse.

  17. The dendritic cell side of the immunological synapse

    NARCIS (Netherlands)

    Verboogen, D.R.J.; Dingjan, I.; Revelo, N.H.; Visser, L.J.; Beest, M.B.A. ter; Bogaart, G. van den

    2016-01-01

    Immune responses are initiated by the interactions between antigen-presenting cells (APCs), such as dendritic cells (DCs), with responder cells, such as T cells, via a tight cellular contact interface called the immunological synapse. The immunological synapse is a highly organized subcellular

  18. Rhythmic changes in synapse numbers in Drosophila melanogaster motor terminals.

    Directory of Open Access Journals (Sweden)

    Santiago Ruiz

    Full Text Available Previous studies have shown that the morphology of the neuromuscular junction of the flight motor neuron MN5 in Drosophila melanogaster undergoes daily rhythmical changes, with smaller synaptic boutons during the night, when the fly is resting, than during the day, when the fly is active. With electron microscopy and laser confocal microscopy, we searched for a rhythmic change in synapse numbers in this neuron, both under light:darkness (LD cycles and constant darkness (DD. We expected the number of synapses to increase during the morning, when the fly has an intense phase of locomotion activity under LD and DD. Surprisingly, only our DD data were consistent with this hypothesis. In LD, we found more synapses at midnight than at midday. We propose that under LD conditions, there is a daily rhythm of formation of new synapses in the dark phase, when the fly is resting, and disassembly over the light phase, when the fly is active. Several parameters appeared to be light dependent, since they were affected differently under LD or DD. The great majority of boutons containing synapses had only one and very few had either two or more, with a 70∶25∶5 ratio (one, two and three or more synapses in LD and 75∶20∶5 in DD. Given the maintenance of this proportion even when both bouton and synapse numbers changed with time, we suggest that there is a homeostatic mechanism regulating synapse distribution among MN5 boutons.

  19. The molecular physiology of the axo-myelinic synapse.

    Science.gov (United States)

    Micu, Ileana; Plemel, Jason R; Lachance, Celia; Proft, Juliane; Jansen, Andrew J; Cummins, Karen; van Minnen, Jan; Stys, Peter K

    2016-02-01

    Myelinated axons efficiently transmit information over long distances. The apposed myelin sheath confers favorable electrical properties, but restricts access of the axon to its extracellular milieu. Therefore, axonal metabolic support may require specific axo-myelinic communication. Here we explored activity-dependent glutamate-mediated signaling from axon to myelin. 2-Photon microscopy was used to image Ca(2+) changes in myelin in response to electrical stimulation of optic nerve axons ex vivo. We show that optic nerve myelin responds to axonal action potentials by a rise in Ca(2+) levels mediated by GluN2D and GluN3A-containing NMDA receptors. Glutamate is released from axons in a vesicular manner that is tetanus toxin-sensitive. The Ca(2+) source for vesicular fusion is provided by ryanodine receptors on axonal Ca(2+) stores, controlled by L-type Ca(2+) channels that sense depolarization of the internodal axolemma. Genetic ablation of GluN2D and GluN3A subunits results in greater lability of the compact myelin. Our results support the existence of a novel synapse between the axon and its myelin, suggesting a means by which traversing action potentials can signal the overlying myelin sheath. This may be an important physiological mechanism by which an axon can signal companion glia for metabolic support or adjust properties of its myelin in a dynamic manner. The axo-myelinic synapse may contribute to learning, while its disturbances may play a role in the pathophysiology of central nervous system disorders such as schizophrenia, where subtle abnormalities of myelinated white matter tracts have been shown in the human, or to frank demyelinating disorders such as multiple sclerosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Deafferented Adult Rod Bipolar Cells Create New Synapses with Photoreceptors to Restore Vision.

    Science.gov (United States)

    Beier, Corinne; Hovhannisyan, Anahit; Weiser, Sydney; Kung, Jennifer; Lee, Seungjun; Lee, Dae Yeong; Huie, Philip; Dalal, Roopa; Palanker, Daniel; Sher, Alexander

    2017-04-26

    Upon degeneration of photoreceptors in the adult retina, interneurons, including bipolar cells, exhibit a plastic response leading to their aberrant rewiring. Photoreceptor reintroduction has been suggested as a potential approach to sight restoration, but the ability of deafferented bipolar cells to establish functional synapses with photoreceptors is poorly understood. Here we use photocoagulation to selectively destroy photoreceptors in adult rabbits while preserving the inner retina. We find that rods and cones shift into the ablation zone over several weeks, reducing the blind spot at scotopic and photopic luminances. During recovery, rod and cone bipolar cells exhibit markedly different responses to deafferentation. Rod bipolar cells extend their dendrites to form new synapses with healthy photoreceptors outside the lesion, thereby restoring visual function in the deafferented retina. Secretagogin-positive cone bipolar cells did not exhibit such obvious dendritic restructuring. These findings are encouraging to the idea of photoreceptor reintroduction for vision restoration in patients blinded by retinal degeneration. At the same time, they draw attention to the postsynaptic side of photoreceptor reintroduction; various bipolar cell types, representing different visual pathways, vary in their response to the photoreceptor loss and in their consequent dendritic restructuring.SIGNIFICANCE STATEMENT Loss of photoreceptors during retinal degeneration results in permanent visual impairment. Strategies for vision restoration based on the reintroduction of photoreceptors inherently rely on the ability of the remaining retinal neurons to correctly synapse with new photoreceptors. We show that deafferented bipolar cells in the adult mammalian retina can reconnect to rods and cones and restore retinal sensitivity at scotopic and photopic luminances. Rod bipolar cells extend their dendrites to form new synapses with healthy rod photoreceptors. These findings support the

  1. Novel Method of Detecting Movement of the Interference Fringes Using One-Dimensional PSD

    Directory of Open Access Journals (Sweden)

    Qi Wang

    2015-06-01

    Full Text Available In this paper, a method of using a one-dimensional position-sensitive detector (PSD by replacing charge-coupled device (CCD to measure the movement of the interference fringes is presented first, and its feasibility is demonstrated through an experimental setup based on the principle of centroid detection. Firstly, the centroid position of the interference fringes in a fiber Mach-Zehnder (M-Z interferometer is solved in theory, showing it has a higher resolution and sensitivity. According to the physical characteristics and principles of PSD, a simulation of the interference fringe’s phase difference in fiber M-Z interferometers and PSD output is carried out. Comparing the simulation results with the relationship between phase differences and centroid positions in fiber M-Z interferometers, the conclusion that the output of interference fringes by PSD is still the centroid position is obtained. Based on massive measurements, the best resolution of the system is achieved with 5.15, 625 μm. Finally, the detection system is evaluated through setup error analysis and an ultra-narrow-band filter structure. The filter structure is configured with a one-dimensional photonic crystal containing positive and negative refraction material, which can eliminate background light in the PSD detection experiment. This detection system has a simple structure, good stability, high precision and easily performs remote measurements, which makes it potentially useful in material small deformation tests, refractivity measurements of optical media and optical wave front detection.

  2. Nonlinear Synapses for Large-Scale Models: An Efficient Representation Enables Complex Synapse Dynamics Modeling in Large-Scale Simulations

    Directory of Open Access Journals (Sweden)

    Eric eHu

    2015-09-01

    Full Text Available Chemical synapses are comprised of a wide collection of intricate signaling pathways involving complex dynamics. These mechanisms are often reduced to simple spikes or exponential representations in order to enable computer simulations at higher spatial levels of complexity. However, these representations cannot capture important nonlinear dynamics found in synaptic transmission. Here, we propose an input-output (IO synapse model capable of generating complex nonlinear dynamics while maintaining low computational complexity. This IO synapse model is an extension of a detailed mechanistic glutamatergic synapse model capable of capturing the input-output relationships of the mechanistic model using the Volterra functional power series. We demonstrate that the IO synapse model is able to successfully track the nonlinear dynamics of the synapse up to the third order with high accuracy. We also evaluate the accuracy of the IO synapse model at different input frequencies and compared its performance with that of kinetic models in compartmental neuron models. Our results demonstrate that the IO synapse model is capable of efficiently replicating complex nonlinear dynamics that were represented in the original mechanistic model and provide a method to replicate complex and diverse synaptic transmission within neuron network simulations.

  3. HIV-1 Virological Synapse is not Simply a Copycat of the Immunological Synapse

    Directory of Open Access Journals (Sweden)

    Gaia Vasiliver-Shamis

    2010-05-01

    Full Text Available The virological synapse (VS is a tight adhesive junction between an HIV-infected cell and an uninfected target cell, across which virus can be efficiently transferred from cell to cell in the absence of cell-cell fusion. The VS has been postulated to resemble, in its morphology, the well-studied immunological synapse (IS. This review article discusses the structural similarities between IS and VS and the shared T cell receptor (TCR signaling components that are found in the VS. However, the IS and the VS display distinct kinetics in disassembly and intracellular signaling events, possibly leading to different biological outcomes. Hence, HIV-1 exploits molecular components of IS and TCR signaling machinery to trigger unique changes in cellular morphology, migration, and activation that facilitate its transmission and cell-to-cell spread.

  4. Synaptic Conversion of Chloride-Dependent Synapses in Spinal Nociceptive Circuits: Roles in Neuropathic Pain

    OpenAIRE

    Cooper, Mark S; Przebinda, Adam S.

    2011-01-01

    Electrophysiological conversion of chloride-dependent synapses from inhibitory to excitatory function, as a result of aberrant neuronal chloride homeostasis, is a known mechanism for the genesis of neuropathic pain. This paper examines theoretically how this type of synaptic conversion can disrupt circuit logic in spinal nociceptive circuits. First, a mathematical scaling factor is developed to represent local aberration in chloride electrochemical driving potential. Using this mathematical ...

  5. Biphasic Alteration of the Inhibitory Synapse Scaffold Protein Gephyrin in Early and Late Stages of an Alzheimer Disease Model.

    Science.gov (United States)

    Kiss, Eva; Gorgas, Karin; Schlicksupp, Andrea; Groß, Dagmar; Kins, Stefan; Kirsch, Joachim; Kuhse, Jochen

    2016-09-01

    The pathogenesis of Alzheimer disease (AD) is thought to begin many years before the diagnosis of dementia. Accumulating evidence indicates the involvement of GABAergic neurotransmission in the physiopathology of AD. However, in comparison to excitatory synapses, the structural and functional alterations of inhibitory synapses in AD are less well characterized. We studied the expression and distribution of proteins specific for inhibitory synapses in hippocampal areas of APPPS1 mice at different ages. Interestingly, by immunoblotting and confocal fluorescence microscopy, we disclosed a robust increase in the expression of gephyrin, an organizer of ligand-gated ion channels at inhibitory synapses in hippocampus CA1 and dentate gyrus of young presymptomatic APPPS1 mice (1 to 3 months) as compared to controls. The postsynaptic γ2-GABA(A)-receptor subunit and the presynaptic vesicular inhibitory amino acid transporter protein showed similar expression patterns. In contrast, adult transgenic animals (12 months) displayed decreased levels of these proteins in comparison to wild type in hippocampus areas devoid of amyloid plaques. Within most plaques, strong gephyrin immunoreactivity was detected, partially colocalizing with vesicular amino acid transporter and GABA(A)-receptor γ2 subunit immunoreactivities. Our results indicate a biphasic alteration in expression of hippocampal inhibitory synapse components in AD. Altered inhibition of neurotransmission might be an early prognostic marker and might even be involved in the pathogenesis of AD. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. A Novel, Noncanonical BMP Pathway Modulates Synapse Maturation at the Drosophila Neuromuscular Junction.

    Directory of Open Access Journals (Sweden)

    Mikolaj J Sulkowski

    2016-01-01

    Full Text Available At the Drosophila NMJ, BMP signaling is critical for synapse growth and homeostasis. Signaling by the BMP7 homolog, Gbb, in motor neurons triggers a canonical pathway-which modulates transcription of BMP target genes, and a noncanonical pathway-which connects local BMP/BMP receptor complexes with the cytoskeleton. Here we describe a novel noncanonical BMP pathway characterized by the accumulation of the pathway effector, the phosphorylated Smad (pMad, at synaptic sites. Using genetic epistasis, histology, super resolution microscopy, and electrophysiology approaches we demonstrate that this novel pathway is genetically distinguishable from all other known BMP signaling cascades. This novel pathway does not require Gbb, but depends on presynaptic BMP receptors and specific postsynaptic glutamate receptor subtypes, the type-A receptors. Synaptic pMad is coordinated to BMP's role in the transcriptional control of target genes by shared pathway components, but it has no role in the regulation of NMJ growth. Instead, selective disruption of presynaptic pMad accumulation reduces the postsynaptic levels of type-A receptors, revealing a positive feedback loop which appears to function to stabilize active type-A receptors at synaptic sites. Thus, BMP pathway may monitor synapse activity then function to adjust synapse growth and maturation during development.

  7. Anatomically Detailed and Large-Scale Simulations Studying Synapse Loss and Synchrony Using NeuroBox

    Science.gov (United States)

    Breit, Markus; Stepniewski, Martin; Grein, Stephan; Gottmann, Pascal; Reinhardt, Lukas; Queisser, Gillian

    2016-01-01

    The morphology of neurons and networks plays an important role in processing electrical and biochemical signals. Based on neuronal reconstructions, which are becoming abundantly available through databases such as NeuroMorpho.org, numerical simulations of Hodgkin-Huxley-type equations, coupled to biochemical models, can be performed in order to systematically investigate the influence of cellular morphology and the connectivity pattern in networks on the underlying function. Development in the area of synthetic neural network generation and morphology reconstruction from microscopy data has brought forth the software tool NeuGen. Coupling this morphology data (either from databases, synthetic, or reconstruction) to the simulation platform UG 4 (which harbors a neuroscientific portfolio) and VRL-Studio, has brought forth the extendible toolbox NeuroBox. NeuroBox allows users to perform numerical simulations on hybrid-dimensional morphology representations. The code basis is designed in a modular way, such that e.g., new channel or synapse types can be added to the library. Workflows can be specified through scripts or through the VRL-Studio graphical workflow representation. Third-party tools, such as ImageJ, can be added to NeuroBox workflows. In this paper, NeuroBox is used to study the electrical and biochemical effects of synapse loss vs. synchrony in neurons, to investigate large morphology data sets within detailed biophysical simulations, and used to demonstrate the capability of utilizing high-performance computing infrastructure for large scale network simulations. Using new synapse distribution methods and Finite Volume based numerical solvers for compartment-type models, our results demonstrate how an increase in synaptic synchronization can compensate synapse loss at the electrical and calcium level, and how detailed neuronal morphology can be integrated in large-scale network simulations. PMID:26903818

  8. Anatomically detailed and large-scale simulations studying synapse loss and synchrony using NeuroBox

    Directory of Open Access Journals (Sweden)

    Markus eBreit

    2016-02-01

    Full Text Available The morphology of neurons and networks plays an important role in processing electrical and biochemical signals. Based on neuronal reconstructions, which are becoming abundantly available through databases such as NeuroMorpho.org, numerical simulations of Hodgkin-Huxley-type equations, coupled to biochemical models, can be performed in order to systematically investigate the influence of cellular morphology and the connectivity pattern in networks on the underlying function. Development in the area of synthetic neural network generation and morphology reconstruction from microscopy data has brought forth the software tool NeuGen. Coupling this morphology data (either from databases, synthetic or reconstruction to the simulation platform UG 4 (which harbors a neuroscientific portfolio and VRL-Studio, has brought forth the extendible toolbox NeuroBox. NeuroBox allows users to perform numerical simulations on hybrid-dimensional morphology representations. The code basis is designed in a modular way, such that e.g. new channel or synapse types can be added to the library. Workflows can be specified through scripts or through the VRL-Studio graphical workflow representation. Third-party tools, such as ImageJ, can be added to NeuroBox workflows. In this paper, NeuroBox is used to study the electrical and biochemical effects of synapse loss vs. synchrony in neurons, to investigate large morphology data sets within detailed biophysical simulations, and used to demonstrate the capability of utilizing high-performance computing infrastructure for large scale network simulations. Using new synapse distribution methods and Finite Volume based numerical solvers for compartment-type models, our results demonstrate how an increase in synaptic synchronization can compensate synapse loss at the electrical and calcium level, and how detailed neuronal morphology can be integrated in large-scale network simulations.

  9. The cytotoxic T lymphocyte immune synapse at a glance.

    Science.gov (United States)

    Dieckmann, Nele M G; Frazer, Gordon L; Asano, Yukako; Stinchcombe, Jane C; Griffiths, Gillian M

    2016-08-01

    The immune synapse provides an important structure for communication with immune cells. Studies on immune synapses formed by cytotoxic T lymphocytes (CTLs) highlight the dynamic changes and specialised mechanisms required to facilitate focal signalling and polarised secretion in immune cells. In this Cell Science at a Glance article and the accompanying poster, we illustrate the different steps that reveal the specialised mechanisms used to focus secretion at the CTL immune synapse and allow CTLs to be such efficient and precise serial killers. © 2016. Published by The Company of Biologists Ltd.

  10. Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring.

    Science.gov (United States)

    Gąssowska, Magdalena; Baranowska-Bosiacka, Irena; Moczydłowska, Joanna; Frontczak-Baniewicz, Małgorzata; Gewartowska, Magdalena; Strużyńska, Lidia; Gutowska, Izabela; Chlubek, Dariusz; Adamczyk, Agata

    2016-12-12

    Lead (Pb), environmentally abundant heavy-metal pollutant, is a strong toxicant for the developing central nervous system. Pb intoxication in children, even at low doses, is found to affect learning and memorizing, with devastating effects on cognitive function and intellectual development. However, the precise mechanism by which Pb impairs synaptic plasticity is not fully elucidated. The purpose of this study was to investigate the effect of pre- and neonatal exposure to low dose of Pb (with Pb concentrations in whole blood below 10μg/dL) on the synaptic structure and the pre- and postsynaptic proteins expression in the developing rat brain. Furthermore, the level of brain-derived neurotrophic factor (BDNF) was analyzed. Pregnant female Wistar rats received 0.1% lead acetate (PbAc) in drinking water from the first day of gestation until weaning of the offspring, while the control animals received drinking water. During the feeding of pups, mothers from the Pb-group were continuously receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-day old pups were sacrificed and the ultrastructural changes as well as expression of presynaptic (VAMP1/2, synaptophysin, synaptotagmin-1, SNAP25, syntaxin-1) and postsynaptic (PSD-95) proteins were analyzed in: forebrain cortex, cerebellum and hippocampus. Our data revealed that pre- and neonatal exposure to low dose of Pb promotes pathological changes in synapses, including nerve endings swelling, blurred and thickened synaptic cleft structure as well as enhanced density of synaptic vesicles in the presynaptic area. Moreover, synaptic mitochondria were elongated, swollen or shrunken in Pb-treated animals. These structural abnormalities were accompanied by decrease in the level of key synaptic proteins: synaptotagmin-1 in cerebellum, SNAP25 in hippocampus and syntaxin-1 in cerebellum and hippocampus. In turn, increased level of synaptophysin was

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

    Science.gov (United States)

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

    2010-01-01

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

  12. Rigidified Clicked Dimeric Ligands for Studying the Dynamics of the PDZ1-2 Supramodule of PSD-95

    DEFF Research Database (Denmark)

    Eildal, Jonas N N; Bach, Anders; Dogan, Jakob

    2015-01-01

    PSD-95 is a scaffolding protein of the MAGUK protein family, and engages in several vital protein-protein interactions in the brain with its PDZ domains. It has been suggested that PSD-95 is composed of two supramodules, one of which is the PDZ1-2 tandem domain. Here we have developed rigidified...

  13. A cortical attractor network with Martinotti cells driven by facilitating synapses.

    Directory of Open Access Journals (Sweden)

    Pradeep Krishnamurthy

    Full Text Available The population of pyramidal cells significantly outnumbers the inhibitory interneurons in the neocortex, while at the same time the diversity of interneuron types is much more pronounced. One acknowledged key role of inhibition is to control the rate and patterning of pyramidal cell firing via negative feedback, but most likely the diversity of inhibitory pathways is matched by a corresponding diversity of functional roles. An important distinguishing feature of cortical interneurons is the variability of the short-term plasticity properties of synapses received from pyramidal cells. The Martinotti cell type has recently come under scrutiny due to the distinctly facilitating nature of the synapses they receive from pyramidal cells. This distinguishes these neurons from basket cells and other inhibitory interneurons typically targeted by depressing synapses. A key aspect of the work reported here has been to pinpoint the role of this variability. We first set out to reproduce quantitatively based on in vitro data the di-synaptic inhibitory microcircuit connecting two pyramidal cells via one or a few Martinotti cells. In a second step, we embedded this microcircuit in a previously developed attractor memory network model of neocortical layers 2/3. This model network demonstrated that basket cells with their characteristic depressing synapses are the first to discharge when the network enters an attractor state and that Martinotti cells respond with a delay, thereby shifting the excitation-inhibition balance and acting to terminate the attractor state. A parameter sensitivity analysis suggested that Martinotti cells might, in fact, play a dominant role in setting the attractor dwell time and thus cortical speed of processing, with cellular adaptation and synaptic depression having a less prominent role than previously thought.

  14. Tuning afferent synapses of hippocampal interneurons by neuropeptide Y

    DEFF Research Database (Denmark)

    Ledri, Marco; Sørensen, Andreas Toft; Erdelyi, Ferenc

    2011-01-01

    extrahippocampal afferents. Various excitatory and inhibitory afferent and efferent synapses of the hippocampal CCK basket cells express serotoninergic, cholinergic, cannabinoid, and benzodiazepine sensitive receptors, all contributing to their functional plasticity. We explored whether CCK basket cells...

  15. Liprin-alpha Proteins Regulate Neuronal Development and Synapse Function

    NARCIS (Netherlands)

    S.A. Spangler (Samantha)

    2009-01-01

    textabstractSynapses are specialized communication junctions between neurons whose plasticity provides the structural and functional basis for information processing and storage in the brain. Recent biochemical, genetic and imaging studies in diverse model systems are beginning to reveal the

  16. Design and synthesis of triazole-based peptidomimetics of a PSD-95 PDZ domain inhibitor

    DEFF Research Database (Denmark)

    Bach, Anders; Pedersen, Thomas B.; Strømgaard, Kristian

    2016-01-01

    PSD-95 PDZ domains are biologically important and promising drug targets. Here, we discover a triazole-based peptidomimetic, 10, by ‘click chemistry’. Compound 10 inhibits the PDZ2/GluN2B interaction with affinity similar to tripeptide SAV and better than current small-molecules. Thus, 10...

  17. Maximum likelihood PSD estimation for speech enhancement in reverberant and noisy conditions

    DEFF Research Database (Denmark)

    Kuklasinski, Adam; Doclo, Simon; Jensen, Jesper

    2016-01-01

    estimator. Instrumental performance measures indicate an advantage of the proposed estimator over the competing one. In a speech intelligibility test all algorithms significantly improved the word intelligibility score. While the results suggest a minor advantage of using the proposed PSD estimator...

  18. Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis.

    Science.gov (United States)

    Fossati, G; Morini, R; Corradini, I; Antonucci, F; Trepte, P; Edry, E; Sharma, V; Papale, A; Pozzi, D; Defilippi, P; Meier, J C; Brambilla, R; Turco, E; Rosenblum, K; Wanker, E E; Ziv, N E; Menna, E; Matteoli, M

    2015-09-01

    Impairment of synaptic function can lead to neuropsychiatric disorders collectively referred to as synaptopathies. The SNARE protein SNAP-25 is implicated in several brain pathologies and, indeed, brain areas of psychiatric patients often display reduced SNAP-25 expression. It has been recently found that acute downregulation of SNAP-25 in brain slices impairs long-term potentiation; however, the processes through which this occurs are still poorly defined. We show that in vivo acute downregulation of SNAP-25 in CA1 hippocampal region affects spine number. Consistently, hippocampal neurons from SNAP-25 heterozygous mice show reduced densities of dendritic spines and defective PSD-95 dynamics. Finally, we show that, in brain, SNAP-25 is part of a molecular complex including PSD-95 and p140Cap, with p140Cap being capable to bind to both SNAP-25 and PSD-95. These data demonstrate an unexpected role of SNAP-25 in controlling PSD-95 clustering and open the possibility that genetic reductions of the protein levels - as occurring in schizophrenia - may contribute to the pathology through an effect on postsynaptic function and plasticity.

  19. Design of a large dynamic range readout unit for the PSD detector of DAMPE

    CERN Document Server

    Zhou, Yong; Sun, Zhiyu; Zhang, Yongjie; Fang, Fang; Chen, Junling; Hu, Bitao

    2016-01-01

    A large dynamic range is required by the Plastic Scintillator Detector (PSD) of DArk Matter Paricle Explorer (DAMPE), and a double-dynode readout has been developed. To verify this design, a prototype detector module has been constructed and tested with cosmic rays and heavy ion beams. The results match with the estimation and the readout unit could easily cover the required dynamic range.

  20. 75 FR 28227 - Prevention of Significant Deterioration (PSD) and Nonattainment New Source Review (NSR): Aggregation

    Science.gov (United States)

    2010-05-20

    ... From the Federal Register Online via the Government Publishing Office ENVIRONMENTAL PROTECTION AGENCY 40 CFR Parts 51 and 52 RIN 2060-AP80 Prevention of Significant Deterioration (PSD) and Nonattainment New Source Review (NSR): Aggregation Correction Proposed Rule document 2010-11578 was...

  1. What does it mean to be pseudo single domain? Demystifying the PSD state

    Science.gov (United States)

    Lascu, I.; Harrison, R. J.; Einsle, J. F.; Ball, M.

    2016-12-01

    Until recently, non-interacting stable single domain grains were thought to be the sole reliable paleomagnetic recorders. However most natural samples contain so-called "non-ideal" paleomagnetic recorders, which are either interacting single domain particles, or magnetic grains larger than single domain grains, but smaller than proper multi domain grains, which are poor paleomagnetic recorders. The grain size range for these recorders, which for magnetite comprises grains from 100 nm to a few μm in size, is known as the pseudo single domain (PSD) state. Natural samples containing abundant PSD grains have been shown time and again to reliably record thermomagnetic remanent magnetizations that are stable over billions of years. Here we attempt to shed new light on the PSD state by investigating obsidian varieties found at Glass Butte, Oregon, which present the opportunity to study simple cases of magnetic grains encapsulated in volcanic glass. We do this by combining rock magnetism, scanning electron microscopy (SEM) nanotomography, and finite-element micromagnetic modeling. Using rock magnetism we have identified PSD signatures in these samples via their fingerprint in first-order reversal curve (FORC) diagrams. Tomographic reconstructions obtained by stacking SEM images acquired via sequential milling through sample volumes of a few tens of cubic μm reveal the presence of abundant grains that span the PSD grain size interval. These grains have a variety of shapes, from simple ellipsoidal particles, to more complex morphologies attained through the coalescence of neighboring grains during crystallization, to intricate "rolling snowball" morphologies in larger grains that contain appendices formed as a result of particle growth in a dynamic environment as the flowing lava cooled. Micromagnetic modeling of the simplest morphologies reveals that these grains are in single vortex states, with the remanence controlled by irregularities in grain morphology. Coalesced

  2. Climbing fiber synapse elimination in cerebellar Purkinje cells

    OpenAIRE

    Watanabe, Masahiko; Kano, Masanobu

    2011-01-01

    Innervation of Purkinje cells (PCs) by multiple climbing fibers (CFs) is refined into mono-innervation during the first three postnatal weeks of rodents' life. In this review article, we will integrate the current knowledge on developmental process and mechanisms of CF synapse elimination. In the "creeper" stage of CF innervation (postnatal day 0 (P0)∼), CFs creep among PC somata to form transient synapses on immature dendrites. In the "pericellular nest" stage (P5∼), CFs densely surround and...

  3. On the road towards the global analysis of human synapses.

    Science.gov (United States)

    Prieto, G Aleph; Cotman, Carl W

    2017-10-01

    Synapses are essential units for the flow of information in the brain. Over the last 70 years, synapses have been widely studied in multiple animal models including worms, fruit flies, and rodents. In comparison, the study of human synapses has evolved significantly slower, mainly because of technical limitations. However, three novel methods allowing the analysis of molecular, morphological, and functional properties of human synapses may expand our knowledge of the human brain. Here, we briefly describe these methods, and evaluate how the information provided by each unique approach may contribute to the functional and anatomical analysis of the synaptic component of human brain circuitries. In particular, using tissue from cryopreserved human brains, synaptic plasticity can be studied in isolated synaptosomes by fluorescence analysis of single-synapse long-term potentiation (FASS-LTP), and subpopulations of synapses can be thoroughly assessed in the ribbons of brain tissue by array tomography (AT). Currently, it is also possible to quantify synaptic density in the living human brain by positron emission tomography (PET), using a novel synaptic radio-ligand. Overall, data provided by FASS-LTP, AT, and PET may significantly contribute to the global understanding of synaptic structure and function in both healthy and diseased human brains, thus directly impacting translational research.

  4. On the road towards the global analysis of human synapses

    Directory of Open Access Journals (Sweden)

    G Aleph Prieto

    2017-01-01

    Full Text Available Synapses are essential units for the flow of information in the brain. Over the last 70 years, synapses have been widely studied in multiple animal models including worms, fruit flies, and rodents. In comparison, the study of human synapses has evolved significantly slower, mainly because of technical limitations. However, three novel methods allowing the analysis of molecular, morphological, and functional properties of human synapses may expand our knowledge of the human brain. Here, we briefly describe these methods, and evaluate how the information provided by each unique approach may contribute to the functional and anatomical analysis of the synaptic component of human brain circuitries. In particular, using tissue from cryopreserved human brains, synaptic plasticity can be studied in isolated synaptosomes by fluorescence analysis of single-synapse long-term potentiation (FASS-LTP, and subpopulations of synapses can be thoroughly assessed in the ribbons of brain tissue by array tomography (AT. Currently, it is also possible to quantify synaptic density in the living human brain by positron emission tomography (PET, using a novel synaptic radio-ligand. Overall, data provided by FASS-LTP, AT, and PET may significantly contribute to the global understanding of synaptic structure and function in both healthy and diseased human brains, thus directly impacting translational research.

  5. CNS Neurons Deposit Laminin α5 to Stabilize Synapses.

    Science.gov (United States)

    Omar, Mitchell H; Campbell, Meghan Kerrisk; Xiao, Xiao; Zhong, Qiaonan; Brunken, William J; Miner, Jeffrey H; Greer, Charles A; Koleske, Anthony J

    2017-10-31

    Synapses in the developing brain are structurally dynamic but become stable by early adulthood. We demonstrate here that an α5-subunit-containing laminin stabilizes synapses during this developmental transition. Hippocampal neurons deposit laminin α5 at synapses during adolescence as connections stabilize. Disruption of laminin α5 in neurons causes dramatic fluctuations in dendritic spine head size that can be rescued by exogenous α5-containing laminin. Conditional deletion of laminin α5 in vivo increases dendritic spine size and leads to an age-dependent loss of synapses accompanied by behavioral defects. Remaining synapses have larger postsynaptic densities and enhanced neurotransmission. Finally, we provide evidence that laminin α5 acts through an integrin α3β1-Abl2 kinase-p190RhoGAP signaling cascade and partners with laminin β2 to regulate dendritic spine density and behavior. Together, our results identify laminin α5 as a stabilizer of dendritic spines and synapses in the brain and elucidate key cellular and molecular mechanisms by which it acts. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. Plastic Bonded Explosive (PBX) Particle Size Distribution (PSD) Measurements Using an Image Analysis System

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, Gregg K. [Univ. of Wyoming, Laramie, WY (United States)

    2003-06-01

    The slurry process for producing plastic bonded explosives (PBX) has been used for many years. However, until recently the mechanisms involved have not been studied quantitatively to determine the effects of the various control variables. Recently, the effects of operating variables on the final product have been studied; however, no attempt was made to measure particle growth during the slurry process. This study applies an image analysis tool to measure particle size distributions (PSDs) during the slurry process to produce PBX 9501, a specific formulation used in nuclear weapons. The observed PBX 9501 slurry behavior leads away from the typical population balance description of agglomeration, that is, a discrete particle-particle coalescence mechanism. The behavior observed in these experiments indicates that the initial state of the system contains a number of smaller particles clustered together. The cluster then coalesces into a large particle as solvent is removed and the slurry continuously mixed. Other small fragments are picked up and a relatively small amount of growth is observed. A mass transfer model adequately describes solvent removal, and an empirical model is developed to describe the growth behavior in terms of measured process variables. The image system is applied to dried molding powders. The PSD measurement results of the PBX 9501 library lots, historic samples set aside as PBX 9501 lots were accepted from the manufacturer, are also discussed and analyzed. A correlation analysis was conducted to find relationships between the measured PSD and other properties such as bulk density and pressed densities. While no significant correlation was found between the measured PSD and averaged bulk densities for the library lots, significant correlations are found between the measured PSD and pressed density. The final part of the study was to scale-up the PSD measurement capability. Since the large-scale processes are not yet operational, this work

  7. Rab3B protein is required for long-term depression of hippocampal inhibitory synapses and for normal reversal learning

    Science.gov (United States)

    Tsetsenis, Theodoros; Younts, Thomas J.; Chiu, Chiayu Q.; Kaeser, Pascal S.; Castillo, Pablo E.; Südhof, Thomas C.

    2011-01-01

    Rab3B, similar to other Rab3 isoforms, is a synaptic vesicle protein that interacts with the Rab3-interacting molecule (RIM) isoforms RIM1α and RIM2α as effector proteins in a GTP-dependent manner. Previous studies showed that at excitatory synapses, Rab3A and RIM1α are essential for presynaptically expressed long-term potentiation (LTP), whereas at inhibitory synapses RIM1α is required for endocannabinoid-dependent long-term depression (referred to as “i-LTD”). However, it remained unknown whether i-LTD also involves a Rab3 isoform and whether i-LTD, similar to other forms of long-term plasticity, is important for learning and memory. Here we show that Rab3B is highly enriched in inhibitory synapses in the CA1 region of the hippocampus. Using electrophysiological recordings in acute slices, we demonstrate that knockout (KO) of Rab3B does not alter the strength or short-term plasticity of excitatory or inhibitory synapses but does impair i-LTD significantly without changing classical NMDA receptor-dependent LTP. Behaviorally, we found that Rab3B KO mice exhibit no detectable changes in all basic parameters tested, including the initial phase of learning and memory. However, Rab3B KO mice did display a selective enhancement in reversal learning, as measured using Morris water-maze and fear-conditioning assays. Our data support the notion that presynaptic forms of long-term plasticity at excitatory and inhibitory synapses generally are mediated by a common Rab3/RIM-dependent pathway, with various types of synapses using distinct Rab3 isoforms. Moreover, our results suggest that i-LTD contributes to learning and memory, presumably by stabilizing circuits established in previous learning processes. PMID:21844341

  8. The Angelman Syndrome-associated ubiquitin ligase Ube3A regulates synapse development by ubiquitinating Arc

    Science.gov (United States)

    Greer, Paul L.; Hanayama, Rikinari; Bloodgood, Brenda L.; Mardinly, Alan R.; Lipton, David M.; Flavell, Steven W.; Kim, Tae-Kyung; Griffith, Eric C.; Waldon, Zachary; Maehr, Rene; Ploegh, Hidde L.; Chowdhury, Shoaib; Worley, Paul F.; Steen, Judith; Greenberg, Michael E.

    2010-01-01

    Angelman Syndrome is a debilitating neurological disorder caused by mutation of the E3 ubiquitin ligase Ube3A, a gene whose mutation has also recently been associated with autism spectrum disorders (ASDs). The function of Ube3A during nervous system development, and how Ube3A mutations give rise to cognitive impairment in individuals with Angleman Syndrome and ASDs are not clear. We report here that experience-driven neuronal activity induces Ube3A transcription and that Ube3A then regulates excitatory synapse development by controlling the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA sub-type of glutamate receptors. We find that disruption of Ube3A function in neurons leads to an increase in Arc expression and a concomitant decrease in the number of AMPA receptors at excitatory synapses. We propose that this deregulation of AMPA receptor expression at synapses may contribute to the cognitive dysfunction that occurs in Angelman Syndrome and possible other ASDs. PMID:20211139

  9. Loss of transforming growth factor-beta 2 leads to impairment of central synapse function

    Directory of Open Access Journals (Sweden)

    Rickmann Michael

    2008-10-01

    Full Text Available Abstract Background The formation of functional synapses is a crucial event in neuronal network formation, and with regard to regulation of breathing it is essential for life. Members of the transforming growth factor-beta (TGF-β superfamily act as intercellular signaling molecules during synaptogenesis of the neuromuscular junction of Drosophila and are involved in synaptic function of sensory neurons of Aplysia. Results Here we show that while TGF-β2 is not crucial for the morphology and function of the neuromuscular junction of the diaphragm muscle of mice, it is essential for proper synaptic function in the pre-Bötzinger complex, a central rhythm organizer located in the brainstem. Genetic deletion of TGF-β2 in mice strongly impaired both GABA/glycinergic and glutamatergic synaptic transmission in the pre-Bötzinger complex area, while numbers and morphology of central synapses of knock-out animals were indistinguishable from their wild-type littermates at embryonic day 18.5. Conclusion The results demonstrate that TGF-β2 influences synaptic function, rather than synaptogenesis, specifically at central synapses. The functional alterations in the respiratory center of the brain are probably the underlying cause of the perinatal death of the TGF-β2 knock-out mice.

  10. Temporal dynamics in an immunological synapse: Role of thermal fluctuations in signaling

    Science.gov (United States)

    Bush, Daniel R.; Chattopadhyay, Amit K.

    2015-07-01

    The article analyzes the contribution of stochastic thermal fluctuations in the attachment times of the immature T-cell receptor TCR: peptide-major-histocompatibility-complex pMHC immunological synapse bond. The key question addressed here is the following: how does a synapse bond remain stabilized in the presence of high-frequency thermal noise that potentially equates to a strong detaching force? Focusing on the average time persistence of an immature synapse, we show that the high-frequency nodes accompanying large fluctuations are counterbalanced by low-frequency nodes that evolve over longer time periods, eventually leading to signaling of the immunological synapse bond primarily decided by nodes of the latter type. Our analysis shows that such a counterintuitive behavior could be easily explained from the fact that the survival probability distribution is governed by two distinct phases, corresponding to two separate time exponents, for the two different time regimes. The relatively shorter timescales correspond to the cohesion:adhesion induced immature bond formation whereas the larger time reciprocates the association:dissociation regime leading to TCR:pMHC signaling. From an estimate of the bond survival probability, we show that, at shorter timescales, this probability PΔ(τ ) scales with time τ as a universal function of a rescaled noise amplitude D/Δ2, such that PΔ(τ ) ˜τ-(Δ/√{D }+1/2 ) ,Δ being the distance from the mean intermembrane (T cell:Antigen Presenting Cell) separation distance. The crossover from this shorter to a longer time regime leads to a universality in the dynamics, at which point the survival probability shows a different power-law scaling compared to the one at shorter timescales. In biological terms, such a crossover indicates that the TCR:pMHC bond has a survival probability with a slower decay rate than the longer LFA-1:ICAM-1 bond justifying its stability.

  11. Minocycline enhances hippocampal memory, neuroplasticity and synapse-associated proteins in aged C57 BL/6 mice.

    Science.gov (United States)

    Jiang, Ying; Liu, Yingying; Zhu, Cansheng; Ma, Xiaomeng; Ma, Lili; Zhou, Linli; Huang, Qiling; Cen, Lei; Pi, Rongbiao; Chen, Xiaohong

    2015-05-01

    Previous studies have suggested that minocycline can attenuate cognitive deficits in animal models of conditions such as Alzheimer's disease and cerebral ischemia through inhibiting microglia associated anti-inflammatory actions. However the pathway that minocycline targets to enhance cognitive performance is not fully defined. Here we examined the effects of minocycline on learning and memory in aged (22-month-old) C57 BL/6 mice. We treated one group of mice with minocycline (30 mg/kg/day), and another group of mice with donepezil (2 mg/kg/day) as a positive control. The Morris water maze and passive avoidance tests were used to evaluate the effects of minocycline on learning and memory deficits. We also used high-frequency stimulation-induced long-term potentiation and Golgi-Cox staining to assess the effect of minocycline on synaptic plasticity and synaptogenesis. The effects of minocycline on synapse-associated signaling proteins were determined by western blot. We found that minocycline ameliorates cognitive deficits, enhances neuroplasticity, activates brain-derived neurotrophic factor- extracellular signal-regulated kinases signaling and increases expression of Arc, EGR1 and PSD-95 in the CA1 and dentate gyrus regions of the hippocampus in aged mice. The effects of minocycline in aged mice were similar to those of donepezil. Our results suggest that minocycline could improve learning and memory through enhancing synaptic plasticity and synaptogenesis, modulating the expression of synapse-associated signaling proteins, which provide a rationale for exploring the viability of using minocycline treatment in cognitive deficits. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Instrumentation for PSD-based neutron diffractometers at Dhruva ...

    Indian Academy of Sciences (India)

    12 bit multiplying digital-to-analog converter (MDAC type 7541A) and successive approximation register logic (SAR). ... the signal input of the ratiometric ADC and the corresponding digital number is subtracted from the SAR output. The RDC can ... It has four links for communication one of which is used to communicate with ...

  13. Federated healthcare record server--the Synapses paradigm.

    Science.gov (United States)

    Grimson, W; Berry, D; Grimson, J; Stephens, G; Felton, E; Given, P; O'Moore, R

    1998-01-01

    The delivery of healthcare relies on the sharing of patient information between those who are providing for the care of the patient and this information is increasingly being expressed in terms of a 'record'. Further, it is desirable that these records are available in electronic form as Electronic HealthCare Records. As it is likely that patient records or parts of records will be stored in many different information systems and in the form of disparate record architectures, uniform access to patient records would be problematic. This paper presents an overview of the Synapses computing environment in which a Federated Healthcare Record Server provides uniform access to patient information stored in connected heterogeneous autonomous information systems and other Synapses servers. The Synapses record architecture is based on the architecture proposed by the Technical Committee 251 of the European Committee for Standardisation and the interfaces to the Synapses server are specified in the ISO standard Interface Definition Language. Synapses is a pan-European project involving a number of hospitals, software companies, universities and research institutes and is partly funded by the EU Health Telematics Programme. The overview is described in terms of the Open Distributed Processing Reference Model.

  14. Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses

    Directory of Open Access Journals (Sweden)

    Steven J. Burden

    2018-02-01

    Full Text Available The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark studies did not reveal the molecular mechanisms responsible for building and maintaining a synapse. During the past two-dozen years, the critical molecular players, responsible for assembling the specialized postsynaptic membrane and regulating nerve terminal differentiation, have begun to be identified and their mechanism of action better understood. Here, we describe and discuss five of these key molecular players, paying heed to their discovery as well as describing their currently understood mechanisms of action. In addition, we discuss the important gaps that remain to better understand how these proteins act to control synaptic differentiation and maintenance.

  15. Ocean thermal energy conversion power system development. Final design report: PSD-I, Phase II

    Energy Technology Data Exchange (ETDEWEB)

    None

    1980-06-30

    The PSD-I program provides a heat exchanger sytem consisting of an evaporator, condenser and various ancillaries with ammonia used as a working fluid in a closed simulated Rankine cycle. It is to be installed on the Chepachet Research Vessel for test and evaluation of a number of OTEC concepts in a true ocean environment. It is one of several test articles to be tested. Primary design concerns include control of biofouling, corrosion and erosion of aluminum tubes, selection of materials, and the development of a basis for scale-up to large heat exchangers so as to ultimately demonstrate economic feasibility on a commercial scale. The PSD-I test article is devised to verify thermodynamic, environmental, and mechanical performance of basic design concepts. The detailed design, development, fabrication, checklist, delivery, installation support, and operation support for the Test Article Heat Exchangers are described. (WHK)

  16. Marshall Space Flight Center Propulsion Systems Department (PSD) Knowledge Management (KM) Initiative

    Science.gov (United States)

    Caraccioli, Paul; Varnedoe, Tom; Smith, Randy; McCarter, Mike; Wilson, Barry; Porter, Richard

    2006-01-01

    NASA Marshall Space Flight Center's Propulsion Systems Department (PSD) is four months into a fifteen month Knowledge Management (KM) initiative to support enhanced engineering decision making and analyses, faster resolution of anomalies (near-term) and effective, efficient knowledge infused engineering processes, reduced knowledge attrition, and reduced anomaly occurrences (long-term). The near-term objective of this initiative is developing a KM Pilot project, within the context of a 3-5 year KM strategy, to introduce and evaluate the use of KM within PSD. An internal NASA/MSFC PSD KM team was established early in project formulation to maintain a practitioner, user-centric focus throughout the conceptual development, planning and deployment of KM technologies and capabilities within the PSD. The PSD internal team is supported by the University of Alabama's Aging Infrastructure Systems Center of Excellence (AISCE), lntergraph Corporation, and The Knowledge Institute. The principle product of the initial four month effort has been strategic planning of PSD KNI implementation by first determining the "as is" state of KM capabilities and developing, planning and documenting the roadmap to achieve the desired "to be" state. Activities undertaken to suppoth e planning phase have included data gathering; cultural surveys, group work-sessions, interviews, documentation review, and independent research. Assessments and analyses have beon pedormed including industry benchmarking, related local and Agency initiatives, specific tools and techniques used and strategies for leveraging existing resources, people and technology to achieve common KM goals. Key findings captured in the PSD KM Strategic Plan include the system vision, purpose, stakeholders, prioritized strategic objectives mapped to the top ten practitioner needs and analysis of current resource usage. Opportunities identified from research, analyses, cultural1KM surveys and practitioner interviews include

  17. Simulated power spectral density (PSD) of background electrocorticogram (ECoG).

    Science.gov (United States)

    Freeman, Walter J; Zhai, Jian

    2009-03-01

    The ECoG background activity of cerebral cortex in states of rest and slow wave sleep resembles broadband noise. The power spectral density (PSD) then may often conform to a power-law distribution: a straight line in coordinates of log power vs. log frequency. The exponent, x, of the distribution, 1/f(x), ranges between 2 and 4. These findings are explained with a model of the neural source of the background activity in mutual excitation among pyramidal cells. The dendritic response of a population of interactive excitatory neurons to an impulse input is a rapid exponential rise and a slow exponential decay, which can be fitted with the sum of two exponential terms. When that function is convolved as the kernel with pulses from a Poisson process and summed, the resulting "brown" or "black noise conforms to the ECoG time series and the PSD in rest and sleep. The PSD slope is dependent on the rate of rise. The variation in the observed slope is attributed to variation in the level of the background activity that is homeostatically regulated by the refractory periods of the excitatory neurons. Departures in behavior from rest and sleep to action are accompanied by local peaks in the PSD, which manifest emergent nonrandom structure in the ECoG, and which prevent reliable estimation of the 1/f(x) exponents in active states. We conclude that the resting ECoG truly is low-dimensional noise, and that the resting state is an optimal starting point for defining and measuring both artifactual and physiological structures emergent in the activated ECoG.

  18. Coding deficits in noise-induced hidden hearing loss may stem from incomplete repair of ribbon synapses in the cochlea

    Directory of Open Access Journals (Sweden)

    Lijuan eShi

    2016-05-01

    Full Text Available Recent evidence has shown that noise-induced damage to the synapse between inner hair cells (IHCs and type I afferent auditory nerve fibers (ANFs may occur in the absence of permanent threshold shift (PTS, and that synapses connecting IHCs with low spontaneous rate (SR ANFs are disproportionately affected. Due to the functional importance of low-SR ANF units for temporal processing and signal coding in noisy backgrounds, deficits in cochlear coding associated with noise-induced damage may result in significant difficulties with temporal processing and hearing in noise (i.e., hidden hearing loss. However, significant noise-induced coding deficits have not been reported at the single unit level following the loss of low-SR units. We have found evidence to suggest that some aspects of neural coding are not significantly changed with the initial loss of low-SR ANFs, and that further coding deficits arise in association with the subsequent reestablishment of the synapses. This suggests that synaptopathy in hidden hearing loss may be the result of insufficient repair of disrupted synapses, and not simply due to the loss of low-SR units. These coding deficits include decreases in driven spike rate for intensity coding as well as several aspects of temporal coding: spike latency, peak-to-sustained spike ratio and the recovery of spike rate as a function of click-interval.

  19. Thyroid hormone is required for pruning, functioning and long-term maintenance of afferent inner hair cell synapses

    Science.gov (United States)

    Sundaresan, Srividya; Kong, Jee-Hyun; Fang, Qing; Salles, Felipe T.; Wangsawihardja, Felix; Ricci, Anthony J.; Mustapha, Mirna

    2016-01-01

    Functional maturation of afferent synaptic connections to inner hair cells (IHCs) involves pruning of excess synapses formed during development, as well as the strengthening and survival of the retained synapses. These events take place during the thyroid hormone (TH)-critical period of cochlear development, which is in the perinatal period for mice and in the third trimester for humans. Here, we used the hypothyroid Snell dwarf mouse (Pit1dw) as a model to study the role of TH in afferent type I synaptic refinement and functional maturation. We observed defects in afferent synaptic pruning and delays in calcium channel clustering in the IHCs of Pit1dw mice. Nevertheless, calcium currents and capacitance reached near normal levels in Pit1dw IHCs by the age of onset of hearing, despite the excess number of retained synapses. We restored normal synaptic pruning in Pit1dw IHCs by supplementing with TH from postnatal day (P)3 to P8, establishing this window as being critical for TH action on this process. Afferent terminals of older Pit1dw IHCs showed evidence of excitotoxic damage accompanied by a concomitant reduction in the levels of the glial glutamate transporter, GLAST. Our results indicate that a lack of TH during a critical period of inner ear development causes defects in pruning and long-term homeostatic maintenance of afferent synapses. PMID:26386265

  20. Learning through ferroelectric domain dynamics in solid-state synapses

    Science.gov (United States)

    Boyn, Sören; Grollier, Julie; Lecerf, Gwendal; Xu, Bin; Locatelli, Nicolas; Fusil, Stéphane; Girod, Stéphanie; Carrétéro, Cécile; Garcia, Karin; Xavier, Stéphane; Tomas, Jean; Bellaiche, Laurent; Bibes, Manuel; Barthélémy, Agnès; Saïghi, Sylvain; Garcia, Vincent

    2017-04-01

    In the brain, learning is achieved through the ability of synapses to reconfigure the strength by which they connect neurons (synaptic plasticity). In promising solid-state synapses called memristors, conductance can be finely tuned by voltage pulses and set to evolve according to a biological learning rule called spike-timing-dependent plasticity (STDP). Future neuromorphic architectures will comprise billions of such nanosynapses, which require a clear understanding of the physical mechanisms responsible for plasticity. Here we report on synapses based on ferroelectric tunnel junctions and show that STDP can be harnessed from inhomogeneous polarization switching. Through combined scanning probe imaging, electrical transport and atomic-scale molecular dynamics, we demonstrate that conductance variations can be modelled by the nucleation-dominated reversal of domains. Based on this physical model, our simulations show that arrays of ferroelectric nanosynapses can autonomously learn to recognize patterns in a predictable way, opening the path towards unsupervised learning in spiking neural networks.

  1. Microglial interactions with synapses are modulated by visual experience.

    Directory of Open Access Journals (Sweden)

    Marie-Ève Tremblay

    2010-11-01

    Full Text Available Microglia are the immune cells of the brain. In the absence of pathological insult, their highly motile processes continually survey the brain parenchyma and transiently contact synaptic elements. Aside from monitoring, their physiological roles at synapses are not known. To gain insight into possible roles of microglia in the modification of synaptic structures, we used immunocytochemical electron microscopy, serial section electron microscopy with three-dimensional reconstructions, and two-photon in vivo imaging to characterize microglial interactions with synapses during normal and altered sensory experience, in the visual cortex of juvenile mice. During normal visual experience, most microglial processes displayed direct apposition with multiple synapse-associated elements, including synaptic clefts. Microglial processes were also distinctively surrounded by pockets of extracellular space. In terms of dynamics, microglial processes localized to the vicinity of small and transiently growing dendritic spines, which were typically lost over 2 d. When experience was manipulated through light deprivation and reexposure, microglial processes changed their morphology, showed altered distributions of extracellular space, displayed phagocytic structures, apposed synaptic clefts more frequently, and enveloped synapse-associated elements more extensively. While light deprivation induced microglia to become less motile and changed their preference of localization to the vicinity of a subset of larger dendritic spines that persistently shrank, light reexposure reversed these behaviors. Taken together, these findings reveal different modalities of microglial interactions with synapses that are subtly altered by sensory experience. These findings suggest that microglia may actively contribute to the experience-dependent modification or elimination of a specific subset of synapses in the healthy brain.

  2. PSD95 gene specific siRNAs attenuate neuropathic pain through modulating neuron sensibility and postsynaptic CaMKIIα phosphorylation.

    Science.gov (United States)

    Le, Shen; Xu, Li; Wen, Chen; Li, Xu; Wei, Liu; Xue-rong, Yu; Yu-guang, Huang

    2011-12-01

    To observe the effects of PSD95 gene specific siRNAs on neuropathic pain relief, neuron viability, and postsynaptic calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) phosphorylation in vitro and in vivo. Gene-specific siRNAs of rat PSD95 were synthesized chemically for transfection. Adult male Sprague-Dawley (SD) rats were randomly divided into 3 groups: naïve group (n=6), sham group (n=6), and sciatic nerve chronic constriction injury (CCI) group (n=24). The CCI group was further divided into 4 groups (n=6 in each group), which were pretreated with normal saline, transfection vehicle, negative control siRNAs, and PSD95 gene specific siRNAs respectively. All the subgroups received corresponding agents intrathecally for 3 days, started one day before the CCI of sciatic nerve. Both mechanical allodynia and thermal hyperalgesia were measured on post-operative day 3 and 7. PSD95 gene silenced NG108-15 cells were further stimulated by glutamate, with the cell viability and the expression/phosphorylation of CaMKIIα measured by MTT cell proliferation assay and Western blot, respectively. The siRNAs decreased PSD95 mRNA level significantly both in vivo and in vitro. Neuropathic pain rats pretreated with PSD95 gene specific siRNAs exhibited significant elevation in the mechanical withdrawal threshold and paw withdrawal thermal latency, without affecting the baseline nociception. PSD95 gene silencing enhanced neuronal tolerance against the glutamate excitotoxicity, meanwhile the phosphorylation of CaMKIIα Thr286 was attenuated. Pre-emptive administration of PSD95 gene specific siRNAs may attenuate the central sensitization CaMKIIα-related signaling cascades, leading to the relief of neuropathic pain.

  3. Multiprocessor and memory architecture of the neurocomputer SYNAPSE-1.

    Science.gov (United States)

    Ramacher, U; Raab, W; Anlauf, J; Hachmann, U; Beichter, J; Brüls, N; Wesseling, M; Sicheneder, E; Männer, R; Glass, J

    1993-12-01

    A general purpose neurocomputer, SYNAPSE-1, which exhibits a multiprocessor and memory architecture is presented. It offers wide flexibility with respect to neural algorithms and a speed-up factor of several orders of magnitude--including learning. The computational power is provided by a 2-dimensional systolic array of neural signal processors. Since the weights are stored outside these NSPs, memory size and processing power can be adapted individually to the application needs. A neural algorithms programming language, embedded in C(+2) has been defined for the user to cope with the neurocomputer. In a benchmark test, the prototype of SYNAPSE-1 was 8000 times as fast as a standard workstation.

  4. Electrolyte-gated organic synapse transistor interfaced with neurons

    CERN Document Server

    Desbief, Simon; Casalini, Stefano; Guerin, David; Tortorella, Silvia; Barbalinardo, Marianna; Kyndiah, Adrica; Murgia, Mauro; Cramer, Tobias; Biscarini, Fabio; Vuillaume, Dominique

    2016-01-01

    We demonstrate an electrolyte-gated hybrid nanoparticle/organic synapstor (synapse-transistor, termed EGOS) that exhibits short-term plasticity as biological synapses. The response of EGOS makes it suitable to be interfaced with neurons: short-term plasticity is observed at spike voltage as low as 50 mV (in a par with the amplitude of action potential in neurons) and with a typical response time in the range of tens milliseconds. Human neuroblastoma stem cells are adhered and differentiated into neurons on top of EGOS. We observe that the presence of the cells does not alter short-term plasticity of the device.

  5. Probing the mechanism of exocytosis at the hair cell ribbon synapse

    NARCIS (Netherlands)

    Neef, Andreas; Khimich, Darina; Pirih, Primoz; Riedel, Dietmar; Wolf, Fred; Moser, Tobias

    2007-01-01

    Hearing relies on faithful synaptic transmission at the ribbon synapse of cochlear inner hair cells (IHCs). Postsynaptic recordings from this synapse in prehearing animals had delivered strong indications for synchronized release of several vesicles. The underlying mechanism, however, remains

  6. Remodelling of cortical actin where lytic granules dock at natural killer cell immune synapses revealed by super-resolution microscopy.

    Science.gov (United States)

    Brown, Alice C N; Oddos, Stephane; Dobbie, Ian M; Alakoskela, Juha-Matti; Parton, Richard M; Eissmann, Philipp; Neil, Mark A A; Dunsby, Christopher; French, Paul M W; Davis, Ilan; Davis, Daniel M

    2011-09-01

    Natural Killer (NK) cells are innate immune cells that secrete lytic granules to directly kill virus-infected or transformed cells across an immune synapse. However, a major gap in understanding this process is in establishing how lytic granules pass through the mesh of cortical actin known to underlie the NK cell membrane. Research has been hampered by the resolution of conventional light microscopy, which is too low to resolve cortical actin during lytic granule secretion. Here we use two high-resolution imaging techniques to probe the synaptic organisation of NK cell receptors and filamentous (F)-actin. A combination of optical tweezers and live cell confocal microscopy reveals that microclusters of NKG2D assemble into a ring-shaped structure at the centre of intercellular synapses, where Vav1 and Grb2 also accumulate. Within this ring-shaped organisation of NK cell proteins, lytic granules accumulate for secretion. Using 3D-structured illumination microscopy (3D-SIM) to gain super-resolution of ~100 nm, cortical actin was detected in a central region of the NK cell synapse irrespective of whether activating or inhibitory signals dominate. Strikingly, the periodicity of the cortical actin mesh increased in specific domains at the synapse when the NK cell was activated. Two-colour super-resolution imaging revealed that lytic granules docked precisely in these domains which were also proximal to where the microtubule-organising centre (MTOC) polarised. Together, these data demonstrate that remodelling of the cortical actin mesh occurs at the central region of the cytolytic NK cell immune synapse. This is likely to occur for other types of cell secretion and also emphasises the importance of emerging super-resolution imaging technology for revealing new biology.

  7. Remodelling of cortical actin where lytic granules dock at natural killer cell immune synapses revealed by super-resolution microscopy.

    Directory of Open Access Journals (Sweden)

    Alice C N Brown

    2011-09-01

    Full Text Available Natural Killer (NK cells are innate immune cells that secrete lytic granules to directly kill virus-infected or transformed cells across an immune synapse. However, a major gap in understanding this process is in establishing how lytic granules pass through the mesh of cortical actin known to underlie the NK cell membrane. Research has been hampered by the resolution of conventional light microscopy, which is too low to resolve cortical actin during lytic granule secretion. Here we use two high-resolution imaging techniques to probe the synaptic organisation of NK cell receptors and filamentous (F-actin. A combination of optical tweezers and live cell confocal microscopy reveals that microclusters of NKG2D assemble into a ring-shaped structure at the centre of intercellular synapses, where Vav1 and Grb2 also accumulate. Within this ring-shaped organisation of NK cell proteins, lytic granules accumulate for secretion. Using 3D-structured illumination microscopy (3D-SIM to gain super-resolution of ~100 nm, cortical actin was detected in a central region of the NK cell synapse irrespective of whether activating or inhibitory signals dominate. Strikingly, the periodicity of the cortical actin mesh increased in specific domains at the synapse when the NK cell was activated. Two-colour super-resolution imaging revealed that lytic granules docked precisely in these domains which were also proximal to where the microtubule-organising centre (MTOC polarised. Together, these data demonstrate that remodelling of the cortical actin mesh occurs at the central region of the cytolytic NK cell immune synapse. This is likely to occur for other types of cell secretion and also emphasises the importance of emerging super-resolution imaging technology for revealing new biology.

  8. Learning-guided automatic three dimensional synapse quantification for drosophila neurons

    OpenAIRE

    Sanders, Jonathan; Singh, Anil; Sterne, Gabriella; Ye, Bing; Zhou, Jie

    2015-01-01

    Background The subcellular distribution of synapses is fundamentally important for the assembly, function, and plasticity of the nervous system. Automated and effective quantification tools are a prerequisite to large-scale studies of the molecular mechanisms of subcellular synapse distribution. Common practices for synapse quantification in neuroscience labs remain largely manual or semi-manual. This is mainly due to computational challenges in automatic quantification of synapses, including...

  9. Developmental changes in short-term plasticity at the rat calyx of Held synapse

    NARCIS (Netherlands)

    T.T.H. Crins (Tom); S.I. Rusu (Silviu); A. Rodríguez-Contreras (Adrián); J.G.G. Borst (Gerard)

    2011-01-01

    textabstractThe calyx of Held synapse of the medial nucleus of the trapezoid body functions as a relay synapse in the auditory brainstem. In vivo recordings have shown that this synapse displays low release probability and that the average size of synaptic potentials does not depend on recent

  10. Short-term ionic plasticity at GABAergic synapses

    Directory of Open Access Journals (Sweden)

    Joseph Valentino Raimondo

    2012-10-01

    Full Text Available Fast synaptic inhibition in the brain is mediated by the pre-synaptic release of the neurotransmitter γ-Aminobutyric acid (GABA and the post-synaptic activation of GABA-sensitive ionotropic receptors. As with excitatory synapses, it is being increasinly appreciated that a variety of plastic processes occur at inhibitory synapses, which operate over a range of timescales. Here we examine a form of activity-dependent plasticity that is somewhat unique to GABAergic transmission. This involves short-lasting changes to the ionic driving force for the postsynaptic receptors, a process referred to as short-term ionic plasticity. These changes are directly related to the history of activity at inhibitory synapses and are influenced by a variety of factors including the location of the synapse and the post-synaptic cell’s ion regulation mechanisms. We explore the processes underlying this form of plasticity, when and where it can occur, and how it is likely to impact network activity.

  11. A Nutrient Combination that Can Affect Synapse Formation

    Directory of Open Access Journals (Sweden)

    Richard J. Wurtman

    2014-04-01

    Full Text Available Brain neurons form synapses throughout the life span. This process is initiated by neuronal depolarization, however the numbers of synapses thus formed depend on brain levels of three key nutrients—uridine, the omega-3 fatty acid DHA, and choline. Given together, these nutrients accelerate formation of synaptic membrane, the major component of synapses. In infants, when synaptogenesis is maximal, relatively large amounts of all three nutrients are provided in bioavailable forms (e.g., uridine in the UMP of mothers’ milk and infant formulas. However, in adults the uridine in foods, mostly present at RNA, is not bioavailable, and no food has ever been compelling demonstrated to elevate plasma uridine levels. Moreover, the quantities of DHA and choline in regular foods can be insufficient for raising their blood levels enough to promote optimal synaptogenesis. In Alzheimer’s disease (AD the need for extra quantities of the three nutrients is enhanced, both because their basal plasma levels may be subnormal (reflecting impaired hepatic synthesis, and because especially high brain levels are needed for correcting the disease-related deficiencies in synaptic membrane and synapses.

  12. Distribution and structure of efferent synapses in the chicken retina

    Science.gov (United States)

    Lindstrom, SH; Nacsa, N; Blankenship, T; Fitzgerald, PG; Weller, C; Vaney, DI; Wilson, M

    2012-01-01

    The visual system of birds includes an efferent projection from a visual area, the isthmooptic nucleus in the midbrain, back to the retina. Using a combination of anterograde labeling of efferent fibers, reconstruction of dye-filled neurons, NADPH-diaphorase staining, and transmission electron microscopy we have examined the distribution of efferent fibers and their synaptic structures in the chicken retina. We show that efferent fibers terminate strictly within the ventral retina. In 2 completely mapped retinas, only 2 fibers from a total of 15,359 terminated in the dorsal retina. The major synapse made by each efferent fiber is with a single Efferent Target Amacrine Cell (TC). This synapse consists of 5-25 boutons of 2μm diameter, each with multiple active zones, pressed into the TC soma or synapsing with a basketwork of rudimentary TC dendrites in the inner nuclear layer (INL). This basketwork, which is sheathed by Muller cells processes, defines a private neuropil in the INL within which TCs were also seen to receive input from retinal neurons. In addition to the major synapse, efferent fibers typically produce several very thin processes that terminate nearby in single small boutons and for which the soma of a local amacrine cell is one of the likely postsynaptic partners. A minority of efferent fibers also give rise to a thicker process terminating in a strongly diaphorase positive ball about 5μm in diameter. PMID:19439107

  13. Efficient supervised learning in networks with binary synapses

    CERN Document Server

    Baldassi, Carlo; Brunel, Nicolas; Zecchina, Riccardo

    2007-01-01

    Recent experimental studies indicate that synaptic changes induced by neuronal activity are discrete jumps between a small number of stable states. Learning in systems with discrete synapses is known to be a computationally hard problem. Here, we study a neurobiologically plausible on-line learning algorithm that derives from Belief Propagation algorithms. We show that it performs remarkably well in a model neuron with binary synapses, and a finite number of `hidden' states per synapse, that has to learn a random classification task. Such system is able to learn a number of associations close to the theoretical limit, in time which is sublinear in system size. This is to our knowledge the first on-line algorithm that is able to achieve efficiently a finite number of patterns learned per binary synapse. Furthermore, we show that performance is optimal for a finite number of hidden states which becomes very small for sparse coding. The algorithm is similar to the standard `perceptron' learning algorithm, with a...

  14. Remodeling of Hippocampal Synapses After Hippocampus-Dependent Associative Learning

    NARCIS (Netherlands)

    Geinisman, Yuri; Disterhoft, John F.; Gundersen, Hans Jørgen G.; McEchron, Matthew D.; Persina, Inna S.; Power, John M.; Zee, Eddy A. van der; West, Mark J.

    2000-01-01

    The aim of this study was to determine whether hippocampus-dependent associative learning involves changes in the number and/or structure of hippocampal synapses. A behavioral paradigm of trace eyeblink conditioning was used. Young adult rabbits were given daily 80 trial sessions to a criterion of

  15. Complement System in Neural Synapse Elimination in Development and Disease.

    Science.gov (United States)

    Presumey, Jessy; Bialas, Allison R; Carroll, Michael C

    2017-01-01

    Recent discoveries implicate the classical complement cascade in normal brain development and in disease. Complement proteins C1q, C3, and C4 participate in synapse elimination, tagging inappropriate synaptic connections between neurons for removal by phagocytic microglia that exist in a special, highly phagocytic state during the synaptic pruning period. Several neurodevelopmental disorders, such as schizophrenia and autism, are thought to be caused by an imbalance in synaptic pruning, and recent studies suggest that dysregulation of complement could promote this synaptic pruning imbalance. Moreover, in the mature brain, complement can be aberrantly activated in early stages of neurodegenerative diseases to stimulate synapse loss. Similar pathways can also be activated in response to inflammation, as in West Nile Virus infection or in lupus, where peripheral inflammation can promote microglia-mediated synapse loss. Whether synapse loss in disease is a true reactivation of developmental synaptic pruning programs remains unclear; nonetheless, complement proteins represent potential therapeutic targets for both neurodevelopmental and neurodegenerative diseases. © 2017 Elsevier Inc. All rights reserved.

  16. Analog memristive synapse in spiking networks implementing unsupervised learning

    Directory of Open Access Journals (Sweden)

    Erika Covi

    2016-10-01

    Full Text Available Emerging brain-inspired architectures call for devices that can emulate the functionality of biological synapses in order to implement new efficient computational schemes able to solve ill-posed problems. Various devices and solutions are still under investigation and, in this respect, a challenge is opened to the researchers in the field. Indeed, the optimal candidate is a device able to reproduce the complete functionality of a synapse, i.e. the typical synaptic process underlying learning in biological systems (activity-dependent synaptic plasticity. This implies a device able to change its resistance (synaptic strength, or weight upon proper electrical stimuli (synaptic activity and showing several stable resistive states throughout its dynamic range (analog behavior. Moreover, it should be able to perform spike timing dependent plasticity (STDP, an associative homosynaptic plasticity learning rule based on the delay time between the two firing neurons the synapse is connected to. This rule is a fundamental learning protocol in state-of-art networks, because it allows unsupervised learning. Notwithstanding this fact, STDP-based unsupervised learning has been proposed several times mainly for binary synapses rather than multilevel synapses composed of many binary memristors. This paper proposes an HfO2-based analog memristor as a synaptic element which performs STDP within a small spiking neuromorphic network operating unsupervised learning for character recognition. The trained network is able to recognize five characters even in case incomplete or noisy characters are displayed and it is robust to a device-to-device variability of up to +/-30%.

  17. PSD Applicability Determination for Power Boiler No. 4 at the Potlatch Corporation Facility in Lewiston, Idaho

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  18. Simpson Pulp and Paper Mill in Tacoma, Washington, PSD applicability determination for Power Boiler No. 7

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  19. Applicability of the PSD Regulations to Certain Modifications Made by Cooper Tire and Rubber Company

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  20. Tire Derived Fuel Classified as Municipal Solid Waste for a PSD Exemption

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  1. Contingency Plan for FGD Systems During Downtime as a Function of PSD

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  2. Automatic or Blanket Exemptions for Excess Emissions During Startup, and Shutdowns Under PSD

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  3. PSD Applicability Determination for AEG Bovoni Power's Waste-to-Energy Project

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  4. PSD and NSPS Applicability Determination for Guardian Industries' Flat Glass Plant in Corsicana, Texas

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  5. Clarification That BACT Analysis Under PSD is Applicable for A Proposed Modification to the Rotary Kiln

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  6. PSD Analysis for SIP Relaxation in Metropolitan Boston Air Pollution Control District - Eastman Gelatin

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  7. Applicablitiy Determinations on the PSD 100 tpy Major Source Threshold Catergory for Fossil Fuel Boilers Industries

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  8. Inclusion of Haul Road Emissions in PSD Applicability Determination for Coal Mine and Preparation Plant

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  9. Applicability of PSD and NSPS to the Cleveland Electric, Incorporated, Plant in Willoughby, Ohio

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  10. NSR Advisory Memo # 1 : TSP PSD Increment Consumption in North Carolina

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  11. Interactions between ethanol and the endocannabinoid system at GABAergic synapses on basolateral amygdala principal neurons

    Science.gov (United States)

    Talani, Giuseppe; Lovinger, David M.

    2015-01-01

    The basolateral amygdala (BLA) plays crucial roles in stimulus value coding, as well as drug and alcohol dependence. Ethanol alters synaptic transmission in the BLA, while endocannabinoids (eCBs) produce presynaptic depression at BLA synapses. Recent studies suggest interactions between ethanol and eCBs that have important consequences for alcohol drinking behavior. To determine how ethanol and eCBs interact in the BLA, we examined the physiology and pharmacology of GABAergic synapses onto BLA pyramidal neurons in neurons from young rats. Application of ethanol at concentrations relevant to intoxication increased, in both young and adult animals, the frequency of spontaneous and miniature GABAergic inhibitory postsynaptic currents, indicating a presynaptic site of ethanol action. The potentiation by ethanol was prevented by inhibition by adenylyl cyclase, and reduced by inhibition by protein kinase A. Activation of type 1 cannabinoid receptors (CB1) in the BLA inhibited GABAergic transmission via an apparent presynaptic mechanism, and prevented ethanol potentiation. Surprisingly, ethanol potentiation was also prevented by CB1 antagonists/inverse agonists. Brief depolarization of BLA pyramidal neurons suppressed GABAergic transmission (depolarization-induced suppression of inhibition [DSI]), an effect previously shown to be mediated by postsynaptic eCB release and presynaptic CB1 activation. A CB1-mediated suppression of GABAergic transmission was also produced by combined afferent stimulation at 0.1 Hz (LFS), and postsynaptic loading with the eCB arachidonoyl ethanolamide (AEA). Both DSI and LFS-induced synaptic depression were prevented by ethanol. Our findings indicate antagonistic interactions between ethanol and eCB/CB1 modulation at GABAergic BLA synapses that may contribute to eCB roles in ethanol seeking and drinking. PMID:26603632

  12. Associative Learning Drives the Formation of Silent Synapses in Neuronal Ensembles of the Nucleus Accumbens.

    Science.gov (United States)

    Whitaker, Leslie R; Carneiro de Oliveira, Paulo E; McPherson, Kylie B; Fallon, Rebecca V; Planeta, Cleopatra S; Bonci, Antonello; Hope, Bruce T

    2016-08-01

    Learned associations between environmental stimuli and rewards play a critical role in addiction. Associative learning requires alterations in sparsely distributed populations of strongly activated neurons, or neuronal ensembles. Until recently, assessment of functional alterations underlying learned behavior was restricted to global neuroadaptations in a particular brain area or cell type, rendering it impossible to identify neuronal ensembles critically involved in learned behavior. We used Fos-GFP transgenic mice that contained a transgene with a Fos promoter driving expression of green fluorescent protein (GFP) to detect neurons that were strongly activated during associative learning, in this case, context-independent and context-specific cocaine-induced locomotor sensitization. Whole-cell electrophysiological recordings were used to assess synaptic alterations in specifically activated GFP-positive (GFP+) neurons compared with surrounding nonactivated GFP-negative (GFP-) neurons 90 min after the sensitized locomotor response. After context-independent cocaine sensitization, cocaine-induced locomotion was equally sensitized by repeated cocaine injections in two different sensitization contexts. Correspondingly, silent synapses in these mice were induced in GFP+ neurons, but not GFP- neurons, after sensitization in both of these contexts. After context-specific cocaine sensitization, cocaine-induced locomotion was sensitized exclusively in mice trained and tested in the same context (paired group), but not in mice that were trained in one context and then tested in a different context (unpaired group). Silent synapses increased in GFP+ neurons, but not in GFP- neurons from mice in the paired group, but not from mice in the unpaired group. Our results indicate that silent synapses are formed only in neuronal ensembles of the nucleus accumbens shell that are related to associative learning. Published by Elsevier Inc.

  13. Super-resolution microscopy reveals γ-secretase at both sides of the neuronal synapse.

    Science.gov (United States)

    Schedin-Weiss, Sophia; Caesar, Ina; Winblad, Bengt; Blom, Hans; Tjernberg, Lars O

    2016-03-31

    The transmembrane protein assembly γ-secretase is a key protease in regulated intramembrane processing (RIP) of around 100 type-1 transmembrane proteins. Importantly, it has a pathological role in Alzheimer disease (AD) as it generates the neurotoxic amyloid β-peptide from the amyloid precursor protein (APP). Studies on γ-secretase location are therefore crucial both from a biological and a therapeutic perspective. Despite several years of efforts in many laboratories, it is not clear where in the neuron γ-secretase exerts it's activities. Technical challenges include the fact that the active enzyme contains four protein components and that most subcellular compartments cannot be spatially resolved by traditional light microscopy. Here, we have used a powerful combination of the two nanoscopy techniques STORM and STED microscopy to visualize the location of γ-secretase in neurons using an active-site specific probe, with a focus on the synapse. We show that γ-secretase is present in both the pre-and postsynaptic compartments. We further show that the enzyme is enriched very close to the synaptic cleft in the postsynaptic membrane, as well as to NMDA receptors, demonstrating that γ-secretase is present in the postsynaptic plasma membrane. Importantly, the expression of γ-secretase increased in the pre- and postsynaptic compartments with the size of the synapse, suggesting a correlation between γ-secretase activity and synapse maturation. Thus, our data shows the synaptic location with high precision in three dimensions and settles the long-lasting debate on the synaptic location of γ-secretase.

  14. Dscam Mediates Trans-Synaptic Interactions for Remodeling of Glutamate Receptors in Aplysia During De Novo and Learning-Related Synapse Formation

    Science.gov (United States)

    Li, Hsiu-Ling; Huang, Ben S.; Vishwasrao, Harshad; Sutedja, Nadia; Chen, Wei; Jin, Iksung; Hawkins, Robert D.; Bailey, Craig H.; Kandel, Eric R.

    2012-01-01

    Summary Trans-synaptic interactions between neurons are essential during both developmental and learning-related synaptic growth. We have used Aplysia neuronal cultures to examine the contribution of trans-synaptic signals in both types of synapse formation. We find that during de novo synaptogenesis, specific presynaptic innervation is required for the clustering of postsynaptic AMPA-like but not NMDA-like receptors. We further find that the cell adhesion molecule Dscam is involved in these trans-synaptic interactions. Inhibition of Dscam either pre- or postsynaptically abolishes the emergence of synaptic transmission and the clustering of AMPA-like receptors. Remodeling of both AMPA-like and NMDA-like receptors also occurs during learning-related synapse formation and again requires the reactivation of Dscam-mediated trans-synaptic interactions. Taken together, these findings suggest that learning-induced synapse formation recapitulates, at least in part, aspects of the mechanisms that govern de novo synaptogenesis. PMID:19249274

  15. Simulated and Real Sheet-of-Light 3D Object Scanning Using a-Si:H Thin Film PSD Arrays

    Directory of Open Access Journals (Sweden)

    Javier Contreras

    2015-11-01

    Full Text Available A MATLAB/SIMULINK software simulation model (structure and component blocks has been constructed in order to view and analyze the potential of the PSD (Position Sensitive Detector array concept technology before it is further expanded or developed. This simulation allows changing most of its parameters, such as the number of elements in the PSD array, the direction of vision, the viewing/scanning angle, the object rotation, translation, sample/scan/simulation time, etc. In addition, results show for the first time the possibility of scanning an object in 3D when using an a-Si:H thin film 128 PSD array sensor and hardware/software system. Moreover, this sensor technology is able to perform these scans and render 3D objects at high speeds and high resolutions when using a sheet-of-light laser within a triangulation platform. As shown by the simulation, a substantial enhancement in 3D object profile image quality and realism can be achieved by increasing the number of elements of the PSD array sensor as well as by achieving an optimal position response from the sensor since clearly the definition of the 3D object profile depends on the correct and accurate position response of each detector as well as on the size of the PSD array.

  16. Piccolo Promotes Vesicle Replenishment at a Fast Central Auditory Synapse

    Directory of Open Access Journals (Sweden)

    Tanvi Butola

    2017-10-01

    Full Text Available Piccolo and Bassoon are the two largest cytomatrix of the active zone (CAZ proteins involved in scaffolding and regulating neurotransmitter release at presynaptic active zones (AZs, but have long been discussed as being functionally redundant. We employed genetic manipulation to bring forth and segregate the role of Piccolo from that of Bassoon at central auditory synapses of the cochlear nucleus—the endbulbs of Held. These synapses specialize in high frequency synaptic transmission, ideally poised to reveal even subtle deficits in the regulation of neurotransmitter release upon molecular perturbation. Combining semi-quantitative immunohistochemistry, electron microscopy, and in vitro and in vivo electrophysiology we first studied signal transmission in Piccolo-deficient mice. Our analysis was not confounded by a cochlear deficit, as a short isoform of Piccolo (“Piccolino” present at the upstream ribbon synapses of cochlear inner hair cells (IHC, is unaffected by the mutation. Disruption of Piccolo increased the abundance of Bassoon at the AZs of endbulbs, while that of RIM1 was reduced and other CAZ proteins remained unaltered. Presynaptic fiber stimulation revealed smaller amplitude of the evoked excitatory postsynaptic currents (eEPSC, while eEPSC kinetics as well as miniature EPSCs (mEPSCs remained unchanged. Cumulative analysis of eEPSC trains indicated that the reduced eEPSC amplitude of Piccolo-deficient endbulb synapses is primarily due to a reduced readily releasable pool (RRP of synaptic vesicles (SV, as was corroborated by a reduction of vesicles at the AZ found on an ultrastructural level. Release probability seemed largely unaltered. Recovery from short-term depression was slowed. We then performed a physiological analysis of endbulb synapses from mice which, in addition to Piccolo deficiency, lacked one functional allele of the Bassoon gene. Analysis of the double-mutant endbulbs revealed an increase in release probability

  17. Local and global synchronization transitions induced by time delays in small-world neuronal networks with chemical synapses.

    Science.gov (United States)

    Yu, Haitao; Wang, Jiang; Du, Jiwei; Deng, Bin; Wei, Xile

    2015-02-01

    Effects of time delay on the local and global synchronization in small-world neuronal networks with chemical synapses are investigated in this paper. Numerical results show that, for both excitatory and inhibitory coupling types, the information transmission delay can always induce synchronization transitions of spiking neurons in small-world networks. In particular, regions of in-phase and out-of-phase synchronization of connected neurons emerge intermittently as the synaptic delay increases. For excitatory coupling, all transitions to spiking synchronization occur approximately at integer multiples of the firing period of individual neurons; while for inhibitory coupling, these transitions appear at the odd multiples of the half of the firing period of neurons. More importantly, the local synchronization transition is more profound than the global synchronization transition, depending on the type of coupling synapse. For excitatory synapses, the local in-phase synchronization observed for some values of the delay also occur at a global scale; while for inhibitory ones, this synchronization, observed at the local scale, disappears at a global scale. Furthermore, the small-world structure can also affect the phase synchronization of neuronal networks. It is demonstrated that increasing the rewiring probability can always improve the global synchronization of neuronal activity, but has little effect on the local synchronization of neighboring neurons.

  18. Targeted gene transfer of different genes to presynaptic and postsynaptic neocortical neurons connected by a glutamatergic synapse.

    Science.gov (United States)

    Zhang, Guo-rong; Zhao, Hua; Cao, Haiyan; Li, Xu; Geller, Alfred I

    2012-09-14

    Genetic approaches to analyzing neuronal circuits and learning would benefit from a technology to first deliver a specific gene into presynaptic neurons, and then deliver a different gene into an identified subset of their postsynaptic neurons, connected by a specific synapse type. Here, we describe targeted gene transfer across a neocortical glutamatergic synapse, using as the model the projection from rat postrhinal to perirhinal cortex. The first gene transfer, into the presynaptic neurons in postrhinal cortex, used a virus vector and standard gene transfer procedures. The vector expresses an artificial peptide neurotransmitter containing a dense core vesicle targeting domain, a NMDA NR1 subunit binding domain (from a monoclonal antibody), and the His tag. Upon release, this peptide neurotransmitter binds to NMDA receptors on the postsynaptic neurons. Antibody-mediated targeted gene transfer to these postsynaptic neurons in perirhinal cortex used a His tag antibody, as the peptide neurotransmitter contains the His tag. Confocal microscopy showed that with untargeted gene transfer, ~3% of the transduced presynaptic axons were proximal to a transduced postsynaptic dendrite. In contrast, with targeted gene transfer, ≥ 20% of the presynaptic axons were proximal to a transduced postsynaptic dendrite. Targeting across other types of synapses might be obtained by modifying the artificial peptide neurotransmitter to contain a binding domain for a different neurotransmitter receptor. This technology may benefit elucidating how specific neurons and subcircuits contribute to circuit physiology, behavior, and learning. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Fuzzy norm method for evaluating random vibration of airborne platform from limited PSD data

    Directory of Open Access Journals (Sweden)

    Wang Zhongyu

    2014-12-01

    Full Text Available For random vibration of airborne platform, the accurate evaluation is a key indicator to ensure normal operation of airborne equipment in flight. However, only limited power spectral density (PSD data can be obtained at the stage of flight test. Thus, those conventional evaluation methods cannot be employed when the distribution characteristics and priori information are unknown. In this paper, the fuzzy norm method (FNM is proposed which combines the advantages of fuzzy theory and norm theory. The proposed method can deeply dig system information from limited data, which probability distribution is not taken into account. Firstly, the FNM is employed to evaluate variable interval and expanded uncertainty from limited PSD data, and the performance of FNM is demonstrated by confidence level, reliability and computing accuracy of expanded uncertainty. In addition, the optimal fuzzy parameters are discussed to meet the requirements of aviation standards and metrological practice. Finally, computer simulation is used to prove the adaptability of FNM. Compared with statistical methods, FNM has superiority for evaluating expanded uncertainty from limited data. The results show that the reliability of calculation and evaluation is superior to 95%.

  20. A Neuron- and a Synapse Chip for Artificial Neural Networks

    DEFF Research Database (Denmark)

    Lansner, John; Lehmann, Torsten

    1992-01-01

    A cascadable, analog, CMOS chip set has been developed for hardware implementations of artificial neural networks (ANN's):I) a neuron chip containing an array of neurons with hyperbolic tangent activation functions and adjustable gains, and II) a synapse chip (or a matrix-vector multiplier) where...... the matrix is stored on-chip as differential voltages on capacitors. In principal any ANN configuration can be made using these chips. A neuron array of 4 neurons and a 4 × 4 matrix-vector multiplier has been fabricated in a standard 2.4 ¿m CMOS process for test purposes. The propagation time through...... the synapse and neuron chips is less than 4 ¿s and the weight matrix has a 10 bit resolution....

  1. Actions of snake neurotoxins on an insect nicotinic cholinergic synapse.

    Science.gov (United States)

    Hue, Bernard; Buckingham, Steven D; Buckingham, David; Sattelle, David B

    2007-09-01

    Here we examine the actions of six snake neurotoxins (alpha-cobratoxin from Naja naja siamensis, erabutoxin-a and b from Laticauda semifasciata; CM12 from N. haje annulifera, toxin III 4 from Notechis scutatus and a long toxin from N. haje) on nicotinic acetylcholine receptors in the cercal afferent, giant interneuron 2 synapse of the cockroach, Periplaneta americana. All toxins tested reduced responses to directly-applied ACh as well as EPSPs evoked by electrical stimulation of nerve XI with similar time courses, suggesting that their action is postsynaptic. Thus, these nicotinic receptors in a well-characterized insect synapse are sensitive to both long and short chain neurotoxins. This considerably expands the range of snake toxins that block insect nicotinic acetylcholine receptors and may enable further pharmacological distinctions between nAChR subtypes.

  2. Microorganism and Fungi Drive Evolution of Plant Synapses

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    Frantisek eBaluska

    2013-08-01

    Full Text Available In the course of plant evolution, there is an obvious trend toward an increased complexity of plant bodies, as well as an increased sophistication of plant behavior and communication. Phenotypic plasticity of plants is based on the polar auxin transport machinery that is directly linked with plant sensory systems impinging on plant behavior and adaptive responses. Similar to the emergence and evolution of eukaryotic cells, evolution of land plants was also shaped and driven by infective and symbiotic microorganisms. These microorganisms are the driving force behind the evolution of plant synapses and other neuronal aspects of higher plants; this is especially pronounced in the root apices. Plant synapses allow synaptic cell-cell communication and coordination in plants, as well as sensory-motor integration in root apices searching for water and mineral nutrition. These neuronal aspects of higher plants are closely linked with their unique ability to adapt to environmental changes.

  3. Microorganism and filamentous fungi drive evolution of plant synapses.

    Science.gov (United States)

    Baluška, František; Mancuso, Stefano

    2013-01-01

    In the course of plant evolution, there is an obvious trend toward an increased complexity of plant bodies, as well as an increased sophistication of plant behavior and communication. Phenotypic plasticity of plants is based on the polar auxin transport machinery that is directly linked with plant sensory systems impinging on plant behavior and adaptive responses. Similar to the emergence and evolution of eukaryotic cells, evolution of land plants was also shaped and driven by infective and symbiotic microorganisms. These microorganisms are the driving force behind the evolution of plant synapses and other neuronal aspects of higher plants; this is especially pronounced in the root apices. Plant synapses allow synaptic cell-cell communication and coordination in plants, as well as sensory-motor integration in root apices searching for water and mineral nutrition. These neuronal aspects of higher plants are closely linked with their unique ability to adapt to environmental changes.

  4. Tolerance to ethanol intoxication after chronic ethanol: role of GluN2A and PSD-95.

    Science.gov (United States)

    Daut, Rachel A; Busch, Erica F; Ihne, Jessica; Fisher, Daniel; Mishina, Masayoshi; Grant, Seth G N; Camp, Marguerite; Holmes, Andrew

    2015-03-01

    The neural and genetic factors underlying chronic tolerance to alcohol are currently unclear. The GluN2A N-methyl-D-aspartate receptors (NMDAR) subunit and the NMDAR-anchoring protein PSD-95 mediate acute alcohol intoxication and represent putative mechanisms mediating tolerance. We found that chronic intermittent ethanol exposure (CIE) did not produce tolerance [loss of righting reflex (LORR)] or withdrawal-anxiety in C57BL/6J, GluN2A or PSD-95 knockout mice assayed 2-3 days later. However, significant tolerance to LORR was evident 1 day after CIE in C57BL/6J and PSD-95 knockouts, but absent in GluN2A knockouts. These data suggest a role for GluN2A in tolerance, extending evidence that human GluN2A gene variation is involved in alcohol dependence. © 2014 Society for the Study of Addiction.

  5. Activity-dependent transport of the transcriptional coactivator CRTC1 from synapse to nucleus.

    Science.gov (United States)

    Ch'ng, Toh Hean; Uzgil, Besim; Lin, Peter; Avliyakulov, Nuraly K; O'Dell, Thomas J; Martin, Kelsey C

    2012-07-06

    Long-lasting changes in synaptic efficacy, such as those underlying long-term memory, require transcription. Activity-dependent transport of synaptically localized transcriptional regulators provides a direct means of coupling synaptic stimulation with changes in transcription. The CREB-regulated transcriptional coactivator (CRTC1), which is required for long-term hippocampal plasticity, binds CREB to potently promote transcription. We show that CRTC1 localizes to synapses in silenced hippocampal neurons but translocates to the nucleus in response to localized synaptic stimulation. Regulated nuclear translocation occurs only in excitatory neurons and requires calcium influx and calcineurin activation. CRTC1 is controlled in a dual fashion with activity regulating CRTC1 nuclear translocation and cAMP modulating its persistence in the nucleus. Neuronal activity triggers a complex change in CRTC1 phosphorylation, suggesting that CRTC1 may link specific types of stimuli to specific changes in gene expression. Together, our results indicate that synapse-to-nuclear transport of CRTC1 dynamically informs the nucleus about synaptic activity. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Swimming against the tide: investigations of the C-Bouton synapse

    Directory of Open Access Journals (Sweden)

    Adam S. Deardorff

    2014-09-01

    Full Text Available C-boutons are important cholinergic modulatory loci for state-dependent alterations in motoneuron firing rate. Type 2 muscarinic acetylcholine (m2 receptors are concentrated postsynaptic to C-boutons, and m2 receptor activation increases motoneuron excitability by reducing the action potential afterhyperpolarization (AHP. Here, using an intensive review of the current literature as well as data from our laboratory, we illustrate that C-bouton postsynaptic sites comprise a unique structural/functional domain containing appropriate cellular machinery (a ‘signaling ensemble’ for cholinergic regulation of outward K+ currents. Moreover, synaptic reorganization at these critical sites has been observed in a variety of pathologic states. Yet despite recent advances, there are still great challenges for understanding the role of C-bouton regulation and dysregulation in human health and disease. The development of new therapeutic interventions for devastating neurological conditions will rely on a complete understanding of the molecular mechanisms that underlie these complex synapses. Therefore, to close this review, we propose a comprehensive hypothetical mechanism for the cholinergic modification of α-MN excitability at C-bouton synapses, based on findings in several well-characterized neuronal systems.

  7. Synaptic Conversion of Chloride-Dependent Synapses in Spinal Nociceptive Circuits: Roles in Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Mark S. Cooper

    2011-01-01

    Full Text Available Electrophysiological conversion of chloride-dependent synapses from inhibitory to excitatory function, as a result of aberrant neuronal chloride homeostasis, is a known mechanism for the genesis of neuropathic pain. This paper examines theoretically how this type of synaptic conversion can disrupt circuit logic in spinal nociceptive circuits. First, a mathematical scaling factor is developed to represent local aberration in chloride electrochemical driving potential. Using this mathematical scaling factor, electrophysiological symbols are developed to represent the magnitude of synaptic conversion within nociceptive circuits. When inserted into a nociceptive circuit diagram, these symbols assist in understanding the generation of neuropathic pain associated with the collapse of transmembrane chloride gradients. A more generalized scaling factor is also derived to represent the interplay of chloride and bicarbonate driving potentials on the function of GABAergic and glycinergic synapses. These mathematical and symbolic representations of synaptic conversion help illustrate the critical role that anion driving potentials play in the transduction of pain. Using these representations, we discuss ramifications of glial-mediated synaptic conversion in the genesis, and treatment, of neuropathic pain.

  8. The space where aging acts: focus on the GABAergic synapse.

    Science.gov (United States)

    Rozycka, Aleksandra; Liguz-Lecznar, Monika

    2017-08-01

    As it was established that aging is not associated with massive neuronal loss, as was believed in the mid-20th Century, scientific interest has addressed the influence of aging on particular neuronal subpopulations and their synaptic contacts, which constitute the substrate for neural plasticity. Inhibitory neurons represent the most complex and diverse group of neurons, showing distinct molecular and physiological characteristics and possessing a compelling ability to control the physiology of neural circuits. This review focuses on the aging of GABAergic neurons and synapses. Understanding how aging affects synapses of particular neuronal subpopulations may help explain the heterogeneity of aging-related effects. We reviewed the literature concerning the effects of aging on the numbers of GABAergic neurons and synapses as well as aging-related alterations in their presynaptic and postsynaptic components. Finally, we discussed the influence of those changes on the plasticity of the GABAergic system, highlighting our results concerning aging in mouse somatosensory cortex and linking them to plasticity impairments and brain disorders. We posit that aging-induced impairments of the GABAergic system lead to an inhibitory/excitatory imbalance, thereby decreasing neuron's ability to respond with plastic changes to environmental and cellular challenges, leaving the brain more vulnerable to cognitive decline and damage by synaptopathic diseases. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  9. Synapse-specific astrocyte gating of amygdala-related behavior.

    Science.gov (United States)

    Martin-Fernandez, Mario; Jamison, Stephanie; Robin, Laurie M; Zhao, Zhe; Martin, Eduardo D; Aguilar, Juan; Benneyworth, Michael A; Marsicano, Giovanni; Araque, Alfonso

    2017-11-01

    The amygdala plays key roles in fear and anxiety. Studies of the amygdala have largely focused on neuronal function and connectivity. Astrocytes functionally interact with neurons, but their role in the amygdala remains largely unknown. We show that astrocytes in the medial subdivision of the central amygdala (CeM) determine the synaptic and behavioral outputs of amygdala circuits. To investigate the role of astrocytes in amygdala-related behavior and identify the underlying synaptic mechanisms, we used exogenous or endogenous signaling to selectively activate CeM astrocytes. Astrocytes depressed excitatory synapses from basolateral amygdala via A 1 adenosine receptor activation and enhanced inhibitory synapses from the lateral subdivision of the central amygdala via A 2A receptor activation. Furthermore, astrocytic activation decreased the firing rate of CeM neurons and reduced fear expression in a fear-conditioning paradigm. Therefore, we conclude that astrocyte activity determines fear responses by selectively regulating specific synapses, which indicates that animal behavior results from the coordinated activity of neurons and astrocytes.

  10. Natural killer cell signal integration balances synapse symmetry and migration.

    Science.gov (United States)

    Culley, Fiona J; Johnson, Matthew; Evans, J Henry; Kumar, Sunil; Crilly, Rupert; Casasbuenas, Juan; Schnyder, Tim; Mehrabi, Maryam; Deonarain, Mahendra P; Ushakov, Dmitry S; Braud, Veronique; Roth, Günter; Brock, Roland; Köhler, Karsten; Davis, Daniel M

    2009-07-01

    Natural killer (NK) cells discern the health of other cells by recognising the balance of activating and inhibitory ligands expressed by each target cell. However, how the integration of activating and inhibitory signals relates to formation of the NK cell immune synapse remains a central question in our understanding of NK cell recognition. Here we report that ligation of LFA-1 on NK cells induced asymmetrical cell spreading and migration. In contrast, ligation of the activating receptor NKG2D induced symmetrical spreading of ruffled lamellipodia encompassing a dynamic ring of f-actin, concurrent with polarization towards a target cell and a "stop" signal. Ligation of both LFA-1 and NKG2D together resulted in symmetrical spreading but co-ligation of inhibitory receptors reverted NK cells to an asymmetrical migratory configuration leading to inhibitory synapses being smaller and more rapidly disassembled. Using micropatterned activating and inhibitory ligands, signals were found to be continuously and locally integrated during spreading. Together, these data demonstrate that NK cells spread to form large, stable, symmetrical synapses if activating signals dominate, whereas asymmetrical migratory "kinapses" are favoured if inhibitory signals dominate. This clarifies how the integration of activating and inhibitory receptor signals is translated to an appropriate NK cell response.

  11. Memory-Relevant Mushroom Body Output Synapses Are Cholinergic.

    Science.gov (United States)

    Barnstedt, Oliver; Owald, David; Felsenberg, Johannes; Brain, Ruth; Moszynski, John-Paul; Talbot, Clifford B; Perrat, Paola N; Waddell, Scott

    2016-03-16

    Memories are stored in the fan-out fan-in neural architectures of the mammalian cerebellum and hippocampus and the insect mushroom bodies. However, whereas key plasticity occurs at glutamatergic synapses in mammals, the neurochemistry of the memory-storing mushroom body Kenyon cell output synapses is unknown. Here we demonstrate a role for acetylcholine (ACh) in Drosophila. Kenyon cells express the ACh-processing proteins ChAT and VAChT, and reducing their expression impairs learned olfactory-driven behavior. Local ACh application, or direct Kenyon cell activation, evokes activity in mushroom body output neurons (MBONs). MBON activation depends on VAChT expression in Kenyon cells and is blocked by ACh receptor antagonism. Furthermore, reducing nicotinic ACh receptor subunit expression in MBONs compromises odor-evoked activation and redirects odor-driven behavior. Lastly, peptidergic corelease enhances ACh-evoked responses in MBONs, suggesting an interaction between the fast- and slow-acting transmitters. Therefore, olfactory memories in Drosophila are likely stored as plasticity of cholinergic synapses. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Remote tactile sensing system integrated with magnetic synapse.

    Science.gov (United States)

    Oh, Sunjong; Jung, Youngdo; Kim, Seonggi; Kim, SungJoon; Hu, Xinghao; Lim, Hyuneui; Kim, CheolGi

    2017-12-05

    Mechanoreceptors in a fingertip convert external tactile stimulations into electrical signals, which are transmitted by the nervous system through synaptic transmitters and then perceived by the brain with high accuracy and reliability. Inspired by the human synapse system, this paper reports a robust tactile sensing system consisting of a remote touch tip and a magnetic synapse. External pressure on the remote touch tip is transferred in the form of air pressure to the magnetic synapse, where its variation is converted into electrical signals. The developed system has high sensitivity and a wide dynamic range. The remote sensing system demonstrated tactile capabilities over wide pressure range with a minimum detectable pressure of 6 Pa. In addition, it could measure tactile stimulation up to 1,000 Hz without distortion and hysteresis, owing to the separation of the touching and sensing parts. The excellent performance of the system in terms of surface texture discrimination, heartbeat measurement from the human wrist, and satisfactory detection quality in water indicates that it has considerable potential for various mechanosensory applications in different environments.

  13. TFH-derived dopamine accelerates productive synapses in germinal centres.

    Science.gov (United States)

    Papa, Ilenia; Saliba, David; Ponzoni, Maurilio; Bustamante, Sonia; Canete, Pablo F; Gonzalez-Figueroa, Paula; McNamara, Hayley A; Valvo, Salvatore; Grimbaldeston, Michele; Sweet, Rebecca A; Vohra, Harpreet; Cockburn, Ian A; Meyer-Hermann, Michael; Dustin, Michael L; Doglioni, Claudio; Vinuesa, Carola G

    2017-07-20

    Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (TFH) cells in germinal centres. The rapid T-B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we show that a proportion of human TFH cells contain dense-core granules marked by chromogranin B, which are normally found in neuronal presynaptic terminals storing catecholamines such as dopamine. TFH cells produce high amounts of dopamine and release it upon cognate interaction with B cells. Dopamine causes rapid translocation of intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and chromogranin B granules at the human TFH cell synapse and increases the synapse area. Mathematical modelling suggests that faster dopamine-induced T-B-cell interactions increase total germinal centre output and accelerate it by days. Delivery of neurotransmitters across the T-B-cell synapse may be advantageous in the face of infection.

  14. PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarisation in cortical spreading depression

    DEFF Research Database (Denmark)

    Kucharz, Krzysztof; Søndergaard Rasmussen, Ida; Bach, Anders

    2017-01-01

    , UCCB01-144 (Tat-N-dimer) ameliorates the persistent effects of cortical spreading depression on cortical function. Using in vivo two-photon microscopy in somatosensory cortex in mice, we show that fluorescently labelled Tat-N-dimer readily crosses blood-brain barrier and accumulates in nerve cells...... depression on cortical blood flow and CMRO2 We suggest that uncoupling of PSD-95 from NMDA receptors reduces overall neuronal excitability and the amplitude of the spreading depolarisation wave. These findings may be of interest for understanding the neuroprotective effects of the nNOS/PSD-95 uncoupling...

  15. Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome.

    Science.gov (United States)

    Ifrim, Marius F; Williams, Kathryn R; Bassell, Gary J

    2015-05-06

    Fragile X syndrome (FXS) is caused by the loss of the fragile X mental retardation protein (FMRP), an RNA binding protein that regulates translation of numerous target mRNAs, some of which are dendritically localized. Our previous biochemical studies using synaptoneurosomes demonstrate a role for FMRP and miR-125a in regulating the translation of PSD-95 mRNA. However, the local translation of PSD-95 mRNA within dendrites and spines, as well as the roles of FMRP or miR-125a, have not been directly studied. Herein, local synthesis of a Venus-PSD-95 fusion protein was directly visualized in dendrites and spines using single-molecule imaging of a diffusion-restricted Venus-PSD-95 reporter under control of the PSD-95 3'UTR. The basal translation rates of Venus-PSD-95 mRNA was increased in cultured hippocampal neurons from Fmr1 KO mice compared with WT neurons, which correlated with a transient elevation of endogenous PSD-95 within dendrites. Following mGluR stimulation with (S)-3,5-dihydroxyphenylglycine, the rate of Venus-PSD-95 mRNA translation increased rapidly in dendrites of WT hippocampal neurons, but not in those of Fmr1 KO neurons or when the binding site of miR125a, previously shown to bind PSD-95 3'UTR, was mutated. This study provides direct support for the hypothesis that local translation within dendrites and spines is dysregulated in FXS. Impairments in the regulated local synthesis of PSD-95, a critical regulator of synaptic structure and function, may affect the spatiotemporal control of PSD-95 levels and affect dendritic spine development and synaptic plasticity in FXS. Copyright © 2015 the authors 0270-6474/15/357116-15$15.00/0.

  16. Sensory experience shapes the development of the visual system's first synapse.

    Science.gov (United States)

    Dunn, Felice A; Della Santina, Luca; Parker, Edward D; Wong, Rachel O L

    2013-12-04

    Specific connectivity patterns among neurons create the basic architecture underlying parallel processing in our nervous system. Here we focus on the visual system's first synapse to examine the structural and functional consequences of sensory deprivation on the establishment of parallel circuits. Dark rearing reduces synaptic strength between cones and cone bipolar cells, a previously unappreciated effect of sensory deprivation. In contrast, rod bipolar cells, which utilize the same glutamate receptor to contact rods, are unaffected by dark rearing. Underlying the physiological changes, we find the localization of metabotropic glutamate receptors within cone bipolar, but not rod bipolar, cell dendrites is a light-dependent process. Furthermore, although cone bipolar cells share common cone partners, each bipolar cell type that we examined depends differentially on sensory input to achieve mature connectivity. Thus, visual experience differentially affects maturation of rod versus cone pathways and of cell types within the cone pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Rett syndrome: genes, synapses, circuits and therapeutics

    Directory of Open Access Journals (Sweden)

    Abhishek eBanerjee

    2012-05-01

    Full Text Available Development of the nervous system proceeds through a set of complex checkpoints which arise from a combination of sequential gene expression and early neural activity sculpted by the environment. Genetic and environmental insults lead to neurodevelopmental disorders which encompass a large group of diseases that result from anatomical and physiological abnormalities during maturation and development of brain circuits. Rett syndrome (RTT is a postnatal neurological disorder of genetic origin, caused by mutations in the X-linked gene MECP2. It features neuropsychiatric abnormalities like motor dysfunctions and mild to severe cognitive impairment. This review discusses several key questions and attempts to evaluate recently developed animal models, cell-type specific function of MeCP2, defects in neural circuit plasticity and possible therapeutic strategies. Finally, we also discuss how genes, proteins and overlapping signaling pathways affect the molecular etiology of apparently unrelated neuropsychiatric disorders, an understanding of which can offer novel therapeutic strategies.

  18. Untangling the two-way signalling route from synapses to the nucleus, and from the nucleus back to the synapses.

    Science.gov (United States)

    Nonaka, Mio; Fujii, Hajime; Kim, Ryang; Kawashima, Takashi; Okuno, Hiroyuki; Bito, Haruhiko

    2014-01-05

    During learning and memory, it has been suggested that the coordinated electrical activity of hippocampal neurons translates information about the external environment into internal neuronal representations, which then are stored initially within the hippocampus and subsequently into other areas of the brain. A widely held hypothesis posits that synaptic plasticity is a key feature that critically modulates the triggering and the maintenance of such representations, some of which are thought to persist over time as traces or tags. However, the molecular and cell biological basis for these traces and tags has remained elusive. Here, we review recent findings that help clarify some of the molecular and cellular mechanisms critical for these events, by untangling a two-way signalling crosstalk route between the synapses and the neuronal soma. In particular, a detailed interrogation of the soma-to-synapse delivery of immediate early gene product Arc/Arg3.1, whose induction is triggered by heightened synaptic activity in many brain areas, teases apart an unsuspected 'inverse' synaptic tagging mechanism that likely contributes to maintaining the contrast of synaptic weight between strengthened and weak synapses within an active ensemble.

  19. Neuregulin1 displayed on motor axons regulates terminal Schwann cell-mediated synapse elimination at developing neuromuscular junctions

    Science.gov (United States)

    Li, Yue; Mikesh, Michelle; Smith, Ian; Nave, Klaus-Armin; Schwab, Markus H.; Thompson, Wesley J.

    2016-01-01

    Synaptic connections in the nervous system are rearranged during development and in adulthood as a feature of growth, plasticity, aging, and disease. Glia are implicated as active participants in these changes. Here we investigated a signal that controls the participation of peripheral glia, the terminal Schwann cells (SCs), at the neuromuscular junction (NMJ) in mice. Transgenic manipulation of the levels of membrane-tethered neuregulin1 (NRG1-III), a potent activator of SCs normally presented on motor axons, alters the rate of loss of motor inputs at NMJs during developmental synapse elimination. In addition, NMJs of adult transgenic mice that expressed excess axonal NRG1-III exhibited continued remodeling, in contrast to the more stable morphologies of controls. In fact, synaptic SCs of these adult mice with NRG1-III overexpression exhibited behaviors evident in wild type neonates during synapse elimination, including an affinity for the postsynaptic myofiber surface and phagocytosis of nerve terminals. Given that levels of NRG1-III expression normally peak during the period of synapse elimination, our findings identify axon-tethered NRG1 as a molecular determinant for SC-driven neuromuscular synaptic plasticity. PMID:26755586

  20. Neuregulin1 displayed on motor axons regulates terminal Schwann cell-mediated synapse elimination at developing neuromuscular junctions.

    Science.gov (United States)

    Lee, Young Il; Li, Yue; Mikesh, Michelle; Smith, Ian; Nave, Klaus-Armin; Schwab, Markus H; Thompson, Wesley J

    2016-01-26

    Synaptic connections in the nervous system are rearranged during development and in adulthood as a feature of growth, plasticity, aging, and disease. Glia are implicated as active participants in these changes. Here we investigated a signal that controls the participation of peripheral glia, the terminal Schwann cells (SCs), at the neuromuscular junction (NMJ) in mice. Transgenic manipulation of the levels of membrane-tethered neuregulin1 (NRG1-III), a potent activator of SCs normally presented on motor axons, alters the rate of loss of motor inputs at NMJs during developmental synapse elimination. In addition, NMJs of adult transgenic mice that expressed excess axonal NRG1-III exhibited continued remodeling, in contrast to the more stable morphologies of controls. In fact, synaptic SCs of these adult mice with NRG1-III overexpression exhibited behaviors evident in wild type neonates during synapse elimination, including an affinity for the postsynaptic myofiber surface and phagocytosis of nerve terminals. Given that levels of NRG1-III expression normally peak during the period of synapse elimination, our findings identify axon-tethered NRG1 as a molecular determinant for SC-driven neuromuscular synaptic plasticity.

  1. PSD Camera Based Position and Posture Control of Redundant Robot Considering Contact Motion

    Science.gov (United States)

    Oda, Naoki; Kotani, Kentaro

    The paper describes a position and posture controller design based on the absolute position by external PSD vision sensor for redundant robot manipulator. The redundancy enables a potential capability to avoid obstacle while continuing given end-effector jobs under contact with middle link of manipulator. Under contact motion, the deformation due to joint torsion obtained by comparing internal and external position sensor, is actively suppressed by internal/external position hybrid controller. The selection matrix of hybrid loop is given by the function of the deformation. And the detected deformation is also utilized in the compliant motion controller for passive obstacle avoidance. The validity of the proposed method is verified by several experimental results of 3link planar redundant manipulator.

  2. ARHGAP12 Functions as a Developmental Brake on Excitatory Synapse Function

    Directory of Open Access Journals (Sweden)

    W. Ba

    2016-02-01

    Full Text Available The molecular mechanisms that promote excitatory synapse development have been extensively studied. However, the molecular events preventing precocious excitatory synapse development so that synapses form at the correct time and place are less well understood. Here, we report the functional characterization of ARHGAP12, a previously uncharacterized Rho GTPase-activating protein (RhoGAP in the brain. ARHGAP12 is specifically expressed in the CA1 region of the hippocampus, where it localizes to the postsynaptic compartment of excitatory synapses. ARHGAP12 negatively controls spine size via its RhoGAP activity and promotes, by interacting with CIP4, postsynaptic AMPA receptor endocytosis. Arhgap12 knockdown results in precocious maturation of excitatory synapses, as indicated by a reduction in the proportion of silent synapses. Collectively, our data show that ARHGAP12 is a synaptic RhoGAP that regulates excitatory synaptic structure and function during development.

  3. UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801

    DEFF Research Database (Denmark)

    Andreasen, Jesper T.; Bach, Anders; Gynther, Mikko

    2013-01-01

    Excessive N-Methyl-d-aspartate receptor (NMDAR)-dependent production of nitric oxide (NO) is involved in the development and maintenance of chronic pain states, and is mediated by postsynaptic density protein-95 (PSD-95). By binding to both the NMDAR and neuronal NO synthase (nNOS), PSD-95 mediates...... the NMDAR/PSD-95/nNOS complex by targeting PSD-95, thereby decreasing NO production without interfering with the NMDAR ion channel function. Here, we compared the effects of a dimeric PSD-95 inhibitor, UCCB01-125, and the NMDAR antagonist, MK-801, on mechanical hypersensitivity in the complete Freund......-induced mechanical hypersensitivity 1 and 24 h after treatment. Moreover, UCCB01-125 was found to reverse CFA-induced hypersensitivity when administered 24 h after CFA treatment, an effect lasting for at least 3 days. At the dose reducing hypersensitivity, MK-801 disrupted attention, long-term memory, and motor...

  4. The Circuit Realization of a Neuromorphic Computing System with Memristor-Based Synapse Design

    Science.gov (United States)

    2013-04-01

    memristor-based neural networks mainly fo- cused on system-level simulations using high level languages [11][12] or restricted the synapse design to...BASED SYNAPSE DESIGN 5a. CONTRACT NUMBER FA8750-11-1-0271 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 62788F 6. AUTHOR(S) Beiye Liu (UPitt...artificial neural systems. In this work, we propose a memristor-based design of bidirectional transmission excitation/inhibition synapses and implement a

  5. Effects of the dimeric PSD-95 inhibitor UCCB01-144 in mouse models of pain, cognition and motor function

    DEFF Research Database (Denmark)

    Andreasen, Jesper T; Nasser, Arafat; Caballero-Puntiverio, Maitane

    2016-01-01

    NMDAR antagonism shows analgesic action in humans and animal pain models, but disrupts cognitive and motor functions. NMDAR-dependent NO production requires tethering of the NMDAR to neuronal NO synthase (nNOS) by the postsynaptic density protein-95 (PSD-95). Perturbing the NMDAR/PSD-95/nNOS inte...... in the STFP test. Collectively, UCCB01-144 reversed both CFA and SNI-induced hypersensitivity, but the efficacy in the SNI model was only transient. This suggests that enhanced BBB permeability of PSD-95 inhibitors improves the analgesic action in neuropathic pain states.......NOS interaction has therefore been proposed as an alternative analgesic mechanism. We recently reported that UCCB01-125, a dimeric PSD-95 inhibitor with limited blood-brain-barrier permeability, reduced mechanical hypersensitivity in the complete Freund's adjuvant (CFA) inflammatory pain model, without disrupting...... of neuropathic pain. Potential cognitive effects of UCCB01-144 were examined using the social transmission of food preference (STFP) test and the V-maze test, and motor coordination was assessed with the rotarod test. UCCB01-144 (10mg/kg) reversed CFA-induced mechanical hypersensitivity after 1h, and completely...

  6. The Role of TSC1 in the Formation and Maintenance of Excitatory Synapses

    National Research Council Canada - National Science Library

    Sabatini, Bernardo L

    2005-01-01

    .... Functional analysis reveals these morphological changes are accompanied by perturbation of electrophysiological properties, including changes in strength and glutamate receptor composition of excitatory synapses...

  7. Nanoelectronic programmable synapses based on phase change materials for brain-inspired computing.

    Science.gov (United States)

    Kuzum, Duygu; Jeyasingh, Rakesh G D; Lee, Byoungil; Wong, H-S Philip

    2012-05-09

    Brain-inspired computing is an emerging field, which aims to extend the capabilities of information technology beyond digital logic. A compact nanoscale device, emulating biological synapses, is needed as the building block for brain-like computational systems. Here, we report a new nanoscale electronic synapse based on technologically mature phase change materials employed in optical data storage and nonvolatile memory applications. We utilize continuous resistance transitions in phase change materials to mimic the analog nature of biological synapses, enabling the implementation of a synaptic learning rule. We demonstrate different forms of spike-timing-dependent plasticity using the same nanoscale synapse with picojoule level energy consumption.

  8. Sialic Acid within the Glycosylphosphatidylinositol Anchor Targets the Cellular Prion Protein to Synapses*

    Science.gov (United States)

    Bate, Clive; Nolan, William; McHale-Owen, Harriet; Williams, Alun

    2016-01-01

    Although the cellular prion protein (PrPC) is concentrated at synapses, the factors that target PrPC to synapses are not understood. Here we demonstrate that exogenous PrPC was rapidly targeted to synapses in recipient neurons derived from Prnp knock-out(0/0) mice. The targeting of PrPC to synapses was dependent upon both neuronal cholesterol concentrations and the lipid and glycan composition of its glycosylphosphatidylinositol (GPI) anchor. Thus, the removal of either an acyl chain or sialic acid from the GPI anchor reduced the targeting of PrPC to synapses. Isolated GPIs (derived from PrPC) were also targeted to synapses, as was IgG conjugated to these GPIs. The removal of sialic acid from GPIs prevented the targeting of either the isolated GPIs or the IgG-GPI conjugate to synapses. Competition studies showed that pretreatment with sialylated GPIs prevented the targeting of PrPC to synapses. These results are consistent with the hypothesis that the sialylated GPI anchor attached to PrPC acts as a synapse homing signal. PMID:27325697

  9. Sialic Acid within the Glycosylphosphatidylinositol Anchor Targets the Cellular Prion Protein to Synapses*

    OpenAIRE

    Bate, Clive; Nolan, William; McHale-Owen, Harriet; Williams, Alun

    2016-01-01

    Although the cellular prion protein (PrPC) is concentrated at synapses, the factors that target PrPC to synapses are not understood. Here we demonstrate that exogenous PrPC was rapidly targeted to synapses in recipient neurons derived from Prnp knock-out(0/0) mice. The targeting of PrPC to synapses was dependent upon both neuronal cholesterol concentrations and the lipid and glycan composition of its glycosylphosphatidylinositol (GPI) anchor. Thus, the removal of either an acyl chain or siali...

  10. Sialic Acid within the Glycosylphosphatidylinositol Anchor Targets the Cellular Prion Protein to Synapses.

    Science.gov (United States)

    Bate, Clive; Nolan, William; McHale-Owen, Harriet; Williams, Alun

    2016-08-12

    Although the cellular prion protein (PrP(C)) is concentrated at synapses, the factors that target PrP(C) to synapses are not understood. Here we demonstrate that exogenous PrP(C) was rapidly targeted to synapses in recipient neurons derived from Prnp knock-out((0/0)) mice. The targeting of PrP(C) to synapses was dependent upon both neuronal cholesterol concentrations and the lipid and glycan composition of its glycosylphosphatidylinositol (GPI) anchor. Thus, the removal of either an acyl chain or sialic acid from the GPI anchor reduced the targeting of PrP(C) to synapses. Isolated GPIs (derived from PrP(C)) were also targeted to synapses, as was IgG conjugated to these GPIs. The removal of sialic acid from GPIs prevented the targeting of either the isolated GPIs or the IgG-GPI conjugate to synapses. Competition studies showed that pretreatment with sialylated GPIs prevented the targeting of PrP(C) to synapses. These results are consistent with the hypothesis that the sialylated GPI anchor attached to PrP(C) acts as a synapse homing signal. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Microglia-Synapse Pathways: Promising Therapeutic Strategy for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Jingdun Xie

    2017-01-01

    Full Text Available The main hallmarks of Alzheimer’s disease (AD are extracellular deposits of amyloid plaques and intracellular accumulation of hyperphosphorylated neurofibrillary tangles (tau. However, the mechanisms underlying these neuropathological changes remain largely unclear. To date, plenty of studies have shown that microglia-mediated neuroinflammation contributes to the pathogenesis of AD, and the microglia-synapse pathways have been repeatedly identified as the crucial factor in the disease process. In this review, evidences from microglia and synapse studies are presented, and the role of microglia in the pathogenesis of AD, the contributing factors to synapse dysfunction, and the role and mechanisms of microglia-synapse pathways will be discussed.

  12. Alterations in the properties of neonatal thalamocortical synapses with time in in vitro slices.

    Science.gov (United States)

    Luz, Liliana L; Currie, Stephen P; Daw, Michael I

    2017-01-01

    New synapses are constantly being generated and lost in the living brain with only a subset of these being stabilized to form an enduring component of neuronal circuitry. The properties of synaptic transmission have primarily been established in a variety of in vitro neuronal preparations. It is not clear, however, if newly-formed and persistent synapses contribute to the results of these studies consistently throughout the lifespan of these preparations. In neonatal somatosensory, barrel, cortex we have previously hypothesized that a population of thalamocortical synapses displaying unusually slow kinetics represent newly-formed, default-transient synapses. This clear phenotype would provide an ideal tool to investigate if such newly formed synapses consistently contribute to synaptic transmission throughout a normal experimental protocol. We show that the proportion of synapses recorded in vitro displaying slow kinetics decreases with time after brain slice preparation. However, slow synapses persist in vitro in the presence of either minocycline, an inhibitor of microglia-mediated synapse elimination, or the TrkB agonist 7,8-dihydroxyflavone a promoter of synapse formation. These findings show that the observed properties of synaptic transmission may systematically change with time in vitro in a standard brain slice preparation.

  13. Alterations in the properties of neonatal thalamocortical synapses with time in in vitro slices.

    Directory of Open Access Journals (Sweden)

    Liliana L Luz

    Full Text Available New synapses are constantly being generated and lost in the living brain with only a subset of these being stabilized to form an enduring component of neuronal circuitry. The properties of synaptic transmission have primarily been established in a variety of in vitro neuronal preparations. It is not clear, however, if newly-formed and persistent synapses contribute to the results of these studies consistently throughout the lifespan of these preparations. In neonatal somatosensory, barrel, cortex we have previously hypothesized that a population of thalamocortical synapses displaying unusually slow kinetics represent newly-formed, default-transient synapses. This clear phenotype would provide an ideal tool to investigate if such newly formed synapses consistently contribute to synaptic transmission throughout a normal experimental protocol. We show that the proportion of synapses recorded in vitro displaying slow kinetics decreases with time after brain slice preparation. However, slow synapses persist in vitro in the presence of either minocycline, an inhibitor of microglia-mediated synapse elimination, or the TrkB agonist 7,8-dihydroxyflavone a promoter of synapse formation. These findings show that the observed properties of synaptic transmission may systematically change with time in vitro in a standard brain slice preparation.

  14. Mammalian Cochlear Hair Cell Regeneration and Ribbon Synapse Reformation

    Directory of Open Access Journals (Sweden)

    Xiaoling Lu

    2016-01-01

    Full Text Available Hair cells (HCs are the sensory preceptor cells in the inner ear, which play an important role in hearing and balance. The HCs of organ of Corti are susceptible to noise, ototoxic drugs, and infections, thus resulting in permanent hearing loss. Recent approaches of HCs regeneration provide new directions for finding the treatment of sensor neural deafness. To have normal hearing function, the regenerated HCs must be reinnervated by nerve fibers and reform ribbon synapse with the dendrite of spiral ganglion neuron through nerve regeneration. In this review, we discuss the research progress in HC regeneration, the synaptic plasticity, and the reinnervation of new regenerated HCs in mammalian inner ear.

  15. Diverse Short-Term Dynamics of Inhibitory Synapses Converging on Striatal Projection Neurons: Differential Changes in a Rodent Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Janet Barroso-Flores

    2015-01-01

    Full Text Available Most neurons in the striatum are projection neurons (SPNs which make synapses with each other within distances of approximately 100 µm. About 5% of striatal neurons are GABAergic interneurons whose axons expand hundreds of microns. Short-term synaptic plasticity (STSP between fast-spiking (FS interneurons and SPNs and between SPNs has been described with electrophysiological and optogenetic techniques. It is difficult to obtain pair recordings from some classes of interneurons and due to limitations of actual techniques, no other types of STSP have been described on SPNs. Diverse STSPs may reflect differences in presynaptic release machineries. Therefore, we focused the present work on answering two questions: Are there different identifiable classes of STSP between GABAergic synapses on SPNs? And, if so, are synapses exhibiting different classes of STSP differentially affected by dopamine depletion? Whole-cell voltage-clamp recordings on SPNs revealed three classes of STSPs: depressing, facilitating, and biphasic (facilitating-depressing, in response to stimulation trains at 20 Hz, in a constant ionic environment. We then used the 6-hydroxydopamine (6-OHDA rodent model of Parkinson’s disease to show that synapses with different STSPs are differentially affected by dopamine depletion. We propose a general model of STSP that fits all the dynamics found in our recordings.

  16. A compound memristive synapse model for statistical learning through STDP in spiking neural networks

    Directory of Open Access Journals (Sweden)

    Johannes eBill

    2014-12-01

    Full Text Available Memristors have recently emerged as promising circuit elements to mimic the function of biological synapses in neuromorphic computing. The fabrication of reliable nanoscale memristive synapses, that feature continuous conductance changes based on the timing of pre- and postsynaptic spikes, has however turned out to be challenging. In this article, we propose an alternative approach, the compound memristive synapse, that circumvents this problem by the use of memristors with binary memristive states. A compound memristive synapse employs multiple bistable memristors in parallel to jointly form one synapse, thereby providing a spectrum of synaptic efficacies. We investigate the computational implications of synaptic plasticity in the compound synapse by integrating the recently observed phenomenon of stochastic filament formation into an abstract model of stochastic switching. Using this abstract model, we first show how standard pulsing schemes give rise to spike-timing dependent plasticity (STDP with a stabilizing weight dependence in compound synapses. In a next step, we study unsupervised learning with compound synapses in networks of spiking neurons organized in a winner-take-all architecture. Our theoretical analysis reveals that compound-synapse STDP implements generalized Expectation-Maximization in the spiking network. Specifically, the emergent synapse configuration represents the most salient features of the input distribution in a Mixture-of-Gaussians generative model. Furthermore, the network’s spike response to spiking input streams approximates a well-defined Bayesian posterior distribution. We show in computer simulations how such networks learn to represent high-dimensional distributions over images of handwritten digits with high fidelity even in presence of substantial device variations and under severe noise conditions. Therefore, the compound memristive synapse may provide a synaptic design principle for future neuromorphic

  17. Unsupervised learning in neural networks with short range synapses

    Science.gov (United States)

    Brunnet, L. G.; Agnes, E. J.; Mizusaki, B. E. P.; Erichsen, R., Jr.

    2013-01-01

    Different areas of the brain are involved in specific aspects of the information being processed both in learning and in memory formation. For example, the hippocampus is important in the consolidation of information from short-term memory to long-term memory, while emotional memory seems to be dealt by the amygdala. On the microscopic scale the underlying structures in these areas differ in the kind of neurons involved, in their connectivity, or in their clustering degree but, at this level, learning and memory are attributed to neuronal synapses mediated by longterm potentiation and long-term depression. In this work we explore the properties of a short range synaptic connection network, a nearest neighbor lattice composed mostly by excitatory neurons and a fraction of inhibitory ones. The mechanism of synaptic modification responsible for the emergence of memory is Spike-Timing-Dependent Plasticity (STDP), a Hebbian-like rule, where potentiation/depression is acquired when causal/non-causal spikes happen in a synapse involving two neurons. The system is intended to store and recognize memories associated to spatial external inputs presented as simple geometrical forms. The synaptic modifications are continuously applied to excitatory connections, including a homeostasis rule and STDP. In this work we explore the different scenarios under which a network with short range connections can accomplish the task of storing and recognizing simple connected patterns.

  18. Integration of nanoscale memristor synapses in neuromorphic computing architectures.

    Science.gov (United States)

    Indiveri, Giacomo; Linares-Barranco, Bernabé; Legenstein, Robert; Deligeorgis, George; Prodromakis, Themistoklis

    2013-09-27

    Conventional neuro-computing architectures and artificial neural networks have often been developed with no or loose connections to neuroscience. As a consequence, they have largely ignored key features of biological neural processing systems, such as their extremely low-power consumption features or their ability to carry out robust and efficient computation using massively parallel arrays of limited precision, highly variable, and unreliable components. Recent developments in nano-technologies are making available extremely compact and low power, but also variable and unreliable solid-state devices that can potentially extend the offerings of availing CMOS technologies. In particular, memristors are regarded as a promising solution for modeling key features of biological synapses due to their nanoscale dimensions, their capacity to store multiple bits of information per element and the low energy required to write distinct states. In this paper, we first review the neuro- and neuromorphic computing approaches that can best exploit the properties of memristor and scale devices, and then propose a novel hybrid memristor-CMOS neuromorphic circuit which represents a radical departure from conventional neuro-computing approaches, as it uses memristors to directly emulate the biophysics and temporal dynamics of real synapses. We point out the differences between the use of memristors in conventional neuro-computing architectures and the hybrid memristor-CMOS circuit proposed, and argue how this circuit represents an ideal building block for implementing brain-inspired probabilistic computing paradigms that are robust to variability and fault tolerant by design.

  19. Integration of nanoscale memristor synapses in neuromorphic computing architectures

    Science.gov (United States)

    Indiveri, Giacomo; Linares-Barranco, Bernabé; Legenstein, Robert; Deligeorgis, George; Prodromakis, Themistoklis

    2013-09-01

    Conventional neuro-computing architectures and artificial neural networks have often been developed with no or loose connections to neuroscience. As a consequence, they have largely ignored key features of biological neural processing systems, such as their extremely low-power consumption features or their ability to carry out robust and efficient computation using massively parallel arrays of limited precision, highly variable, and unreliable components. Recent developments in nano-technologies are making available extremely compact and low power, but also variable and unreliable solid-state devices that can potentially extend the offerings of availing CMOS technologies. In particular, memristors are regarded as a promising solution for modeling key features of biological synapses due to their nanoscale dimensions, their capacity to store multiple bits of information per element and the low energy required to write distinct states. In this paper, we first review the neuro- and neuromorphic computing approaches that can best exploit the properties of memristor and scale devices, and then propose a novel hybrid memristor-CMOS neuromorphic circuit which represents a radical departure from conventional neuro-computing approaches, as it uses memristors to directly emulate the biophysics and temporal dynamics of real synapses. We point out the differences between the use of memristors in conventional neuro-computing architectures and the hybrid memristor-CMOS circuit proposed, and argue how this circuit represents an ideal building block for implementing brain-inspired probabilistic computing paradigms that are robust to variability and fault tolerant by design.

  20. A Reinforcement Learning Framework for Spiking Networks with Dynamic Synapses

    Directory of Open Access Journals (Sweden)

    Karim El-Laithy

    2011-01-01

    Full Text Available An integration of both the Hebbian-based and reinforcement learning (RL rules is presented for dynamic synapses. The proposed framework permits the Hebbian rule to update the hidden synaptic model parameters regulating the synaptic response rather than the synaptic weights. This is performed using both the value and the sign of the temporal difference in the reward signal after each trial. Applying this framework, a spiking network with spike-timing-dependent synapses is tested to learn the exclusive-OR computation on a temporally coded basis. Reward values are calculated with the distance between the output spike train of the network and a reference target one. Results show that the network is able to capture the required dynamics and that the proposed framework can reveal indeed an integrated version of Hebbian and RL. The proposed framework is tractable and less computationally expensive. The framework is applicable to a wide class of synaptic models and is not restricted to the used neural representation. This generality, along with the reported results, supports adopting the introduced approach to benefit from the biologically plausible synaptic models in a wide range of intuitive signal processing.

  1. Distinct target cell-dependent forms of short-term plasticity of the central visceral afferent synapses of the rat

    Directory of Open Access Journals (Sweden)

    Watabe Ayako M

    2010-10-01

    Full Text Available Abstract Background The visceral afferents from various cervico-abdominal sensory receptors project to the dorsal vagal complex (DVC, which is composed of the nucleus of the solitary tract (NTS, the area postrema and the dorsal motor nucleus of the vagus nerve (DMX, via the vagus and glossopharyngeal nerves and then the solitary tract (TS in the brainstem. While the excitatory transmission at the TS-NTS synapses shows strong frequency-dependent suppression in response to repeated stimulation of the afferents, the frequency dependence and short-term plasticity at the TS-DMX synapses, which also transmit monosynaptic information from the visceral afferents to the DVC neurons, remain largely unknown. Results Recording of the EPSCs activated by paired or repeated TS stimulation in the brainstem slices of rats revealed that, unlike NTS neurons whose paired-pulse ratio (PPR is consistently below 0.6, the distribution of the PPR of DMX neurons shows bimodal peaks that are composed of type I (PPR, 0.6-1.5; 53% of 120 neurons recorded and type II (PPR, Conclusions These two general types of short-term plasticity might contribute to the differential activation of distinct vago-vagal reflex circuits, depending on the firing frequency and type of visceral afferents.

  2. Simulations of a PSD Plastic Neutron Collar for Assaying Fresh Fuel

    Energy Technology Data Exchange (ETDEWEB)

    Hausladen, Paul [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Newby, Jason [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); McElroy, Robert Dennis [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2016-11-01

    The potential performance of a notional active coincidence collar for assaying uranium fuel based on segmented detectors constructed from the new PSD plastic fast organic scintillator with pulse shape discrimination capability was investigated in simulation. Like the International Atomic Energy Agency's present Uranium Neutron Collar for LEU (UNCL), the PSD plastic collar would also function by stimulating fission in the 235U content of the fuel with a moderated 241Am/Li neutron source and detecting instances of induced fission via neutron coincidence counting. In contrast to the moderated detectors of the UNCL, the fast time scale of detection in the scintillator eliminates statistical errors due to accidental coincidences that limit the performance of the UNCL. However, the potential to detect a single neutron multiple times historically has been one of the properties of organic scintillator detectors that has prevented their adoption for international safeguards applications. Consequently, as part of the analysis of simulated data, a method was developed by which true neutron-neutron coincidences can be distinguished from inter-detector scatter that takes advantage of the position and timing resolution of segmented detectors. Then, the performance of the notional simulated coincidence collar was evaluated for assaying a variety of fresh fuels, including some containing burnable poisons and partial defects. In these simulations, particular attention was paid to the analysis of fast mode measurements. In fast mode, a Cd liner is placed inside the collar to shield the fuel from the interrogating source and detector moderators, thereby eliminating the thermal neutron flux that is most sensitive to the presence of burnable poisons that are ubiquitous in modern nuclear fuels. The simulations indicate that the predicted precision of fast mode measurements is similar to what can be achieved by the present UNCL in thermal mode. For example, the

  3. The GABAB1a isoform mediates heterosynaptic depression at hippocampal mossy fiber synapses

    DEFF Research Database (Denmark)

    Guetg, Nicole; Seddik, Riad; Vigot, Réjan

    2009-01-01

    neuron synapses more GABA(B1a) than GABA(B1b) protein is present at presynaptic sites, consistent with the findings at other glutamatergic synapses. In the presence of baclofen at concentrations >or=1 microm, both GABA(B(1a,2)) and GABA(B(1b,2)) receptors contribute to presynaptic inhibition of glutamate...

  4. Synapses, spines and kinases in mammalian learning and memory, and the impact of aging

    NARCIS (Netherlands)

    van der Zee, Eddy A

    Synapses are the building blocks of neuronal networks. Spines, the postsynaptic elements, are morphologically the most plastic part of the synapse. It is thought that spine plasticity underlies learning and memory processes, driven by kinases and cytoskeleton protein reorganization. Spine strength

  5. Remodeling of Hippocampal Spine Synapses in the Rat Learned Helplessness Model of Depression

    Science.gov (United States)

    Hajszan, Tibor; Dow, Antonia; Warner-Schmidt, Jennifer L.; Szigeti-Buck, Klara; Sallam, Nermin L.; Parducz, Arpad; Leranth, Csaba; Duman, Ronald S.

    2009-01-01

    Background Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications. Methods We analyzed hippocampal spine synapses of male rats (n=127) with electron microscopic stereology in association with performance in the learned helplessness paradigm. Results Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for six days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that desipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared to nonstressed controls. Shorter, one-day or three-day desipramine treatments, however, had neither synaptic nor behavioral effects. Conclusions These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism may be an important component in the neurobiology of stress-related disorders such as depression. PMID:19006787

  6. Cadm1-expressing synapses on Purkinje cell dendrites are involved in mouse ultrasonic vocalization activity.

    Science.gov (United States)

    Fujita, Eriko; Tanabe, Yuko; Imhof, Beat A; Momoi, Mariko Y; Momoi, Takashi

    2012-01-01

    Foxp2(R552H) knock-in (KI) mouse pups with a mutation related to human speech-language disorders exhibit poor development of cerebellar Purkinje cells and impaired ultrasonic vocalization (USV), a communication tool for mother-offspring interactions. Thus, human speech and mouse USV appear to have a Foxp2-mediated common molecular basis in the cerebellum. Mutations in the gene encoding the synaptic adhesion molecule CADM1 (RA175/Necl2/SynCAM1/Cadm1) have been identified in people with autism spectrum disorder (ASD) who have impaired speech and language. In the present study, we show that both Cadm1-deficient knockout (KO) pups and Foxp2(R552H) KI pups exhibit impaired USV and smaller cerebellums. Cadm1 was preferentially localized to the apical-distal portion of the dendritic arbor of Purkinje cells in the molecular layer of wild-type pups, and VGluT1 level decreased in the cerebellum of Cadm1 KO mice. In addition, we detected reduced immunoreactivity of Cadm1 and VGluT1 on the poorly developed dendritic arbor of Purkinje cells in the Foxp2(R552H) KI pups. However, Cadm1 mRNA expression was not altered in the Foxp2(R552H) KI pups. These results suggest that although the Foxp2 transcription factor does not target Cadm1, Cadm1 at the synapses of Purkinje cells and parallel fibers is necessary for USV function. The loss of Cadm1-expressing synapses on the dendrites of Purkinje cells may be associated with the USV impairment that Cadm1 KO and Foxp2(R552H) KI mice exhibit.

  7. Self-control of chaos in neural circuits with plastic electrical synapses

    Science.gov (United States)

    Zhigulin, V. P.; Rabinovich, M. I.

    2004-10-01

    Two kinds of connections are known to exist in neural circuits: electrical (also called gap junctions) and chemical. Whereas chemical synapses are known to be plastic (i. e., modifiable), but slow, electrical transmission through gap junctions is not modifiable, but is very fast. We suggest the new artificial synapse that combines the best properties of both: the fast reaction of a gap junction and the plasticity of a chemical synapse. Such a plastic electrical synapse can be used in hybrid neural circuits and for the development of neural prosthetics, i.e., implanted devices that can interact with the real nervous system. Based on the computer modelling we show that such a plastic electrical synapse regularizes chaos in the minimal neural circuit consisting of two chaotic bursting neurons.

  8. Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons.

    Science.gov (United States)

    Mosca, Timothy J; Luginbuhl, David J; Wang, Irving E; Luo, Liqun

    2017-06-13

    Precise coordination of synaptic connections ensures proper information flow within circuits. The activity of presynaptic organizing molecules signaling to downstream pathways is essential for such coordination, though such entities remain incompletely known. We show that LRP4, a conserved transmembrane protein known for its postsynaptic roles, functions presynaptically as an organizing molecule. In the Drosophila brain, LRP4 localizes to the nerve terminals at or near active zones. Loss of presynaptic LRP4 reduces excitatory (not inhibitory) synapse number, impairs active zone architecture, and abolishes olfactory attraction - the latter of which can be suppressed by reducing presynaptic GABA B receptors. LRP4 overexpression increases synapse number in excitatory and inhibitory neurons, suggesting an instructive role and a common downstream synapse addition pathway. Mechanistically, LRP4 functions via the conserved kinase SRPK79D to ensure normal synapse number and behavior. This highlights a presynaptic function for LRP4, enabling deeper understanding of how synapse organization is coordinated.

  9. Functional inactivation of a fraction of excitatory synapses in mice deficient for the active zone protein bassoon

    DEFF Research Database (Denmark)

    Altrock, Wilko D; tom Dieck, Susanne; Sokolov, Maxim

    2003-01-01

    in normal synaptic transmission, which can be attributed to the inactivation of a significant fraction of glutamatergic synapses. At these synapses, vesicles are clustered and docked in normal numbers but are unable to fuse. Phenotypically, the loss of Bassoon causes spontaneous epileptic seizures....... These data show that Bassoon is not essential for synapse formation but plays an essential role in the regulated neurotransmitter release from a subset of glutamatergic synapses....

  10. Players over the Surface: Unraveling the Role of Exopolysaccharides in Zinc Biosorption by Fluorescent Pseudomonas Strain Psd.

    Science.gov (United States)

    Upadhyay, Anamika; Kochar, Mandira; Rajam, Manchikatla V; Srivastava, Sheela

    2017-01-01

    Fluorescent Pseudomonas strain Psd is a soil isolate, possessing multiple plant growth promoting (PGP) properties and biocontrol potential. In addition, the strain also possesses high Zn2+ biosorption capability. In this study, we have investigated the role exopolysaccharides (EPS) play in Zn2+ biosorption. We have identified that alginates are the prime components contributing to Zn2+ biosorption. Deletion of the alg8 gene, which codes for a sub-unit of alginate polymerase, led to a significant reduction in EPS production by the organism. We have also demonstrated that the increased alginate production in response to Zn2+ exposure leads to improved biofilm formation by the strain. In the alg8 deletion mutant, however, biofilm formation was severely compromised. Further, we have studied the functional implications of Zn2+ biosorption by Pseudomonas strain Psd by demonstrating the effect on the PGP and biocontrol potential of the strain.

  11. Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

    Science.gov (United States)

    Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

    2016-01-01

    Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets. PMID:27035941

  12. Model of an excitatory synapse based on stochastic processes.

    Science.gov (United States)

    L'Espérance, Pierre-Yves; Labib, Richard

    2013-09-01

    We present a mathematical model of a biological synapse based on stochastic processes to establish the temporal behavior of the postsynaptic potential following a quantal synaptic transmission. This potential form is the basis of the neural code. We suppose that the release of neurotransmitters in the synaptic cleft follows a Poisson process, and that they diffuse according to integrated Ornstein-Uhlenbeck processes in 3-D with random initial positions and velocities. The diffusion occurs in an isotropic environment between two infinite parallel planes representing the pre- and postsynaptic membrane. We state that the presynaptic membrane is perfectly reflecting and that the other is perfectly absorbing. The activation of the receptors polarizes the postsynaptic membrane according to a parallel RC circuit scheme. We present the results obtained by simulations according to a Gillespie algorithm and we show that our model exhibits realistic postsynaptic behaviors from a simple quantal occurrence.

  13. Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses.

    Science.gov (United States)

    Wasser, Catherine R; Herz, Joachim

    2017-01-27

    Over half a century ago, D. S. Falconer first reported a mouse with a reeling gate. Four decades later, the Reln gene was isolated and identified as the cause of the reeler phenotype. Initial studies found that loss of Reelin, a large, secreted glycoprotein encoded by the Reln gene, results in abnormal neuronal layering throughout several regions of the brain. In the years since, the known functions of Reelin signaling in the brain have expanded to include multiple postdevelopmental neuromodulatory roles, revealing an ever increasing body of evidence to suggest that Reelin signaling is a critical player in the modulation of synaptic function. In writing this review, we intend to highlight the most fundamental aspects of Reelin signaling and integrate how these various neuromodulatory effects shape and protect synapses. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Elastohydrodynamics and kinetics of protein patterning in the immunological synapse

    CERN Document Server

    Carlson, Andreas

    2015-01-01

    The cellular basis for the adaptive immune response during antigen recognition relies on a specialized protein interface known as the immunological synapse (IS). Understanding the biophysical basis for protein patterning by deciphering the quantitative rules for their formation and motion is an important aspect of characterizing immune cell recognition and thence the rules for immune system activation. We propose a minimal mathematical model for the physical basis of membrane protein patterning in the IS, which encompass membrane mechanics, protein binding kinetics and motion, and fluid flow in the synaptic cleft. Our theory leads to simple predictions for the spatial and temporal scales of protein cluster formation, growth and arrest as a function of membrane stiffness, rigidity and kinetics of the adhesive proteins, and the fluid in the synaptic cleft. Numerical simulations complement these scaling laws by quantifying the nucleation, growth and stabilization of proteins domains on the size of the cell. Dire...

  15. Spin switches for compact implementation of neuron and synapse

    Energy Technology Data Exchange (ETDEWEB)

    Quang Diep, Vinh, E-mail: vdiep@purdue.edu; Sutton, Brian; Datta, Supriyo [School of Electrical and Computer Engineering, Purdue University, West Lafayette, Indiana 47907 (United States); Behin-Aein, Behtash [GLOBALFOUNDRIES, Inc., Sunnyvale, California 94085 (United States)

    2014-06-02

    Nanomagnets driven by spin currents provide a natural implementation for a neuron and a synapse: currents allow convenient summation of multiple inputs, while the magnet provides the threshold function. The objective of this paper is to explore the possibility of a hardware neural network implementation using a spin switch (SS) as its basic building block. SS is a recently proposed device based on established technology with a transistor-like gain and input-output isolation. This allows neural networks to be constructed with purely passive interconnections without intervening clocks or amplifiers. The weights for the neural network are conveniently adjusted through analog voltages that can be stored in a non-volatile manner in an underlying CMOS layer using a floating gate low dropout voltage regulator. The operation of a multi-layer SS neural network designed for character recognition is demonstrated using a standard simulation model based on coupled Landau-Lifshitz-Gilbert equations, one for each magnet in the network.

  16. Independent origins of neurons and synapses: insights from ctenophores.

    Science.gov (United States)

    Moroz, Leonid L; Kohn, Andrea B

    2016-01-05

    There is more than one way to develop neuronal complexity, and animals frequently use different molecular toolkits to achieve similar functional outcomes. Genomics and metabolomics data from basal metazoans suggest that neural signalling evolved independently in ctenophores and cnidarians/bilaterians. This polygenesis hypothesis explains the lack of pan-neuronal and pan-synaptic genes across metazoans, including remarkable examples of lineage-specific evolution of neurogenic and signalling molecules as well as synaptic components. Sponges and placozoans are two lineages without neural and muscular systems. The possibility of secondary loss of neurons and synapses in the Porifera/Placozoa clades is a highly unlikely and less parsimonious scenario. We conclude that acetylcholine, serotonin, histamine, dopamine, octopamine and gamma-aminobutyric acid (GABA) were recruited as transmitters in the neural systems in cnidarian and bilaterian lineages. By contrast, ctenophores independently evolved numerous secretory peptides, indicating extensive adaptations within the clade and suggesting that early neural systems might be peptidergic. Comparative analysis of glutamate signalling also shows numerous lineage-specific innovations, implying the extensive use of this ubiquitous metabolite and intercellular messenger over the course of convergent and parallel evolution of mechanisms of intercellular communication. Therefore: (i) we view a neuron as a functional character but not a genetic character, and (ii) any given neural system cannot be considered as a single character because it is composed of different cell lineages with distinct genealogies, origins and evolutionary histories. Thus, when reconstructing the evolution of nervous systems, we ought to start with the identification of particular cell lineages by establishing distant neural homologies or examples of convergent evolution. In a corollary of the hypothesis of the independent origins of neurons, our analyses

  17. G quadruplex RNA structures in PSD-95 mRNA: potential regulators of miR-125a seed binding site accessibility.

    Science.gov (United States)

    Stefanovic, Snezana; Bassell, Gary J; Mihailescu, Mihaela Rita

    2015-01-01

    Fragile X syndrome (FXS) is the most common inherited form of intellectual disability caused by the CGG trinucleotide expansion in the 3'-untranslated region of the FMR1 gene on the X chromosome, that silences the expression of the Fragile X mental retardation protein (FMRP). FMRP has been shown to bind to a G-rich region within the PSD-95 mRNA which encodes for the postsynaptic density protein 95 (PSD-95), and together with the microRNA miR-125a, to play an important role in the reversible inhibition of the PSD-95 mRNA translation in neurons. The loss of FMRP in Fmr1 KO mice disables this translation control in the production of the PSD-95 protein. Interestingly, the miR-125a binding site on PSD-95 mRNA is embedded in the G-rich region bound by FMRP and postulated to adopt one or more G quadruplex structures. In this study, we have used different biophysical techniques to validate and characterize the formation of parallel G quadruplex structures and binding of miR-125a to its complementary sequence located within the 3' UTR of PSD-95 mRNA. Our results indicate that the PSD-95 mRNA G-rich region folds into alternate G quadruplex conformations that coexist in equilibrium. miR-125a forms a stable complex with PSD-95 mRNA, as evident by characteristic Watson-Crick base-pairing that coexists with one of the G quadruplex forms, suggesting a novel mechanism for G quadruplex structures to regulate the access of miR-125a to its binding site. © 2014 Stefanovic et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  18. ADF/cofilin: a crucial regulator of synapse physiology and behavior.

    Science.gov (United States)

    Rust, Marco B

    2015-09-01

    Actin filaments (F-actin) are the major structural component of excitatory synapses, being present in presynaptic terminals and in postsynaptic dendritic spines. In the last decade, it has been appreciated that actin dynamics, the assembly and disassembly of F-actin, is crucial not only for the structure of excitatory synapses, but also for pre- and postsynaptic physiology. Hence, regulators of actin dynamics take a central role in mediating neurotransmitter release, synaptic plasticity, and ultimately behavior. Actin depolymerizing proteins of the ADF/cofilin family are essential regulators of actin dynamics, and a number of recent studies highlighted their crucial functions in excitatory synapses. In dendritic spines, ADF/cofilin activity is required for spine enlargement during initial long-term potentiation (LTP), but needs to be switched off during spine stabilization and LTP consolidation. Conversely, active ADF/cofilin is needed for spine pruning during long-term depression (LTD). Moreover, ADF/cofilin controls activity-induced synaptic availability of glutamate receptors, and exocytosis of synaptic vesicles. These data show that the activity of ADF/cofilin in synapses needs to be spatially and temporally tightly controlled through several upstream regulatory pathways, which have been identified recently. Hence, ADF/cofilin-controlled actin dynamics emerged as a critical and central regulator of synapse physiology. In this review, I will summarize and discuss our current knowledge on the roles of ADF/cofilin in synapse physiology and behavior, by focusing on excitatory synapses of the mammalian central nervous system.

  19. FGF22 protects hearing function from gentamycin ototoxicity by maintaining ribbon synapse number.

    Science.gov (United States)

    Li, Shuna; Hang, Lihua; Ma, Yongming

    2016-02-01

    Inner hair cell (IHC) ribbon synapses of cochlea play important role in transmitting sound signal into auditory nerve and are sensitive to ototoxicity. However, ototoxic damage of ribbon synapses is not understood clearly. Roles of fibroblast growth factor 22 (FGF22) on synapse formation were explored under gentamycin ototoxicity. 6-week-old mice were injected intraperitoneally once daily with 50-150 mg/kg gentamicin for 10 days. Immunostaining with anti- GluR2&3/CtBP2 was used to estimate the number of ribbon synapses in the cochlea. Expression of FGF22 and myocyte enhancer factor 2D (MEF2D) was assayed with RT-PCR. Expression and localization of FGF22 protein were visualized with anti-FGF22 immunostaining. Hearing thresholds were assessed using auditory brainstem responses. Gentamicin administration caused reduction in ribbon synapse number and hearing impairment without effect on hair cells in CBA/J mouse model. Immunohistochemistry showed that FGF22 protein was expressed in IHCs, but not OHCs of cochlea. Gentamycin attenuated expression of FGF22 but enhanced expression of MEF2D. Cochlear infusion of recombinant FGF22 inhibited expression of MEF2D, preserved ribbon synapses, and restored hearing function impaired by gentamycin. FGF22 restores hearing loss through maintaining ribbon synapse number, likely via inhibition of MEF2D. Activating FGF22 might provide the conceptual basis for the therapeutic strategies. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Production of the active antifungal Pisum sativum defensin 1 (Psd1) in Pichia pastoris: overcoming the inefficiency of the STE13 protease.

    Science.gov (United States)

    Cabral, Kátia M S; Almeida, Marcius S; Valente, Ana Paula; Almeida, Fábio C L; Kurtenbach, Eleonora

    2003-09-01

    Plant defensins are small cysteine-rich proteins that present high activity against fungi and bacteria and inhibition of insect proteases and alpha-amylases. Here, we present the expression in Pichia pastoris, purification and characterization of the recombinant Pisum sativum defensin 1(rPsd1); a pea defensin which presents four disulfide bridges and high antifungal activity. For this, we had to overcome the inefficiency of the STE13 protease. Our strategy was to clone the corresponding cDNA directly in-frame with a variant of the widely used secretion signal from the Saccharomyces cerevisiae alpha-mating factor, devoid of the STE13 proteolytic signal cleavage sequence. Using an optimized expression protocol, which included a buffered basal salt media formulation, it was possible to obtain about 63.0mg/L of 15N-labeled and unlabeled rPsd1. The recombinants were purified to homogeneity by gel filtration chromatography, followed by reversed-phase HPLC. Mass spectrometry of native and recombinant Psd1 revealed that the protein expressed heterologously was post-translationally processed to the same mature protein as the native one. Circular dichroism and nuclear magnetic resonance spectroscopy analysis indicated that the recombinant protein had the same folding when compared to native Psd1. In addition, the rPsd1 was fully active against Aspergillus niger, if compared with native Psd1. To our knowledge, this is the first heterologous expression of a fully active plant defensin in a high-yield flask.

  1. DA Negatively Regulates IGF-I Actions Implicated in Cognitive Function via Interaction of PSD95 and nNOS in Minimal Hepatic Encephalopathy

    Directory of Open Access Journals (Sweden)

    Saidan Ding

    2017-09-01

    Full Text Available Insulin-like growth factor I (IGF-I has been positively correlated with cognitive ability. Cognitive decline in minimal hepatic encephalopathy (MHE was shown to be induced by elevated intracranial dopamine (DA. The beneficial effect of IGF-I signaling in MHE remains unknown. In this study, we found that IGF-I content was reduced in MHE rats and that IGF-I administration mitigated cognitive decline of MHE rats. A protective effect of IGF-I on the DA-induced interaction between postsynaptic density protein 95 (PSD95 and neuronal nitric oxide synthase (nNOS was found in neurons. Ribosomal S6 protein kinase (RSK phosphorylated nNOS in response to IGF-I by recruiting extracellular signal-regulated kinase (ERK1/2. In turn, DA inactivated the ERK1/2/RSK pathway and stimulated the PSD95–nNOS interaction by downregulating IGF-I. Inhibition of the interaction between PSD95 and nNOS ameliorated DA-induced memory impairment. As DA induced deficits in the ERK1/2/RSK pathway and the interaction between PSD95 and nNOS in MHE brains, IGF-I administration exerted a protective effect via interruption of the interaction between PSD95 and nNOS. These results suggest that IGF-I antagonizes DA-induced cognitive loss by disrupting PSD95–nNOS interactions in MHE.

  2. From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function.

    Science.gov (United States)

    Greer, Paul L; Greenberg, Michael E

    2008-09-25

    One of the unique characteristics of higher organisms is their ability to learn and adapt to changes in their environment. This plasticity is largely a result of the brain's ability to convert transient stimuli into long-lasting alterations in neuronal structure and function. This process is complex and involves changes in receptor trafficking, local mRNA translation, protein turnover, and new gene synthesis. Here, we review how neuronal activity triggers calcium-dependent gene expression to regulate synapse development, maturation, and refinement. Interestingly, many components of the activity-dependent gene expression program are mutated in human cognitive disorders, which suggest that this program is essential for proper brain development and function.

  3. Endocannabinoid release modulates electrical coupling between CCK cells connected via chemical and electrical synapses in CA1

    Directory of Open Access Journals (Sweden)

    Jonathan eIball

    2011-11-01

    Full Text Available Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholesystokinin (CCK interneurons which co-express cannbinoid type-1 (CB1 receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labelling in acute slices of rat hippocampus at P18-20 days. CA1 stratum radiatum CCK Schaffer collateral associated (SCA cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released IPSPs that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5M resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI, maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization.

  4. The actin-binding protein Abp1 controls dendritic spine morphology and is important for spine head and synapse formation.

    Science.gov (United States)

    Haeckel, Akvile; Ahuja, Rashmi; Gundelfinger, Eckart D; Qualmann, Britta; Kessels, Michael M

    2008-10-01

    Polymerization and organization of actin into complex superstructures, including those found in dendritic spines, is indispensable for structure and function of neuronal networks. Here we show that the filamentous actin (F-actin)-binding protein 1 (Abp1), which controls Arp2/3 complex-mediated actin nucleation and binds to postsynaptic scaffold proteins of the ProSAP (proline-rich synapse-associated protein 1)/Shank family, has a profound impact on synaptic organization. Overexpression of the two Abp1 F-actin-binding domains increases the length of thin, filopodia-like and mushroom-type spines but dramatically reduces mushroom spine density, attributable to lack of the Abp1 Src homology 3 (SH3) domain. In contrast, overexpression of full-length Abp1 increases mushroom spine and synapse density. The SH3 domain alone has a dominant-negative effect on mushroom spines, whereas the density of filopodia and thin, immature spines remains unchanged. This suggests that both actin-binding and SH3 domain interactions are crucial for the role of Abp1 in spine maturation. Indeed, Abp1 knockdown significantly reduces mushroom spine and synapse density. Abp1 hereby works in close conjunction with ProSAP1/Shank2 and ProSAP2/Shank3, because Abp1 effects were suppressed by ProSAP2 RNA interference and the ProSAP/Shank-induced increase of spine head width is further promoted by Abp1 cooverexpression and reduced on Abp1 knockdown. Also, interfering with the formation of functional Abp1-ProSAP protein complexes prevents ProSAP-mediated spine head extension. Spine head extension furthermore depends on local Arp2/3 complex-mediated actin polymerization, which is controlled by Abp1 via the Arp2/3 complex activator N-WASP (neural Wiskott-Aldrich syndrome protein). Abp1 thus plays an important role in the formation and morphology control of synapses by making a required functional connection between postsynaptic density components and postsynaptic actin dynamics.

  5. Mechanisms of enhanced HIV spread through T-cell virological synapses.

    Science.gov (United States)

    Dale, Benjamin M; Alvarez, Raymond A; Chen, Benjamin K

    2013-01-01

    An elaborate network of cell-cell interactions in the immune system is essential for vertebrates to mount adaptive immune responses against invading pathogens. For lymphotropic viruses such as the human immunodeficiency virus type 1 (HIV-1), these immune cell interactions can also promote the spread of the virus within the host. The main target of HIV-1 infection is the CD4(+) helper T lymphocyte, a cell type that is responsible for coordinating immune responses and modulating effector responses to foreign antigens. As part of their normal immune surveillance duties, these cells migrate actively within lymphoid tissues and can travel from inductive sites to effector sites in search of their cognate antigen. For CD4(+) T cells, there is an ongoing search for a unique peptide antigen presented in the context of class II MHC that can activate a proliferative or tolerogenic response. This iterative and continual probing and interrogation of other cells determine the outcome of immune responses. Recent studies in vitro have revealed that the viral infection program induces cell-cell interactions called virological synapses between infected and uninfected CD4(+) T cells. These long-lived, virally induced adhesive contacts greatly enhance the rate of productive infection and may be central to the spread of the virus in vivo. Here, we review aspects of this efficient mode of cell-to-cell infection and the implications for our understanding of HIV-1 pathogenesis. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

  6. Postsynaptic density-95 scaffolding of Shaker-type K⁺ channels in smooth muscle cells regulates the diameter of cerebral arteries.

    Science.gov (United States)

    Joseph, Biny K; Thakali, Keshari M; Pathan, Asif R; Kang, Eunju; Rusch, Nancy J; Rhee, Sung W

    2011-11-01

    Postsynaptic density-95 (PSD95) is a 95 kDa scaffolding molecule in the brain that clusters postsynaptic proteins including ion channels, receptors, enzymes and other signalling partners required for normal cognition. The voltage-gated, Shaker-type K(+) (K(V)1) channel is one key binding partner of PSD95 scaffolds in neurons. However, K(V)1 channels composed of α1.2 and α1.5 pore-forming subunits also are expressed in the vascular smooth muscle cells (cVSMCs) of the cerebral circulation, although the identity of their molecular scaffolds is unknown. Since α1.2 contains a binding motif for PSD95, we explored the possibility that cVSMCs express PSD95 as a scaffold to promote K(V)1 channel expression and cerebral vasodilatation. Cerebral arteries from Sprague-Dawley rats were isolated for analysis of PSD95 and K(V)1 channel proteins. PSD95 was detected in cVSMCs and it co-immunoprecipitated and co-localized with the pore-forming α1.2 subunit of the K(V)1 channel. Antisense-mediated knockdown of PSD95 profoundly reduced K(V)1 channel expression and suppressed K(V)1 current in patch-clamped cVSMCs. Loss of PSD95 also depolarized cVSMCs in pressurized cerebral arteries and induced a strong constriction associated with a loss of functional K(V)1 channels. Our findings provide initial evidence that PSD95 is expressed in cVSMCs, and the K(V)1 channel is one of its important binding partners. PSD95 appears to function as a critical 'dilator' scaffold in cerebral arteries by increasing the number of functional K(V)1 channels at the plasma membrane.

  7. Cytoskeletal actin dynamics shape a ramifying actin network underpinning immunological synapse formation

    DEFF Research Database (Denmark)

    Fritzsche, Marco; Fernandes, Ricardo A.; Chang, Veronica T.

    2017-01-01

    T cell activation and especially trafficking of T cell receptor microclusters during immunological synapse formation are widely thought to rely on cytoskeletal remodeling. However, important details on the involvement of actin in the latter transport processes are missing. Using a suite of advanced...... optical microscopes to analyze resting and activated T cells, we show that, following contact formation with activating surfaces, these cells sequentially rearrange their cortical actin across the entire cell, creating a previously unreported ramifying actin network above the immunological synapse...... lengths of two differently sized filamentous actin populations, wherein forminmediated long actin filaments support a very flat and stiff contact at the immunological synapse interface. The initiation of immunological synapse formation, as highlighted by calcium release, requires markedly little contact...

  8. The Many Forms and Functions of Long Term Plasticity at GABAergic Synapses

    Directory of Open Access Journals (Sweden)

    Arianna Maffei

    2011-01-01

    Full Text Available On February 12th 1973, Bliss and Lomo submitted their findings on activity-dependent plasticity of glutamatergic synapses. After this groundbreaking discovery, long-term potentiation (LTP and depression (LTD gained center stage in the study of learning, memory, and experience-dependent refinement of neural circuits. While LTP and LTD are extensively studied and their relevance to brain function is widely accepted, new experimental and theoretical work recently demonstrates that brain development and function relies on additional forms of plasticity, some of which occur at nonglutamatergic synapses. The strength of GABAergic synapses is modulated by activity, and new functions for inhibitory synaptic plasticity are emerging. Together with excitatory neurons, inhibitory neurons shape the excitability and dynamic range of neural circuits. Thus, the understanding of inhibitory synaptic plasticity is crucial to fully comprehend the physiology of brain circuits. Here, I will review recent findings about plasticity at GABAergic synapses and discuss how it may contribute to circuit function.

  9. How the immune system talks to itself: the varied role of synapses

    OpenAIRE

    Xie, Jianming; Tato, Cristina M.; Davis, Mark M

    2013-01-01

    Using an elaborately evolved language of cytokines and chemokines as well as cell-cell interactions, the different components of the immune system communicate with each other and orchestrate a response (or wind one down). Immunological synapses are a key feature of the system in the ways in which they can facilitate and direct these responses. Studies analyzing the structure of an immune synapse as it forms between two cells have provided insight into how the stability and kinetics of this in...

  10. The Extracellular Region of Lrp4 is Sufficient to Mediate Neuromuscular Synapse Formation

    OpenAIRE

    Gomez, Andrea; Burden, Steven J.

    2011-01-01

    Neuromuscular synapse formation requires an exchange of signals between motor neurons and muscle. Agrin, supplied by motor neurons, binds to Lrp4 in muscle, stimulating phosphorylation of MuSK and recruitment of a signaling complex essential for synapse-specific transcription and anchoring of key proteins in the postsynaptic membrane. Lrp4, like the LDLR and other Lrp-family members, contains an intracellular region with motifs that can regulate receptor trafficking, as well as assembly of an...

  11. Decrease in neuronal nicotinic acetylcholine receptor subunit and PSD-93 transcript levels in the male mouse MPG after cavernous nerve injury or explant culture

    Science.gov (United States)

    Girard, Beatrice M.; Merriam, Laura A.; Tompkins, John D.; Vizzard, Margaret A.

    2013-01-01

    Quantitative real-time PCR was used to test whether cavernous nerve injury leads to a decrease in major pelvic ganglia (MPG) neuronal nicotinic ACh receptor (nAChR) subunit and postsynaptic density (PSD)-93 transcript levels. Subunits α3, β4, and α7, commonly expressed in the MPG, were selected for analysis. After 72 h in explant culture, MPG transcript levels for α3, β4, α7, and PSD-93 were significantly depressed. Three days after cavernous nerve axotomy or crush in vivo, transcript levels for α3, β4, and PSD-93, but not for α7, were significantly depressed. Three days after dissection of the cavernous nerve free of underlying tissue and application of a 5-mm lateral stretch (manipulation), transcript levels for α3 and PSD-93 were also significantly decreased. Seven days after all three surgical procedures, α3 transcript levels remained depressed, but PSD-93 transcript levels were still decreased only after axotomy or nerve crush. At 30 days postsurgery, transcript levels for the nAChR subunits and PSD-93 had recovered. ACh-induced currents were significantly smaller in MPG neurons dissociated from 3-day explant cultured ganglia than from those recorded in neurons dissociated from acutely isolated ganglia; this observation provides direct evidence showing that a decrease in nAChR function was coincident with a decrease in nAChR subunit transcript levels. We conclude that a downregulation of nAChR subunit and PSD-93 expression after cavernous nerve injury, or even manipulation, could interrupt synaptic transmission within the MPG and thus contribute to the loss of neural control of urogenital organs after pelvic surgeries. PMID:24049141

  12. AP180 and CALM in the developing hippocampus: expression at the nascent synapse and localization to trafficking organelles.

    Science.gov (United States)

    Petralia, Ronald S; Yao, Pamela J

    2007-09-20

    Genetic and biochemical evidence has established that clathrin assembly protein AP180 is required for the proper assembly of synaptic vesicles via clathrin-mediated endocytosis. The assembly protein CALM, the ubiquitously expressed homolog of AP180, also regulates the formation of clathrin-coated vesicles. In this study we found high expression levels of AP180 and CALM in hippocampal tissues as early as embryonic day 18, before the expression of synaptophysin. We also used immunoelectron microscopy to establish the distribution of AP180 and CALM in the developing hippocampal synapses. We found AP180 and CALM in synapses at all developmental stages and in nonsynaptic growing processes. In addition to localization on the plasma membrane and clathrin-coated vesicles that originated from the plasma membrane, we also report the presence of AP180 and CALM on other types of membrane structures. Our observations link AP180 and CALM to multiple vesicular organelles and raise the possibility that these proteins may play additional roles in developing neurons.

  13. Myosin IIA modulates T cell receptor transport and CasL phosphorylation during early immunological synapse formation.

    Directory of Open Access Journals (Sweden)

    Yan Yu

    Full Text Available Activation of T cell receptor (TCR by antigens occurs in concert with an elaborate multi-scale spatial reorganization of proteins at the immunological synapse, the junction between a T cell and an antigen-presenting cell (APC. The directed movement of molecules, which intrinsically requires physical forces, is known to modulate biochemical signaling. It remains unclear, however, if mechanical forces exert any direct influence on the signaling cascades. We use T cells from AND transgenic mice expressing TCRs specific to the moth cytochrome c 88-103 peptide, and replace the APC with a synthetic supported lipid membrane. Through a series of high spatiotemporal molecular tracking studies in live T cells, we demonstrate that the molecular motor, non-muscle myosin IIA, transiently drives TCR transport during the first one to two minutes of immunological synapse formation. Myosin inhibition reduces calcium influx and colocalization of active ZAP-70 (zeta-chain associated protein kinase 70 with TCR, revealing an influence on signaling activity. More tellingly, its inhibition also significantly reduces phosphorylation of the mechanosensing protein CasL (Crk-associated substrate the lymphocyte type, raising the possibility of a direct mechanical mechanism of signal modulation involving CasL.

  14. What came first: PKCtheta or the immune synapse?

    Science.gov (United States)

    Villalba, Martin

    2004-01-01

    Stimulation of T cells by peptide-presenting antigen-presenting cells (APCs) induces formation of a highly organized complex of receptors, signaling molecules and cytoskeleton components at the immune synapse (IS), the contact site between T cells and APCs. Conjugate formation between T cells and APCs initiates the formation of the IS. After this event, micrometer-scale molecular movements occur in the T cell plasma membrane and the actin cytoskeleton undergoes reorganization. Our current knowledge suggests that formation of the IS is an essential step during T cell activation. This is probably related to the proper localization of certain proteins in specific compartments. One of these proteins is protein kinase Ctheta (PKCtheta), which is absolutely required for T cell activation. During the last years we have made great advances in understanding the function and targets of this kinase, and recent reviews have summarized these findings. In contrast, we do not know the exact mechanism that activates PKCtheta after TCR engagement and the role of PKCtheta activation in the formation of the IS. In this review I analyze the mechanism of the translocation of PKCtheta and discuss the function of PKCtheta in the formation of the IS and, vice versa, the role of the IS in the translocation of PKCtheta.

  15. Localized chemical release from an artificial synapse chip

    Science.gov (United States)

    Peterman, Mark C.; Noolandi, Jaan; Blumenkranz, Mark S.; Fishman, Harvey A.

    2004-07-01

    A device that releases chemical compounds in small volumes and at multiple, well defined locations would be a powerful tool for clinical therapeutics and biological research. Many biomedical devices such as neurotransmitter-based prostheses or drug delivery devices require precise release of chemical compounds. Additionally, the ability to control chemical gradients will have applications in basic research such as studies of cell microenvironments, stem cell niches, metaplasia, or chemotaxis. We present such a device with repeatable delivery of chemical compounds at multiple locations on a chip surface. Using electroosmosis to drive flow through microfluidic channels, we pulse minute quantities of a bradykinin solution through four 5-µm apertures onto PC12 cells and show stimulation of individual cells using a Ca2+-sensitive fluorescent dye. We also present basic computational results with experimental verification of both fluid ejection and fluid withdrawal by imaging pH changes by using a fluorescent dye. This "artificial synapse chip" is a prototype neural interface that introduces a new paradigm for neural stimulation, with eventual application in treating macular degeneration and other neurological disorders.

  16. Neuronal LRP4 regulates synapse formation in the developing CNS.

    Science.gov (United States)

    Karakatsani, Andromachi; Marichal, Nicolás; Urban, Severino; Kalamakis, Georgios; Ghanem, Alexander; Schick, Anna; Zhang, Yina; Conzelmann, Karl-Klaus; Rüegg, Markus A; Berninger, Benedikt; Ruiz de Almodovar, Carmen; Gascón, Sergio; Kröger, Stephan

    2017-12-15

    The low-density lipoprotein receptor-related protein 4 (LRP4) is essential in muscle fibers for the establishment of the neuromuscular junction. Here, we show that LRP4 is also expressed by embryonic cortical and hippocampal neurons, and that downregulation of LRP4 in these neurons causes a reduction in density of synapses and number of primary dendrites. Accordingly, overexpression of LRP4 in cultured neurons had the opposite effect inducing more but shorter primary dendrites with an increased number of spines. Transsynaptic tracing mediated by rabies virus revealed a reduced number of neurons presynaptic to the cortical neurons in which LRP4 was knocked down. Moreover, neuron-specific knockdown of LRP4 by in utero electroporation of LRP4 miRNA in vivo also resulted in neurons with fewer primary dendrites and a lower density of spines in the developing cortex and hippocampus. Collectively, our results demonstrate an essential and novel role of neuronal LRP4 in dendritic development and synaptogenesis in the CNS. © 2017. Published by The Company of Biologists Ltd.

  17. Calcium signaling in synapse-to-nucleus communication.

    Science.gov (United States)

    Hagenston, Anna M; Bading, Hilmar

    2011-11-01

    Changes in the intracellular concentration of calcium ions in neurons are involved in neurite growth, development, and remodeling, regulation of neuronal excitability, increases and decreases in the strength of synaptic connections, and the activation of survival and programmed cell death pathways. An important aspect of the signals that trigger these processes is that they are frequently initiated in the form of glutamatergic neurotransmission within dendritic trees, while their completion involves specific changes in the patterns of genes expressed within neuronal nuclei. Accordingly, two prominent aims of research concerned with calcium signaling in neurons are determination of the mechanisms governing information conveyance between synapse and nucleus, and discovery of the rules dictating translation of specific patterns of inputs into appropriate and specific transcriptional responses. In this article, we present an overview of the avenues by which glutamatergic excitation of dendrites may be communicated to the neuronal nucleus and the primary calcium-dependent signaling pathways by which synaptic activity can invoke changes in neuronal gene expression programs.

  18. Novel functions for ADF/cofilin in excitatory synapses - lessons from gene-targeted mice.

    Science.gov (United States)

    Rust, Marco B

    2015-01-01

    Actin filaments (F-actin) are the major structural component of excitatory synapses. In excitatory synapses, F-actin is enriched in presynaptic terminals and in postsynaptic dendritic spines, and actin dynamics - the spatiotemporally controlled assembly and disassembly of F-actin - have been implicated in pre- and postsynaptic physiology, additionally to their function in synapse morphology. Hence, actin binding proteins that control actin dynamics have moved into the focus as regulators of synapse morphology and physiology. Actin depolymerizing proteins of the ADF/cofilin family are important regulators of actin dynamics, and several recent studies highlighted the relevance of cofilin 1 for dendritic spine morphology, trafficking of postsynaptic glutamate receptors, and synaptic plasticity. Conversely, almost nothing was known about the synaptic function of ADF, a second ADF/cofilin family member present at excitatory synapses, and it remained unknown whether ADF/cofilin is relevant for presynaptic physiology. To comprehensively characterize the synaptic function of ADF/cofilin we made use of mutant mice lacking either ADF or cofilin 1 or both proteins. Our analysis revealed presynaptic defects (altered distribution and enhanced exocytosis of synaptic vesicles) and behavioral abnormalities reminiscent of attention deficit-hyperactivity disorder in double mutants that were not present in single mutants. Hence, by exploiting gene-targeted mice, we demonstrated the relevance of ADF for excitatory synapses, and we unraveled novel functions for ADF/cofilin in presynaptic physiology and behavior.

  19. Metaplasticity at CA1 Synapses by Homeostatic Control of Presynaptic Release Dynamics

    Directory of Open Access Journals (Sweden)

    Cary Soares

    2017-10-01

    Full Text Available Summary: Hebbian and homeostatic forms of plasticity operate on different timescales to regulate synaptic strength. The degree of mechanistic overlap between these processes and their mutual influence are still incompletely understood. Here, we report that homeostatic synaptic strengthening induced by prolonged network inactivity compromised the ability of CA1 synapses to exhibit LTP. This effect could not be accounted for by an obvious deficit in the postsynaptic capacity for LTP expression, since neither the fraction of silent synapses nor the ability to induce LTP by two-photon glutamate uncaging were reduced by the homeostatic process. Rather, optical quantal analysis reveals that homeostatically strengthened synapses display a reduced capacity to maintain glutamate release fidelity during repetitive stimulation, ultimately impeding the induction, and thus expression, of LTP. By regulating the short-term dynamics of glutamate release, the homeostatic process thus influences key aspects of dynamic network function and exhibits features of metaplasticity. : Several forms of synaptic plasticity operating over distinct spatiotemporal scales have been described at hippocampal synapses. Whether these distinct plasticity mechanisms interact and influence one another remains incompletely understood. Here, Soares et al. show that homeostatic plasticity induced by network silencing influences short-term release dynamics and Hebbian plasticity rules at hippocampal synapses. Keywords: synapse, LTP, homeostatic plasticity, metaplasticity, iGluSNFR

  20. Effects of Estradiol on Learned Helplessness and Associated Remodeling of Hippocampal Spine Synapses in Female Rats

    Science.gov (United States)

    Hajszan, Tibor; Szigeti-Buck, Klara; Sallam, Nermin L; Bober, Jeremy; Parducz, Arpad; MacLusky, Neil J; Leranth, Csaba; Duman, Ronald S

    2009-01-01

    Background Despite the fact that women are twice as likely to develop depression as men, our understanding of depression neurobiology in females is limited. We have recently reported in male rats that development of helpless behavior is associated with a severe loss of hippocampal spine synapses, which is reversed by treatment with the antidepressant, desipramine. Considering the fact that estradiol has a hippocampal synaptogenic effect similar to those of antidepressants, the presence of estradiol during the female reproductive life may influence behavioral and synaptic responses to stress and depression. Methods Using electron microscopic stereology, we analyzed hippocampal spine synapses in association with helpless behavior in ovariectomized female rats (n=70), under different conditions of estradiol exposure. Results Stress induced an acute and persistent loss of hippocampal spine synapses, while subchronic treatment with desipramine reversed the stress-induced synaptic loss. Estradiol supplementation given either prior to stress or prior to escape testing of nonstressed animals both increased the number of hippocampal spine synapses. Correlation analysis demonstrated a statistically significant negative correlation between the severity of helpless behavior and hippocampal spine synapse numbers. Conclusions These findings suggest that hippocampal spine synapse remodeling may be a critical factor underlying learned helplessness and, possibly, the neurobiology of depression. PMID:19811775

  1. A Reaction-Diffusion Model for Synapse Growth and Long-Term Memory

    Science.gov (United States)

    Liu, Kang; Lisman, John; Hagan, Michael

    Memory storage involves strengthening of synaptic transmission known as long-term potentiation (LTP). The late phase of LTP is associated with structural processes that enlarge the synapse. Yet, synapses must be stable, despite continual subunit turnover, over the lifetime of an encoded memory. These considerations suggest that synapses are variable-size stable structure (VSSS), meaning they can switch between multiple metastable structures with different sizes. The mechanisms underlying VSSS are poorly understood. While experiments and theory have suggested that the interplay between diffusion and receptor-scaffold interactions can lead to a preferred stable size for synaptic domains, such a mechanism cannot explain how synapses adopt widely different sizes. Here we develop a minimal reaction-diffusion model of VSSS for synapse growth, incorporating the recent observation from super-resolution microscopy that neural activity can build compositional heterogeneities within synaptic domains. We find that introducing such heterogeneities can change the stable domain size in a controlled manner. We discuss a potential connection between this model and experimental data on synapse sizes, and how it provides a possible mechanism to structurally encode graded long-term memory. We acknowledge the support from NSF INSPIRE Award number IOS-1526941 (KL, MFH, JL) and the Brandeis Center for Bioinspired Soft Materials, an NSF MRSEC, DMR- 1420382 (MFH).

  2. Fear learning increases the number of polyribosomes associated with excitatory and inhibitory synapses in the barrel cortex.

    Directory of Open Access Journals (Sweden)

    Malgorzata Jasinska

    Full Text Available Associative fear learning, resulting from whisker stimulation paired with application of a mild electric shock to the tail in a classical conditioning paradigm, changes the motor behavior of mice and modifies the cortical functional representation of sensory receptors involved in the conditioning. It also induces the formation of new inhibitory synapses on double-synapse spines of the cognate barrel hollows. We studied density and distribution of polyribosomes, the putative structural markers of enhanced synaptic activation, following conditioning. By analyzing serial sections of the barrel cortex by electron microscopy and stereology, we found that the density of polyribosomes was significantly increased in dendrites of the barrel activated during conditioning. The results revealed fear learning-induced increase in the density of polyribosomes associated with both excitatory and inhibitory synapses located on dendritic spines (in both single- and double-synapse spines and only with the inhibitory synapses located on dendritic shafts. This effect was accompanied by a significant increase in the postsynaptic density area of the excitatory synapses on single-synapse spines and of the inhibitory synapses on double-synapse spines containing polyribosomes. The present results show that associative fear learning not only induces inhibitory synaptogenesis, as demonstrated in the previous studies, but also stimulates local protein synthesis and produces modifications of the synapses that indicate their potentiation.

  3. Response to Request for Guidance on PSD Definition Referencing Cogeneration Gas Turbines that are Separated by One-Half Mile

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  4. Determination of the Applicability of NSPS and PSD to Stationary Gas Turbines Converting From Middle Distillates to Natural Gas

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  5. Effects of dimeric PSD-95 inhibition on excitotoxic cell death and outcome after controlled cortical impact in rats

    DEFF Research Database (Denmark)

    Sommer, Jens Bak; Bach, Anders; Rytter, Hana Malá

    2017-01-01

    be an effective therapeutic strategy in TBI. The objectives of the present study were to assess the effects of a dimeric inhibitor of PSD-95, UCCB01-144, on excitotoxic cell death in vitro and outcome after experimental TBI in rats in vivo. In addition, the pharmacokinetic parameters of UCCB01-144 were...... assessed in a water maze at two weeks post-trauma, and at four weeks lesion volumes were estimated. Overall, UCCB01-144 did not protect against NMDA-toxicity in neuronal cultures or experimental TBI in rats. Important factors that should be investigated further in future studies assessing the effects...

  6. PSD Applicability Analysis for a Past Change at the Georgia-Pacific Taylorsville Facility Particleboard Plant, Taylorsville, Mississippi

    Science.gov (United States)

    This document may be of assistance in applying the New Source Review (NSR) air permitting regulations including the Prevention of Significant Deterioration (PSD) requirements. This document is part of the NSR Policy and Guidance Database. Some documents in the database are a scanned or retyped version of a paper photocopy of the original. Although we have taken considerable effort to quality assure the documents, some may contain typographical errors. Contact the office that issued the document if you need a copy of the original.

  7. Cell Biological Mechanisms of Activity-Dependent Synapse to Nucleus Translocation of CRTC1 in Neurons

    Directory of Open Access Journals (Sweden)

    Toh Hean eCh'ng

    2015-09-01

    Full Text Available Previous studies have revealed a critical role for CREB-regulated transcriptional coactivator (CRTC1 in regulating neuronal gene expression during learning and memory. CRTC1 localizes to synapses but undergoes activity-dependent nuclear translocation to regulate the transcription of CREB target genes. Here we investigate the long-distance retrograde transport of CRTC1 in hippocampal neurons. We show that local elevations in calcium, triggered by activation of synaptic glutamate receptors and L-type voltage-gated calcium channels, initiate active, dynein-mediated retrograde transport of CRTC1 along microtubules. We identify a nuclear localization signal within CRTC1, and characterize three conserved serine residues whose dephosphorylation is required for nuclear import. Domain analysis reveals that the amino-terminal third of CRTC1 contains all of the signals required for regulated nucleocytoplasmic trafficking. We fuse this region to Dendra2 to generate a reporter construct and perform live-cell imaging coupled with local uncaging of glutamate and photoconversion to characterize the dynamics of stimulus-induced retrograde transport and nuclear accumulation.

  8. Cell biological mechanisms of activity-dependent synapse to nucleus translocation of CRTC1 in neurons.

    Science.gov (United States)

    Ch'ng, Toh Hean; DeSalvo, Martina; Lin, Peter; Vashisht, Ajay; Wohlschlegel, James A; Martin, Kelsey C

    2015-01-01

    Previous studies have revealed a critical role for CREB-regulated transcriptional coactivator (CRTC1) in regulating neuronal gene expression during learning and memory. CRTC1 localizes to synapses but undergoes activity-dependent nuclear translocation to regulate the transcription of CREB target genes. Here we investigate the long-distance retrograde transport of CRTC1 in hippocampal neurons. We show that local elevations in calcium, triggered by activation of glutamate receptors and L-type voltage-gated calcium channels, initiate active, dynein-mediated retrograde transport of CRTC1 along microtubules. We identify a nuclear localization signal within CRTC1, and characterize three conserved serine residues whose dephosphorylation is required for nuclear import. Domain analysis reveals that the amino-terminal third of CRTC1 contains all of the signals required for regulated nucleocytoplasmic trafficking. We fuse this region to Dendra2 to generate a reporter construct and perform live-cell imaging coupled with local uncaging of glutamate and photoconversion to characterize the dynamics of stimulus-induced retrograde transport and nuclear accumulation.

  9. Synapse Stability in the Precuneus Early in the Progression of Alzheimer’s Disease

    Science.gov (United States)

    Scheff, S. W.; Price, D.A.; Schmitt, F.A.; Roberts, K.N.; Ikonomovic, M.D.; Mufson, E.J.

    2014-01-01

    Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the progression from no cognitive impairment (NCI) to Alzheimer’s disease (AD). Individuals with aMCI have increased levels of AD-type neuropathology in multiple regions of the neocortex and hippocampus and demonstrate a loss of synaptic connectivity. Recent neuroimaging studies have reported increased levels of 11C-PiB (Pittsburgh, compound B) in regions of the neocortex including the precuneus region of the medial parietal lobe. This cortical region has been implicated in episodic memory, which is disrupted early in the progression of AD. In this study, unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the precuneus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI did not reveal a statistically significant decline in total synapses compared to the NCI cohort while the AD group did show a modest but significant decline. Synaptic numbers failed to correlate with several different cognitive tasks including the Mini Mental State Examination scores and episodic memory scores. Although levels of [3H]PiB binding were elevated in both the aMCI and AD groups, it did not strongly correlate with synaptic counts. These results support the idea that despite increased amyloid load, the precuneus region does not show early changes in synaptic decline during the progression of AD. PMID:23478309

  10. Exosomal transfer of proteins and RNAs at synapses in the nervous system

    Directory of Open Access Journals (Sweden)

    Smalheiser Neil R

    2007-11-01

    Full Text Available Abstract Background Many cell types have been reported to secrete small vesicles called exosomes, that are derived from multivesicular bodies and that can also form from endocytic-like lipid raft domains of the plasma membrane. Secretory exosomes contain a characteristic composition of proteins, and a recent report indicates that mast cell exosomes harbor a variety of mRNAs and microRNAs as well. Exosomes express cell recognition molecules on their surface that facilitate their selective targeting and uptake into recipient cells. Results In this review, I suggest that exosomal secretion of proteins and RNAs may be a fundamental mode of communication within the nervous system, supplementing the known mechanisms of anterograde and retrograde signaling across synapses. In one specific scenario, exosomes are proposed to bud from the lipid raft region of the postsynaptic membrane adjacent to the postsynaptic density, in a manner that is stimulated by stimuli that elicit long-term potentiation. The exosomes would then transfer newly synthesized synaptic proteins (such as CAM kinase II alpha and synaptic RNAs to the presynaptic terminal, where they would contribute to synaptic plasticity. Conclusion The model is consistent with the known cellular and molecular features of synaptic neurobiology and makes a number of predictions that can be tested in vitro and in vivo. Open peer review Reviewed by Etienne Joly, Gaspar Jekely, Juergen Brosius and Eugene Koonin. For the full reviews, please go to the Reviewers' comments section.

  11. Effect of synapse dilution on the memory retrieval in structured attractor neural networks

    Science.gov (United States)

    Brunel, N.

    1993-08-01

    We investigate a simple model of structured attractor neural network (ANN). In this network a module codes for the category of the stored information, while another group of neurons codes for the remaining information. The probability distribution of stabilities of the patterns and the prototypes of the categories are calculated, for two different synaptic structures. The stability of the prototypes is shown to increase when the fraction of neurons coding for the category goes down. Then the effect of synapse destruction on the retrieval is studied in two opposite situations : first analytically in sparsely connected networks, then numerically in completely connected ones. In both cases the behaviour of the structured network and that of the usual homogeneous networks are compared. When lesions increase, two transitions are shown to appear in the behaviour of the structured network when one of the patterns is presented to the network. After the first transition the network recognizes the category of the pattern but not the individual pattern. After the second transition the network recognizes nothing. These effects are similar to syndromes caused by lesions in the central visual system, namely prosopagnosia and agnosia. In both types of networks (structured or homogeneous) the stability of the prototype is greater than the stability of individual patterns, however the first transition, for completely connected networks, occurs only when the network is structured.

  12. Detergent-dependent separation of postsynaptic density, membrane rafts and other subsynaptic structures from the synaptic plasma membrane of rat forebrain.

    Science.gov (United States)

    Zhao, LiYing; Sakagami, Hiroyuki; Suzuki, Tatsuo

    2014-10-01

    We systematically investigated the purification process of post-synaptic density (PSD) and post-synaptic membrane rafts (PSRs) from the rat forebrain synaptic plasma membranes by examining the components and the structures of the materials obtained after the treatment of synaptic plasma membranes with TX-100, n-octyl β-d-glucoside (OG) or 3-([3-cholamidopropyl]dimethylammonio)-2-hydroxy-1-propanesulfonate (CHAPSO). These three detergents exhibited distinct separation profiles for the synaptic subdomains. Type I and type II PSD proteins displayed mutually exclusive distribution. After TX-100 treatment, type I PSD was recovered in two fractions: a pellet and an insoluble fraction 8, which contained partially broken PSD-PSR complexes. Conventional PSD was suggested to be a mixture of these two PSD pools and did not contain type II PSD. An association of type I PSD with PSRs was identified in the TX-100 treatment, and those with type II PSD in the OG and CHAPSO treatments. An association of GABA receptors with gephyrin was easily dissociated. OG at a high concentration solubilized the type I PSD proteins. CHAPSO treatment resulted in a variety of distinct fractions, which contained certain novel structures. Two different pools of GluA, either PSD or possibly raft-associated, were identified in the OG and CHAPSO treatments. These results are useful in advancing our understanding of the structural organization of synapses at the molecular level. We systematically investigated the purification process of post-synaptic density (PSD) and synaptic membrane rafts by examining the structures obtained after treatment of the SPMs with TX-100, n-octyl β-d-glucoside or CHAPSO. Differential distribution of type I and type II PSD, synaptic membrane rafts, and other novel subdomains in the SPM give clues to understand the structural organization of synapses at the molecular level. © 2014 International Society for Neurochemistry.

  13. ELKS controls the pool of readily releasable vesicles at excitatory synapses through its N-terminal coiled-coil domains.

    Science.gov (United States)

    Held, Richard G; Liu, Changliang; Kaeser, Pascal S

    2016-06-02

    In a presynaptic nerve terminal, synaptic strength is determined by the pool of readily releasable vesicles (RRP) and the probability of release (P) of each RRP vesicle. These parameters are controlled at the active zone and vary across synapses, but how such synapse specific control is achieved is not understood. ELKS proteins are enriched at vertebrate active zones and enhance P at inhibitory hippocampal synapses, but ELKS functions at excitatory synapses are not known. Studying conditional knockout mice for ELKS, we find that ELKS enhances the RRP at excitatory synapses without affecting P. Surprisingly, ELKS C-terminal sequences, which interact with RIM, are dispensable for RRP enhancement. Instead, the N-terminal ELKS coiled-coil domains that bind to Liprin-α and Bassoon are necessary to control RRP. Thus, ELKS removal has differential, synapse-specific effects on RRP and P, and our findings establish important roles for ELKS N-terminal domains in synaptic vesicle priming.

  14. Indoor Positioning System Based on a PSD Detector, Precise Positioning of Agents in Motion Using AoA Techniques.

    Science.gov (United States)

    Rodríguez-Navarro, David; Lázaro-Galilea, José Luis; De-La-Llana-Calvo, Álvaro; Bravo-Muñoz, Ignacio; Gardel-Vicente, Alfredo; Tsirigotis, Georgios; Iglesias-Miguel, Juan

    2017-09-15

    Here, we present an indoor positioning system (IPS) for detecting mobile agents based on a single Position Sensitive Device sensor (PSD) sited in the environment and InfraRed Emitter Diode (IRED) located on mobile agents. The main goal of the work is to develop an alternative IPS to other sensing technologies, cheaper, easier to install and with a low computational load to obtain a high rate of measurements per second. The proposed IPS has the capacity to accurately determine 3D position from the angle of arrival (AoA) of the signal received at the PSD sensor. In this first approach to the method, the agents are considered to move along a plane. We propose two alternatives for determining position: in one, tones are emitted on a frequency unique to each transmitter, while in the other, sequences are emitted.The paper proposes and set up a very simple and easy to deploy system capable of performing 3D positioning with a single analog sensor, obtaining a high accurate positioning and a reduced execution time for the signal processing. The low computational load of the IPS makes it possible to obtain a very high position update rate (more than 100 times per second), yielding millimetric accuracies.

  15. Presynaptic [Ca2+] and GCAPs: aspects on the structure and function of photoreceptor ribbon synapses

    Directory of Open Access Journals (Sweden)

    Frank eSchmitz

    2014-02-01

    Full Text Available Changes in intracellular calcium ions [Ca2+] play important roles in photoreceptor signalling. Consequently, intracellular [Ca2+] levels need to be tightly controlled. In the light-sensitive outer segments (OS of photoreceptors, Ca2+ regulates the activity of retinal guanylate cyclases (ret-GCs thus playing a central role in phototransduction and light-adaptation by restoring light-induced decreases in cGMP. In the synaptic terminals, changes of intracellular Ca2+ trigger various aspects of neurotransmission. Photoreceptors employ tonically active ribbon synapses that encode light-induced, graded changes of membrane potential into different rates of synaptic vesicle exocytosis. The active zones of ribbon synapses contain large electron-dense structures, synaptic ribbons, that are associated with large numbers of synaptic vesicles. Synaptic coding at ribbon synapses differs from synaptic coding at conventional (phasic synapses. Recent studies revealed new insights how synaptic ribbons are involved in this process. This review focuses on the regulation of [Ca2+] in presynaptic photoreceptor terminals and on the function of a particular Ca2+-regulated protein, the neuronal calcium sensor protein GCAP2 (guanylate cyclase-activating protein-2 in the photoreceptor ribbon synapse. GCAP2, an EF hand-containing protein plays multiple roles in the OS and in the photoreceptor synapse. In the OS, GCAP2 works as a Ca2+-sensor within a Ca2+-regulated feedback loop that adjusts cGMP levels. In the photoreceptor synapse, GCAP2 binds to RIBEYE, a component of synaptic ribbons, and mediates Ca2+-dependent plasticity at that site. Possible mechanisms are discussed.

  16. Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse

    Science.gov (United States)

    Choudhuri, Kaushik; Llodrá, Jaime; Roth, Eric W.; Tsai, Jones; Gordo, Susana; Wucherpfennig, Kai W.; Kam, Lance C.; Stokes, David L.; Dustin, Michael L.

    2014-03-01

    The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse, which is characterized by central accumulation of TCRs, adjacent to a secretory domain, both surrounded by an adhesive ring. Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function, this domain is itself largely devoid of TCR signalling activity, and is characterized by an unexplained immobilization of TCR-pMHC complexes relative to the highly dynamic immunological synapse periphery. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These

  17. Functional hallmarks of GABAergic synapse maturation and the diverse roles of neurotrophins

    Directory of Open Access Journals (Sweden)

    Rosemarie eGrantyn

    2011-07-01

    Full Text Available Functional impairment of the adult brain can result from deficits in the ontogeny of GABAergic synaptic transmission. Gene defects underlying autism spectrum disorders, Rett’s syndrome or some forms of epilepsy, but also a diverse set of syndromes accompanying perinatal trauma, hormonal imbalances, intake of sleep-inducing or mood-improving drugs or, quite common, alcohol intake during pregnancy can alter GABA signaling early in life. The search for therapeutically relevant endogenous molecules or exogenous compounds able to alleviate the consequences of dysfunction of GABAergic transmission in the embryonic or postnatal brain requires a clear understanding of its site- and state-dependent development. At the level of single synapses, it is necessary to discriminate between presynaptic and postsynaptic alterations, and to define parameters that can be regarded as both suitable and accessible for the quantification of developmental changes. Here we focus on the performance of GABAergic synapses in two brain structures, the hippocampus and the superior colliculus, describe some novel aspects of neurotrophin effects during the development of GABAergic synaptic transmission and examine the applicability of the following rules: 1 Synaptic transmission starts with GABA, 2 Nascent/immature GABAergic synapses operate in a ballistic mode (multivesicular release, 3 Immature synaptic terminals release vesicles with higher probability than mature synapses, 4 Immature GABAergic synapses are prone to paired pulse and tetanic depression, 5 Synapse maturation is characterized by an increasing dominance of synchronous over asynchronous release, 6 In immature neurons GABA acts as a depolarizing transmitter, 7 Synapse maturation implies IPSC shortening due to an increase in alpha1 subunit expression, 8 Extrasynaptic (tonic conductances can inhibit the development of synaptic (phasic GABA actions.

  18. Toxoplasma gondii Infections Alter GABAergic Synapses and Signaling in the Central Nervous System

    Science.gov (United States)

    Brooks, Justin M.; Carrillo, Gabriela L.; Su, Jianmin; Lindsay, David S.; Blader, Ira J.

    2015-01-01

    ABSTRACT During infections with the protozoan parasite Toxoplasma gondii, gamma-aminobutyric acid (GABA) is utilized as a carbon source for parasite metabolism and also to facilitate parasite dissemination by stimulating dendritic-cell motility. The best-recognized function for GABA, however, is its role in the nervous system as an inhibitory neurotransmitter that regulates the flow and timing of excitatory neurotransmission. When this pathway is altered, seizures develop. Human toxoplasmosis patients suffer from seizures, suggesting that Toxoplasma interferes with GABA signaling in the brain. Here, we show that while excitatory glutamatergic presynaptic proteins appeared normal, infection with type II ME49 Toxoplasma tissue cysts led to global changes in the distribution of glutamic acid decarboxylase 67 (GAD67), a key enzyme that catalyzes GABA synthesis in the brain. Alterations in GAD67 staining were not due to decreased expression but rather to a change from GAD67 clustering at presynaptic termini to a more diffuse localization throughout the neuropil. Consistent with a loss of GAD67 from the synaptic terminals, Toxoplasma-infected mice develop spontaneous seizures and are more susceptible to drugs that induce seizures by antagonizing GABA receptors. Interestingly, GABAergic protein mislocalization and the response to seizure-inducing drugs were observed in mice infected with type II ME49 but not type III CEP strain parasites, indicating a role for a polymorphic parasite factor(s) in regulating GABAergic synapses. Taken together, these data support a model in which seizures and other neurological complications seen in Toxoplasma-infected individuals are due, at least in part, to changes in GABAergic signaling. PMID:26507232

  19. Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions

    DEFF Research Database (Denmark)

    Bach, Anders

    2015-01-01

    ZL006 and IC87201 have been presented as efficient inhibitors of the nNOS/PSD-95 protein-protein interaction and shown great promise in cellular experiments and animal models of ischemic stroke and pain. Here, we investigate the proposed mechanism of action of ZL006 and IC87201 using biochemical...... and biophysical methods, such as fluorescence polarization (FP), isothermal titration calorimetry (ITC), and (1)H-(15)N HSQC NMR. Our data show that under the applied in vitro conditions, ZL006 and IC87201 do not interact with the PDZ domains of nNOS or PSD-95, nor inhibit the nNOS-PDZ/PSD-95-PDZ interface...... by interacting with the β-finger of nNOS-PDZ. Our findings have implications for further medicinal chemistry efforts of ZL006, IC87201 and analogues, and challenge the general and widespread view on their mechanism of action....

  20. Investigation of the Deposition and Densification Parameters on the Mechanical Properties of Pressurized Spray Deposited (PSD) 3-D Printed Ceramic Components

    Energy Technology Data Exchange (ETDEWEB)

    Menchhofer, Paul A [ORNL; Becker, Benjamin [Hot End Works

    2016-07-28

    Oak Ridge National Laboratory (ORNL) and HotEnd Works teamed to investigate the use of pressurized spray deposition (PSD) technology for the production of ceramic parts via additive manufacturing. Scanning electron microscopy of sintered parts provided by HotEnd Works revealed voids large enough to compromise the mechanical properties of PSD manufactured parts. Scanning electron microscopy and particle size analysis of the alumina oxide powder feedstocks indicated that the powders contained some large particles and some agglomerations in the powder. Further classification of the powder feedstocks and removal of the agglomerates by sonication in the liquid used for the PSD process are recommended. Analysis of sintered parts indicated that the sonic modulus for the alumina part is consistent with other known values for alumina. The density for this part was determined by standard Archimedes immersion density methods and was found to be > 99.7 % of the theoretical density for pure alumina.

  1. PSD95 suppresses dendritic arbor development in mature hippocampal neurons by occluding the clustering of NR2B-NMDA receptors.

    Directory of Open Access Journals (Sweden)

    Fernando J Bustos

    Full Text Available Considerable evidence indicates that the NMDA receptor (NMDAR subunits NR2A and NR2B are critical mediators of synaptic plasticity and dendritogenesis; however, how they differentially regulate these processes is unclear. Here we investigate the roles of the NR2A and NR2B subunits, and of their scaffolding proteins PSD-95 and SAP102, in remodeling the dendritic architecture of developing hippocampal neurons (2-25 DIV. Analysis of the dendritic architecture and the temporal and spatial expression patterns of the NMDARs and anchoring proteins in immature cultures revealed a strong positive correlation between synaptic expression of the NR2B subunit and dendritogenesis. With maturation, the pruning of dendritic branches was paralleled by a strong reduction in overall and synaptic expression of NR2B, and a significant elevation in synaptic expression of NR2A and PSD95. Using constructs that alter the synaptic composition, we found that either over-expression of NR2B or knock-down of PSD95 by shRNA-PSD95 augmented dendritogenesis in immature neurons. Reactivation of dendritogenesis could also be achieved in mature cultured neurons, but required both manipulations simultaneously, and was accompanied by increased dendritic clustering of NR2B. Our results indicate that the developmental increase in synaptic expression of PSD95 obstructs the synaptic clustering of NR2B-NMDARs, and thereby restricts reactivation of dendritic branching. Experiments with shRNA-PSD95 and chimeric NR2A/NR2B constructs further revealed that C-terminus of the NR2B subunit (tail was sufficient to induce robust dendritic branching in mature hippocampal neurons, and suggest that the NR2B tail is important in recruiting calcium-dependent signaling proteins and scaffolding proteins necessary for dendritogenesis.

  2. Optimal and Local Connectivity Between Neuron and Synapse Array in the Quantum Dot/Silicon Brain

    Science.gov (United States)

    Duong, Tuan A.; Assad, Christopher; Thakoor, Anikumar P.

    2010-01-01

    This innovation is used to connect between synapse and neuron arrays using nanowire in quantum dot and metal in CMOS (complementary metal oxide semiconductor) technology to enable the density of a brain-like connection in hardware. The hardware implementation combines three technologies: 1. Quantum dot and nanowire-based compact synaptic cell (50x50 sq nm) with inherently low parasitic capacitance (hence, low dynamic power approx.l0(exp -11) watts/synapse), 2. Neuron and learning circuits implemented in 50-nm CMOS technology, to be integrated with quantum dot and nanowire synapse, and 3. 3D stacking approach to achieve the overall numbers of high density O(10(exp 12)) synapses and O(10(exp 8)) neurons in the overall system. In a 1-sq cm of quantum dot layer sitting on a 50-nm CMOS layer, innovators were able to pack a 10(exp 6)-neuron and 10(exp 10)-synapse array; however, the constraint for the connection scheme is that each neuron will receive a non-identical 10(exp 4)-synapse set, including itself, via its efficacy of the connection. This is not a fully connected system where the 100x100 synapse array only has a 100-input data bus and 100-output data bus. Due to the data bus sharing, it poses a great challenge to have a complete connected system, and its constraint within the quantum dot and silicon wafer layer. For an effective connection scheme, there are three conditions to be met: 1. Local connection. 2. The nanowire should be connected locally, not globally from which it helps to maximize the data flow by sharing the same wire space location. 3. Each synapse can have an alternate summation line if needed (this option is doable based on the simple mask creation). The 10(exp 3)x10(exp 3)-neuron array was partitioned into a 10-block, 10(exp 2)x10(exp 3)-neuron array. This building block can be completely mapped within itself (10,000 synapses to a neuron).

  3. Extracellular proteolysis in structural and functional plasticity of mossy fiber synapses in hippocampus

    Directory of Open Access Journals (Sweden)

    Grzegorz eWiera

    2015-11-01

    Full Text Available Brain is continuously altered in response to experience and environmental changes. One of the underlying mechanisms is synaptic plasticity, which is manifested by modification of synapse structure and function. It is becoming clear that regulated extracellular proteolysis plays a pivotal role in the structural and functional remodeling of synapses during brain development, learning and memory formation. Clearly, plasticity mechanisms may substantially differ between projections. Mossy fiber synapses onto CA3 pyramidal cells display several unique functional features, including pronounced short-term facilitation, a presynaptically expressed LTP that is independent of NMDAR activation, and NMDA-dependent metaplasticity. Moreover, structural plasticity at mossy fiber synapses ranges from the reorganization of projection topology after hippocampus-dependent learning, through intrinsically different dynamic properties of synaptic boutons to pre- and postsynaptic structural changes accompanying LTP induction. Although concomitant functional and structural plasticity in this pathway strongly suggests a role of extracellular proteolysis, its impact only starts to be investigated in this projection. In the present report, we review the role of extracellular proteolysis in various aspects of synaptic plasticity in hippocampal mossy fiber synapses. A growing body of evidence demonstrates that among perisynaptic proteases, tPA/plasmin system, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1 and metalloproteinases play a crucial role in shaping plastic changes in this projection. We discuss recent advances and emerging hypotheses on the roles of proteases in mechanisms underlying mossy fiber target specific synaptic plasticity and memory formation.

  4. 3D reconstruction of synapses with deep learning based on EM Images

    Science.gov (United States)

    Xiao, Chi; Rao, Qiang; Zhang, Dandan; Chen, Xi; Han, Hua; Xie, Qiwei

    2017-03-01

    Recently, due to the rapid development of electron microscope (EM) with its high resolution, stacks delivered by EM can be used to analyze a variety of components that are critical to understand brain function. Since synaptic study is essential in neurobiology and can be analyzed by EM stacks, the automated routines for reconstruction of synapses based on EM Images can become a very useful tool for analyzing large volumes of brain tissue and providing the ability to understand the mechanism of brain. In this article, we propose a novel automated method to realize 3D reconstruction of synapses for Automated Tapecollecting Ultra Microtome Scanning Electron Microscopy (ATUM-SEM) with deep learning. Being different from other reconstruction algorithms, which employ classifier to segment synaptic clefts directly. We utilize deep learning method and segmentation algorithm to obtain synaptic clefts as well as promote the accuracy of reconstruction. The proposed method contains five parts: (1) using modified Moving Least Square (MLS) deformation algorithm and Scale Invariant Feature Transform (SIFT) features to register adjacent sections, (2) adopting Faster Region Convolutional Neural Networks (Faster R-CNN) algorithm to detect synapses, (3) utilizing screening method which takes context cues of synapses into consideration to reduce the false positive rate, (4) combining a practical morphology algorithm with a suitable fitting function to segment synaptic clefts and optimize the shape of them, (5) applying the plugin in FIJI to show the final 3D visualization of synapses. Experimental results on ATUM-SEM images demonstrate the effectiveness of our proposed method.

  5. Molecular switches at the synapse emerge from receptor and kinase traffic.

    Directory of Open Access Journals (Sweden)

    Arnold Hayer

    2005-07-01

    Full Text Available Changes in the synaptic connection strengths between neurons are believed to play a role in memory formation. An important mechanism for changing synaptic strength is through movement of neurotransmitter receptors and regulatory proteins to and from the synapse. Several activity-triggered biochemical events control these movements. Here we use computer models to explore how these putative memory-related changes can be stabilised long after the initial trigger, and beyond the lifetime of synaptic molecules. We base our models on published biochemical data and experiments on the activity-dependent movement of a glutamate receptor, AMPAR, and a calcium-dependent kinase, CaMKII. We find that both of these molecules participate in distinct bistable switches. These simulated switches are effective for long periods despite molecular turnover and biochemical fluctuations arising from the small numbers of molecules in the synapse. The AMPAR switch arises from a novel self-recruitment process where the presence of sufficient receptors biases the receptor movement cycle to insert still more receptors into the synapse. The CaMKII switch arises from autophosphorylation of the kinase. The switches may function in a tightly coupled manner, or relatively independently. The latter case leads to multiple stable states of the synapse. We propose that similar self-recruitment cycles may be important for maintaining levels of many molecules that undergo regulated movement, and that these may lead to combinatorial possible stable states of systems like the synapse.

  6. Neuron-NG2 Cell Synapses: Novel Functions for Regulating NG2 Cell Proliferation and Differentiation

    Directory of Open Access Journals (Sweden)

    Qian-Kun Yang

    2013-01-01

    Full Text Available NG2 cells are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes, and microglia. These cells can be identified by their NG2 proteoglycan expression. NG2 cells have a highly branched morphology, with abundant processes radiating from the cell body, and express a complex set of voltage-gated channels, AMPA/kainate, and GABA receptors. Neurons notably form classical and nonclassical synapses with NG2 cells, which have varied characteristics and functions. Neuron-NG2 cell synapses could fine-tune NG2 cell activities, including the NG2 cell cycle, differentiation, migration, and myelination, and may be a novel potential therapeutic target for NG2 cell-related diseases, such as hypoxia-ischemia injury and periventricular leukomalacia. Furthermore, neuron-NG2 cell synapses may be correlated with the plasticity of CNS in adulthood with the synaptic contacts passing onto their progenies during proliferation, and synaptic contacts decrease rapidly upon NG2 cell differentiation. In this review, we highlight the characteristics of classical and nonclassical neuron-NG2 cell synapses, the potential functions, and the fate of synaptic contacts during proliferation and differentiation, with the emphasis on the regulation of the NG2 cell cycle by neuron-NG2 cell synapses and their potential underlying mechanisms.

  7. Whisker Deprivation Drives Two Phases of Inhibitory Synapse Weakening in Layer 4 of Rat Somatosensory Cortex.

    Directory of Open Access Journals (Sweden)

    Melanie A Gainey

    Full Text Available Inhibitory synapse development in sensory neocortex is experience-dependent, with sustained sensory deprivation yielding fewer and weaker inhibitory synapses. Whether this represents arrest of synapse maturation, or a more complex set of processes, is unclear. To test this, we measured the dynamics of inhibitory synapse development in layer 4 of rat somatosensory cortex (S1 during continuous whisker deprivation from postnatal day 7, and in age-matched controls. In deprived columns, spontaneous miniature inhibitory postsynaptic currents (mIPSCs and evoked IPSCs developed normally until P15, when IPSC amplitude transiently decreased, recovering by P16 despite ongoing deprivation. IPSCs remained normal until P22, when a second, sustained phase of weakening began. Delaying deprivation onset by 5 days prevented the P15 weakening. Both early and late phase weakening involved measurable reduction in IPSC amplitude relative to prior time points. Thus, deprivation appears to drive two distinct phases of active IPSC weakening, rather than simple arrest of synapse maturation.

  8. The urodelean Mauthner cell. Morphology of the afferent synapses to the M-cell of larval Salamandra salamandra

    Energy Technology Data Exchange (ETDEWEB)

    Cioni, C.; De Palma, F.; De Vito, L.; Stefanelli, A. [Rome, Univ. (Italy). Dipt. di Biologia Animale e dell`Uomo

    1997-12-31

    In the present work the fine morphology and the distribution of the afferent synapses to the Mauthner cell of larval Salamandra salamandra are described. The aim of the study is to characterize the synaptic bed in the larvae of this terrestrial salamander in order to compare it with that of larval axolotl and larval anurans. Four main types of afferent endings have been identified: myelinated club endings, round-vesicle end bulbs, flattened-vesicle end bulbs and spiral fibers endings. The M-cell afferent synaptology of larval stages of terrestrial amphibians is quite similar to that previously observed in larval stages of aquatic species. This fact can be related to the fundamental similarities between the larval lifestyles.

  9. Physical Realization of a Supervised Learning System Built with Organic Memristive Synapses

    Science.gov (United States)

    Lin, Yu-Pu; Bennett, Christopher H.; Cabaret, Théo; Vodenicarevic, Damir; Chabi, Djaafar; Querlioz, Damien; Jousselme, Bruno; Derycke, Vincent; Klein, Jacques-Olivier

    2016-09-01

    Multiple modern applications of electronics call for inexpensive chips that can perform complex operations on natural data with limited energy. A vision for accomplishing this is implementing hardware neural networks, which fuse computation and memory, with low cost organic electronics. A challenge, however, is the implementation of synapses (analog memories) composed of such materials. In this work, we introduce robust, fastly programmable, nonvolatile organic memristive nanodevices based on electrografted redox complexes that implement synapses thanks to a wide range of accessible intermediate conductivity states. We demonstrate experimentally an elementary neural network, capable of learning functions, which combines four pairs of organic memristors as synapses and conventional electronics as neurons. Our architecture is highly resilient to issues caused by imperfect devices. It tolerates inter-device variability and an adaptable learning rule offers immunity against asymmetries in device switching. Highly compliant with conventional fabrication processes, the system can be extended to larger computing systems capable of complex cognitive tasks, as demonstrated in complementary simulations.

  10. Plant synapses: actin-based domains for cell-to-cell communication.

    Science.gov (United States)

    Baluska, Frantisek; Volkmann, Dieter; Menzel, Diedrik

    2005-03-01

    For many years it has been known that plants perform rapid long-distance signalling using classical action potentials that have impacts on diverse processes in plants. Plants also synthesize numerous neuronal molecules and fulfill some criteria for intelligent behaviour. Analysis of recent breakthrough data from ecophysiology studies has revealed that plant roots can discriminate between 'self' and 'non-self'; in animals, this ability to discriminate is dependent on the activities of neuronal synapses. Here, we propose that plant cells establish modes of information exchange between each other that have properties in common with neuronal synapses. Moreover, plants also assemble adhesive contacts that orchestrate cell-to-cell communication between the host cells when challenged with pathogens, parasites and potential symbionts. We propose that these adhesive contacts resemble the immunological synapses found in animals.

  11. Physical Realization of a Supervised Learning System Built with Organic Memristive Synapses.

    Science.gov (United States)

    Lin, Yu-Pu; Bennett, Christopher H; Cabaret, Théo; Vodenicarevic, Damir; Chabi, Djaafar; Querlioz, Damien; Jousselme, Bruno; Derycke, Vincent; Klein, Jacques-Olivier

    2016-09-07

    Multiple modern applications of electronics call for inexpensive chips that can perform complex operations on natural data with limited energy. A vision for accomplishing this is implementing hardware neural networks, which fuse computation and memory, with low cost organic electronics. A challenge, however, is the implementation of synapses (analog memories) composed of such materials. In this work, we introduce robust, fastly programmable, nonvolatile organic memristive nanodevices based on electrografted redox complexes that implement synapses thanks to a wide range of accessible intermediate conductivity states. We demonstrate experimentally an elementary neural network, capable of learning functions, which combines four pairs of organic memristors as synapses and conventional electronics as neurons. Our architecture is highly resilient to issues caused by imperfect devices. It tolerates inter-device variability and an adaptable learning rule offers immunity against asymmetries in device switching. Highly compliant with conventional fabrication processes, the system can be extended to larger computing systems capable of complex cognitive tasks, as demonstrated in complementary simulations.

  12. Unsupervised learning by spike timing dependent plasticity in phase change memory (PCM synapses

    Directory of Open Access Journals (Sweden)

    Stefano eAmbrogio

    2016-03-01

    Full Text Available We present a novel one-transistor/one-resistor (1T1R synapse for neuromorphic networks, based on phase change memory (PCM technology. The synapse is capable of spike-timing dependent plasticity (STDP, where gradual potentiation relies on set transition, namely crystallization, in the PCM, while depression is achieved via reset or amorphization of a chalcogenide active volume. STDP characteristics are demonstrated by experiments under variable initial conditions and number of pulses. Finally, we support the applicability of the 1T1R synapse for learning and recognition of visual patterns by simulations of fully connected neuromorphic networks with 2 or 3 layers with high recognition efficiency. The proposed scheme provides a feasible low-power solution for on-line unsupervised machine learning in smart reconfigurable sensors.

  13. δ-Catenin Regulates Spine and Synapse Morphogenesis and Function in Hippocampal Neurons during Development

    Science.gov (United States)

    Arikkath, Jyothi; Peng, I-Feng; Ng, Yu Gie; Israely, Inbal; Liu, Xin; Ullian, Erik M.; Reichardt, Louis F.

    2009-01-01

    The maintenance of spine and synapse number during development is critical for neuronal circuit formation and function. Here we show that δ-catenin, a component of the cadherin-catenin cell adhesion complex, regulates spine and synapse morphogenesis during development. Genetic ablation or acute knockdown of δ-catenin leads to increases in spine and synapse density, accompanied by a decrease in tetrodotoxin induced spine plasticity. Our results indicate that δ-catenin may mediate conversion of activity-dependent signals to morphological spine plasticity. The functional role of δ-catenin in regulating spine density does not require binding to cadherins, but does require interactions with PDZ domain-containing proteins. We propose that the perturbations in spine and synaptic structure and function observed after depletion of δ-catenin during development may contribute to functional alterations in neural circuitry, the cognitive deficits observed in mutant mice, and the mental retardation pathology of Cri-du-chat syndrome. PMID:19403811

  14. Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses

    Science.gov (United States)

    Trouche, Stéphanie; Sasaki, Jennifer M.; Tu, Tiffany; Reijmers, Leon G.

    2013-01-01

    SUMMARY A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. PMID:24183705

  15. Acid-Sensing Ion Channels Activated by Evoked Released Protons Modulate Synaptic Transmission at the Mouse Calyx of Held Synapse.

    Science.gov (United States)

    González-Inchauspe, Carlota; Urbano, Francisco J; Di Guilmi, Mariano N; Uchitel, Osvaldo D

    2017-03-08

    Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in neurodegenerative diseases. We found that these channels can be activated in neurons of the medial nucleus of the trapezoid body (MNTB) of the auditory system in the CNS. A drop in extracellular pH induces transient inward ASIC currents (IASICs) in postsynaptic MNTB neurons from wild-type mice. The inhibition of IASICs by psalmotoxin-1 (PcTx1) and the absence of these currents in knock-out mice for ASIC-1a subunit (ASIC1a(-/-)) suggest that homomeric ASIC-1as are mediating these currents in MNTB neurons. Furthermore, we detect ASIC1a-dependent currents during synaptic transmission, suggesting an acidification of the synaptic cleft due to the corelease of neurotransmitter and H(+) from synaptic vesicles. These currents are capable of eliciting action potentials in the absence of glutamatergic currents. A significant characteristic of these homomeric ASIC-1as is their permeability to Ca(2+) Activation of ASIC-1a in MNTB neurons by exogenous H(+) induces an increase in intracellular Ca(2+) Furthermore, the activation of postsynaptic ASIC-1as during high-frequency stimulation (HFS) of the presynaptic nerve terminal leads to a PcTx1-sensitive increase in intracellular Ca(2+) in MNTB neurons, which is independent of glutamate receptors and is absent in neurons from ASIC1a(-/-) mice. During HFS, the lack of functional ASICs in synaptic transmission results in an enhanced short-term depression of glutamatergic EPSCs. These results strongly support the hypothesis of protons as neurotransmitters and demonstrate that presynaptic released protons modulate synaptic transmission by activating ASIC-1as at the calyx of Held-MNTB synapse.SIGNIFICANCE STATEMENT The manuscript demonstrates that postsynaptic neurons of the medial nucleus of the trapezoid body at the mouse calyx of Held synapse express functional homomeric Acid-sensing ion channel-1a (ASIC-1as) that can be activated by protons

  16. Visualizing the distribution of synapses from individual neurons in the mouse brain.

    Directory of Open Access Journals (Sweden)

    Ling Li

    2010-07-01

    Full Text Available Proper function of the mammalian brain relies on the establishment of highly specific synaptic connections among billions of neurons. To understand how complex neural circuits function, it is crucial to precisely describe neuronal connectivity and the distributions of synapses to and from individual neurons.In this study, we present a new genetic synaptic labeling method that relies on expression of a presynaptic marker, synaptophysin-GFP (Syp-GFP in individual neurons in vivo. We assess the reliability of this method and use it to analyze the spatial patterning of synapses in developing and mature cerebellar granule cells (GCs. In immature GCs, Syp-GFP is distributed in both axonal and dendritic regions. Upon maturation, it becomes strongly enriched in axons. In mature GCs, we analyzed synapses along their ascending segments and parallel fibers. We observe no differences in presynaptic distribution between GCs born at different developmental time points and thus having varied depths of projections in the molecular layer. We found that the mean densities of synapses along the parallel fiber and the ascending segment above the Purkinje cell (PC layer are statistically indistinguishable, and higher than previous estimates. Interestingly, presynaptic terminals were also found in the ascending segments of GCs below and within the PC layer, with the mean densities two-fold lower than that above the PC layer. The difference in the density of synapses in these parts of the ascending segment likely reflects the regional differences in postsynaptic target cells of GCs.The ability to visualize synapses of single neurons in vivo is valuable for studying synaptogenesis and synaptic plasticity within individual neurons as well as information flow in neural circuits.

  17. Meclofenamic acid blocks electrical synapses of retinal AII amacrine and on-cone bipolar cells.

    Science.gov (United States)

    Veruki, Margaret Lin; Hartveit, Espen

    2009-05-01

    Gap junction channels constitute specialized intercellular contacts that can serve as electrical synapses. In the rod pathway of the retina, electrical synapses between AII amacrine cells express connexin 36 (Cx36) and electrical synapses between AII amacrines and on-cone bipolar cells express Cx36 on the amacrine side and Cx36 or Cx45 on the bipolar side. For physiological investigations of the properties and functions of these electrical synapses, it is highly desirable to have access to potent pharmacological blockers with selective and reversible action. Here we use dual whole cell voltage-clamp recordings of pairs of AII amacrine cells and pairs of AII amacrine and on-cone bipolar cells in rat retinal slices to directly measure the junctional conductance (G(j)) between electrically coupled cells and to study the effect of the drug meclofenamic acid (MFA) on G(j). Consistent with previous tracer coupling studies, we found that MFA reversibly blocked the electrical synapse currents in a concentration-dependent manner, with complete block at 100 muM. Whereas MFA evoked a detectable decrease in G(j) within minutes of application, the time to complete block of G(j) was considerably longer, typically 20-40 min. After washout, G(j) recovered to 20-90% of the control level, but the time to maximum recovery was typically >1 h. These results suggest that MFA can be a useful drug to investigate the physiological functions of electrical synapses in the rod pathway, but that the slow kinetics of block and reversal might compromise interpretation of the results and that explicit monitoring of G(j) is desirable.

  18. p-sd Shell Gap Reduction in Neutron-Rich Systems and Cross-ShellExcitations in 20O

    Energy Technology Data Exchange (ETDEWEB)

    Wiedeking, M.; Tabor, S.L.; Pavan, J.; Volya, A.; Aguilar, A.L.; Calderin, I.J.; Campbell, D.B.; Cluff, W.T.; Diffenderfer, E.; Fridmann,J.; Hoffman, C.R.; Kemper, K.W.; Lee, S.; Riley, M.A.; Roeder, B.T.; Teal, C.; Tripathi, V.; Wiedenhover, I.

    2005-04-07

    Excited states in {sup 20}O were populated in the reaction {sup 10}Be({sup 14}C,{alpha}) at Florida State University (FSU). Charged particles were detected with a particle telescope consisting of 4 annularly segmented Si surface barrier detectors and {gamma} radiation was detected with the FSU {gamma} detector array. Five new states were observed below 6 MeV from the {alpha}-{gamma} and {alpha}-{gamma}-{gamma} coincidence data. Shell model calculations suggest that most of the newly observed states are core-excited 1p-1h excitations across the N=Z=8 shell gap. Comparisons between experimental data and calculations for the neutron-rich O and F isotopes imply a steady reduction of the p-sd shell gap as neutrons are added.

  19. Paramembranous densities of 'C' terminal-motoneuron synapses in the spinal cord of the rat

    DEFF Research Database (Denmark)

    Schrøder, H D

    1979-01-01

    A category of large boutons forming synapses with the soma and proximal dendrites of spinal motoneurons was studied in glutaraldehyde-fixed, non-osmicated tissue stained with uranyl acetate and lead citrate. The identity of these boutons with 'C' boutons was indicated by their shape, frequency...... and distribution as well as by the ultrastructural characteristics of the boutons and the associated postsynaptic structures. In contrast to previous descriptions based on osmicated tissue, this study demonstrates that paramembranous densities are a feature of 'C' terminal-motoneuron synapses....

  20. A trace of silence: memory and microRNA at the synapse.

    Science.gov (United States)

    Ashraf, Shovon I; Kunes, Sam

    2006-10-01

    Identifying the neural circuits that mediate particular behaviors and uncovering their plasticity is an endeavor at the heart of neuroscience. This effort is allied with the elucidation of plasticity mechanisms, because the molecular determinants of plasticity can be markers for the neurons and synapses that are modified by experience. Of particular interest is protein synthesis localized to the synapse, which might establish and maintain the stable modification of neuronal properties, including the pattern and strength of synaptic connections. Recent studies reveal that microRNAs and the RISC pathway regulate synaptic protein synthesis. Is synaptic activity of the RISC pathway a molecular signature of memory?

  1. A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage

    DEFF Research Database (Denmark)

    Bach, Anders*; Clausen, Bettina H; Møller, Magda

    2012-01-01

    Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-d-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors...

  2. Reduced cortical distribution volume of iodine-123 iomazenil in Alzheimer's disease as a measure of loss of synapses

    DEFF Research Database (Denmark)

    Soricelli, A; Postiglione, A; Grivet-Fojaja, M R

    1996-01-01

    Iodine-123 labelled iomazenil (IMZ) is a specific tracer for the GABAA receptor, the dominant inhibitory synapse of the brain. The cerebral distribution volume (Vd) of IMZ may be taken as a quantitative measure of these synapses in Alzheimer's disease (AD), where synaptic loss tends...

  3. cAMP-Inhibits Cytoplasmic Phospholipase A2 and Protects Neurons against Amyloid-β-Induced Synapse Damage

    Directory of Open Access Journals (Sweden)

    Clive Bate

    2015-09-01

    Full Text Available A key event in Alzheimer’s disease (AD is the production of amyloid-β (Aβ peptides and the loss of synapses. In cultured neurons Aβ triggered synapse damage as measured by the loss of synaptic proteins. α-synuclein (αSN, aggregates of which accumulate in Parkinson’s disease, also caused synapse damage. Synapse damage was associated with activation of cytoplasmic phospholipase A2 (cPLA2, an enzyme that regulates synapse function and structure, and the production of prostaglandin (PG E2. In synaptosomes PGE2 increased concentrations of cyclic adenosine monophosphate (cAMP which suppressed the activation of cPLA2 demonstrating an inhibitory feedback system. Thus, Aβ/αSN-induced activated cPLA2 produces PGE2 which increases cAMP which in turn suppresses cPLA2 and, hence, its own production. Neurons pre-treated with pentoxifylline and caffeine (broad spectrum phosphodiesterase (PDE inhibitors or the PDE4 specific inhibitor rolipram significantly increased the Aβ/αSN-induced increase in cAMP and consequently protected neurons against synapse damage. The addition of cAMP analogues also inhibited cPLA2 and protected neurons against synapse damage. These results suggest that drugs that inhibit Aβ-induced activation of cPLA2 and cross the blood–brain barrier may reduce synapse damage in AD.

  4. The contribution of electrical synapses to field potential oscillations in the hippocampal formation

    Directory of Open Access Journals (Sweden)

    Anna ePosłuszny

    2014-04-01

    Full Text Available Electrical synapses are a type of cellular membrane junction referred to as gap junctions (GJs. GJs have been regarded as an important component within the neuronal networks that underlie synchronous neuronal activity and field potential oscillations. Initially, GJs appeared to play a particularly key role in the generation of high frequency oscillatory patterns in field potentials. In order to assess the scale of neuronal GJs contribution to field potential oscillations in the hippocampal formation, in vivo and in vitro studies are reviewed here. These investigations have shown that blocking the main neuronal GJs, those containing connexin 36 (Cx36-GJs, or knocking out the Cx36 gene affect field potential oscillatory patterns related to awake active behavior (gamma and theta rhythm but have no effect on high frequency oscillations occurring during silent wake and sleep. Precisely how Cx36-GJs influence population activity of neurons is more complex than previously thought. Analysis of studies on the properties of transmission through GJ channels as well as Cx36-GJs functioning in pairs of coupled neurons provides some explanations of the specific influence of Cx36-GJs on field potential oscillations. It is proposed here that GJ transmission is strongly modulated by the level of neuronal network activity and changing behavioral states. Therefore, contribution of GJs to field potential oscillatory patterns depends on the behavioral state. I propose here a model, based on large body of experimental data gathered in this field by several authors, in which Cx36-GJ transmission especially contributes to oscillations related to active behavior, where it plays a role in filtering and enhancing coherent signals in the network under high-noise conditions. In contrast, oscillations related to silent wake or sleep, especially high frequency oscillations, do not require transmission by neuronal GJs.

  5. Dendro-dendritic bundling and shared synapses between gonadotropin-releasing hormone neurons

    Science.gov (United States)

    Campbell, Rebecca E.; Gaidamaka, Galina; Han, Seong-Kyu; Herbison, Allan E.

    2009-01-01

    The pulsatile release of gonadotropin-releasing hormone (GnRH) is critical for mammalian fertility, but the mechanisms underlying the synchronization of GnRH neurons are unknown. In the present study, the full extent of the GnRH neuron dendritic tree was visualized by patching and filling individual GnRH neurons with biocytin in acute brain slices from adult GnRH-green fluorescent protein (GFP) transgenic mice. Confocal analysis of 42 filled GnRH neurons from male and female adult mice revealed that the dendrites of the great majority of GnRH neurons (86%) formed multiple close appositions with dendrites of other GnRH neurons. Two types of interactions were encountered; the predominant interaction was one of vertical dendritic bundling where dendrites were found to wrap around each other in the same axis. The other interaction was one in which a GnRH neuron dendrite intercepted other GnRH neuron dendrites in a perpendicular fashion. Electron microscopy using pre-embedded, silver-enhanced immunogold labeling for both GnRH and GFP peptides in GnRH-GFP transgenic mice, confirmed that GnRH neuron dendrites were often immediately juxtaposed. Membrane specializations, including punctae and zonula adherens, were found connecting adjacent dendritic elements of GnRH neurons. Remarkably, individual afferent axon terminals were found to synapse with multiple GnRH neuron dendrites at sites of bundling. Together, these data demonstrate that GnRH neurons are not isolated from one another but, rather, interconnected via their long dendritic extensions. The observation of shared synaptic input to bundled GnRH neuron dendrites suggests a mechanism of GnRH neuron synchronization. PMID:19541658

  6. Synapse-Assembly Proteins Maintain Synaptic Vesicle Cluster Stability and Regulate Synaptic Vesicle Transport in Caenorhabditis elegans.

    Science.gov (United States)

    Edwards, Stacey L; Yorks, Rosalina M; Morrison, Logan M; Hoover, Christopher M; Miller, Kenneth G

    2015-09-01

    The functional integrity of neurons requires the bidirectional active transport of synaptic vesicles (SVs) in axons. The kinesin motor KIF1A transports SVs from somas to stable SV clusters at synapses, while dynein moves them in the opposite direction. However, it is unclear how SV transport is regulated and how SVs at clusters interact with motor proteins. We addressed these questions by isolating a rare temperature-sensitive allele of Caenorhabditis elegans unc-104 (KIF1A) that allowed us to manipulate SV levels in axons and dendrites. Growth at 20° and 14° resulted in locomotion rates that were ∼3 and 50% of wild type, respectively, with similar effects on axonal SV levels. Corresponding with the loss of SVs from axons, mutants grown at 14° and 20° showed a 10- and 24-fold dynein-dependent accumulation of SVs in their dendrites. Mutants grown at 14° and switched to 25° showed an abrupt irreversible 50% decrease in locomotion and a 50% loss of SVs from the synaptic region 12-hr post-shift, with no further decreases at later time points, suggesting that the remaining clustered SVs are stable and resistant to retrograde removal by dynein. The data further showed that the synapse-assembly proteins SYD-1, SYD-2, and SAD-1 protected SV clusters from degradation by motor proteins. In syd-1, syd-2, and sad-1 mutants, SVs accumulate in an UNC-104-dependent manner in the distal axon region that normally lacks SVs. In addition to their roles in SV cluster stability, all three proteins also regulate SV transport. Copyright © 2015 by the Genetics Society of America.

  7. Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment.

    Science.gov (United States)

    Whitfield, David R; Vallortigara, Julie; Alghamdi, Amani; Howlett, David; Hortobágyi, Tibor; Johnson, Mary; Attems, Johannes; Newhouse, Stephen; Ballard, Clive; Thomas, Alan J; O'Brien, John T; Aarsland, Dag; Francis, Paul T

    2014-12-01

    The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice, and the protein has been associated with plaques. We investigated the levels of ZnT3 and postsynaptic density protein 95 (PSD95), a marker of the postsynaptic terminal, in people with Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and controls (n = 24), using semiquantitative western blotting and immunohistochemistry in 3 cortical regions. Standardized cognitive assessments during life and semiquantitative scoring of amyloid β (Aβ), tau, and α-synuclein at postmortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology. Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p = 0.001 and p = 0.002, respectively) and between ZnT3 levels in the parietal cortex and cognitive impairment (p = 0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of Aβ (p = 0.003) and tau (p = 0.011) pathologies. DLB and PDD were characterized by significant reductions of PSD95 (p < 0.05) and ZnT3 (p < 0.001) in prefrontal cortex compared with controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared with controls (p = 0.02) and PDD (p = 0.005). This study has identified Zn(2+) modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD and the potential for synaptic proteins to be used as a biomarker for the differentiation of DLB and PDD from AD. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Autophagy Attenuates the Adaptive Immune Response by Destabilizing the Immunologic Synapse

    NARCIS (Netherlands)

    Wildenberg, Manon E.; Vos, Anne Christine W.; Wolfkamp, Simone C. S.; Duijvestein, Marjolijn; Verhaar, Auke P.; te Velde, Anje A.; van den Brink, Gijs R.; Hommes, Daniel W.

    2012-01-01

    BACKGROUND & AIMS: Variants in the genes ATG16L1 and IRGM affect autophagy and are associated with the development of Crohn's disease. It is not clear how autophagy is linked to loss of immune tolerance in the intestine. We investigated the involvement of the immunologic synapse-the site of contact

  9. How the immune system talks to itself: the varied role of synapses.

    Science.gov (United States)

    Xie, Jianming; Tato, Cristina M; Davis, Mark M

    2013-01-01

    Using an elaborately evolved language of cytokines and chemokines as well as cell-cell interactions, the different components of the immune system communicate with each other and orchestrate a response (or wind one down). Immunological synapses are a key feature of the system in the ways in which they can facilitate and direct these responses. Studies analyzing the structure of an immune synapse as it forms between two cells have provided insight into how the stability and kinetics of this interaction ultimately affect the sensitivity, potency, and magnitude of a given response. Furthermore, we have gained an appreciation of how the immunological synapse provides directionality and contextual cues for downstream signaling and cellular decision-making. In this review, we discuss how using a variety of techniques, developed over the last decade, have allowed us to visualize and quantify key aspects of the dynamic synaptic interface and have furthered our understanding of their function. We describe some of the many characteristics of the immunological synapse that make it a vital part of intercellular communication and some of the questions that remain to be answered. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

  10. Presynaptic Membrane Receptors Modulate ACh Release, Axonal Competition and Synapse Elimination during Neuromuscular Junction Development

    Directory of Open Access Journals (Sweden)

    Josep Tomàs

    2017-05-01

    Full Text Available During the histogenesis of the nervous system a lush production of neurons, which establish an excessive number of synapses, is followed by a drop in both neurons and synaptic contacts as maturation proceeds. Hebbian competition between axons with different activities leads to the loss of roughly half of the neurons initially produced so connectivity is refined and specificity gained. The skeletal muscle fibers in the newborn neuromuscular junction (NMJ are polyinnervated but by the end of the competition, 2 weeks later, the NMJ are innervated by only one axon. This peripheral synapse has long been used as a convenient model for synapse development. In the last few years, we have studied transmitter release and the local involvement of the presynaptic muscarinic acetylcholine autoreceptors (mAChR, adenosine autoreceptors (AR and trophic factor receptors (TFR, for neurotrophins and trophic cytokines during the development of NMJ and in the adult. This review article brings together previously published data and proposes a molecular background for developmental axonal competition and loss. At the end of the first week postnatal, these receptors modulate transmitter release in the various nerve terminals on polyinnervated NMJ and contribute to axonal competition and synapse elimination.

  11. Experience-Dependent Regulation of Presynaptic NMDARs Enhances Neurotransmitter Release at Neocortical Synapses

    Science.gov (United States)

    Urban-Ciecko, Joanna; Wen, Jing A.; Parekh, Puja K.; Barth, Alison L.

    2015-01-01

    Sensory experience can selectively alter excitatory synaptic strength at neocortical synapses. The rapid increase in synaptic strength induced by selective whisker stimulation (single-row experience/SRE, where all but one row of whiskers has been removed from the mouse face) is due, at least in part, to the trafficking of AMPA receptors (AMPARs)…

  12. ZAP-70 kinase regulates HIV cell-to-cell spread and virological synapse formation.

    Science.gov (United States)

    Sol-Foulon, Nathalie; Sourisseau, Marion; Porrot, Françoise; Thoulouze, Maria-Isabel; Trouillet, Céline; Nobile, Cinzia; Blanchet, Fabien; di Bartolo, Vincenzo; Noraz, Nelly; Taylor, Naomi; Alcover, Andres; Hivroz, Claire; Schwartz, Olivier

    2007-01-24

    HIV efficiently spreads in lymphocytes, likely through virological synapses (VSs). These cell-cell junctions share some characteristics with immunological synapses, but cellular proteins required for their constitution remain poorly characterized. We have examined here the role of ZAP-70, a key kinase regulating T-cell activation and immunological synapse formation, in HIV replication. In lymphocytes deficient for ZAP-70, or expressing a kinase-dead mutant of the protein, HIV replication was strikingly delayed. We have characterized further this replication defect. ZAP-70 was dispensable for the early steps of viral cycle, from entry to expression of viral proteins. However, in the absence of ZAP-70, intracellular Gag localization was impaired. ZAP-70 was required in infected donor cells for efficient cell-to-cell HIV transmission to recipients and for formation of VSs. These results bring novel insights into the links that exist between T-cell activation and HIV spread, and suggest that HIV usurps components of the immunological synapse machinery to ensure its own spread through cell-to-cell contacts.

  13. NMDAR-mediated calcium transients elicited by glutamate co-release at developing inhibitory synapses

    Directory of Open Access Journals (Sweden)

    Abigail Kalmbach

    2010-07-01

    Full Text Available Before hearing onset, the topographic organization of the inhibitory sound localization pathway from the medial nucleus of the trapezoid body (MNTB to the lateral superior olive (LSO is refined by means of synaptic silencing and strengthening. During this refinement period MNTB-LSO synapses not only release GABA and glycine but also release glutamate. This co-released glutamate can elicit postsynaptic currents that are predominantly mediated by NMDA receptors (NMDARs. To gain a better understanding of how glutamate contributes to synaptic signaling at developing MNTB-LSO inhibitory synapse, we investigated to what degree and under what conditions NMDARs contribute to postsynaptic calcium responses. Our results demonstrate that MNTB-LSO synapses can elicit compartmentalized calcium responses along aspiny LSO dendrites. These responses are significantly attenuated by the NMDARs antagonist APV. APV, however, has no effect on somatically recorded electrical postsynaptic responses, indicating little, if any, contribution of NMDARs to spike generation. Small NMDAR-mediated calcium responses were also observed under physiological levels of extracellular magnesium concentrations indicating that MNTB-LSO synapses activate magnesium sensitive NMDAR on immature LSO dendrites. In Fura-2 AM loaded neurons, blocking GABAA and glycine receptors decreased NMDAR contribution to somatic calcium responses suggesting that GABA and glycine, perhaps by shunting backpropagating action potentials, decrease the level of NMDAR activation under strong stimulus conditions.

  14. Super resolution imaging of genetically labelled synapses in Drosophila brain tissue

    Directory of Open Access Journals (Sweden)

    Isabelle Ayumi Spühler

    2016-05-01

    Full Text Available Understanding synaptic connectivity and plasticity within brain circuits and their relationship to learning and behavior is a fundamental quest in neuroscience. Visualizing the fine details of synapses using optical microscopy remains however a major technical challenge. Super resolution microscopy opens the possibility to reveal molecular features of synapses beyond the diffraction limit. With direct stochastic optical reconstruction microscopy, dSTORM, we image synaptic proteins in the brain tissue of the fruit fly, Drosophila melanogaster. Super resolution imaging of brain tissue harbors difficulties due to light scattering and the density of signals. In order to reduce out of focus signal, we take advantage of the genetic tools available in the Drosophila and have fluorescently tagged synaptic proteins expressed in only a small number of neurons. These neurons form synapses within the calyx of the mushroom body, a distinct brain region involved in associative memory formation. Our results show that super resolution microscopy, in combination with genetically labelled synaptic proteins, is a powerful tool to investigate synapses in a quantitative fashion providing an entry point for studies on synaptic plasticity during learning and memory formation

  15. A Preferentially Segregated Recycling Vesicle Pool of Limited Size Supports Neurotransmission in Native Central Synapses

    Science.gov (United States)

    Marra, Vincenzo; Burden, Jemima J.; Thorpe, Julian R.; Smith, Ikuko T.; Smith, Spencer L.; Häusser, Michael; Branco, Tiago; Staras, Kevin

    2012-01-01

    Summary At small central synapses, efficient turnover of vesicles is crucial for stimulus-driven transmission, but how the structure of this recycling pool relates to its functional role remains unclear. Here we characterize the organizational principles of functional vesicles at native hippocampal synapses with nanoscale resolution using fluorescent dye labeling and electron microscopy. We show that the recycling pool broadly scales with the magnitude of the total vesicle pool, but its average size is small (∼45 vesicles), highly variable, and regulated by CDK5/calcineurin activity. Spatial analysis demonstrates that recycling vesicles are preferentially arranged near the active zone and this segregation is abolished by actin stabilization, slowing the rate of activity-driven exocytosis. Our approach reveals a similarly biased recycling pool distribution at synapses in visual cortex activated by sensory stimulation in vivo. We suggest that in small native central synapses, efficient release of a limited pool of vesicles relies on their favored spatial positioning within the terminal. PMID:23141069

  16. Mechanisms of TSC-mediated control of synapse assembly and axon guidance.

    Directory of Open Access Journals (Sweden)

    Sarah Knox

    2007-04-01

    Full Text Available Tuberous sclerosis complex is a dominant genetic disorder produced by mutations in either of two tumor suppressor genes, TSC1 and TSC2; it is characterized by hamartomatous tumors, and is associated with severe neurological and behavioral disturbances. Mutations in TSC1 or TSC2 deregulate a conserved growth control pathway that includes Ras homolog enriched in brain (Rheb and Target of Rapamycin (TOR. To understand the function of this pathway in neural development, we have examined the contributions of multiple components of this pathway in both neuromuscular junction assembly and photoreceptor axon guidance in Drosophila. Expression of Rheb in the motoneuron, but not the muscle of the larval neuromuscular junction produced synaptic overgrowth and enhanced synaptic function, while reductions in Rheb function compromised synapse development. Synapse growth produced by Rheb is insensitive to rapamycin, an inhibitor of Tor complex 1, and requires wishful thinking, a bone morphogenetic protein receptor critical for functional synapse expansion. In the visual system, loss of Tsc1 in the developing retina disrupted axon guidance independently of cellular growth. Inhibiting Tor complex 1 with rapamycin or eliminating the Tor complex 1 effector, S6 kinase (S6k, did not rescue axon guidance abnormalities of Tsc1 mosaics, while reductions in Tor function suppressed those phenotypes. These findings show that Tsc-mediated control of axon guidance and synapse assembly occurs via growth-independent signaling mechanisms, and suggest that Tor complex 2, a regulator of actin organization, is critical in these aspects of neuronal development.

  17. Electron Microscopic Analysis of Hippocampal Axo-Somatic Synapses in a Chronic Stress Model for Depression

    DEFF Research Database (Denmark)

    Csabai, David; Seress, Laszlo; Varga, Zsofia

    2017-01-01

    %; Synapse number/100 terminal=120; Average terminal length=920nm. None of these parameters were affected by the stress exposure. Overall, these data indicate that despite the depressivelike behavior and the decrease in the number of perisomatic PV+ neurons in the light microscopic preparations, the number...

  18. Specific recycling receptors are targeted to the immune synapse by the intraflagellar transport system

    Science.gov (United States)

    Finetti, Francesca; Patrussi, Laura; Masi, Giulia; Onnis, Anna; Galgano, Donatella; Lucherini, Orso Maria; Pazour, Gregory J.; Baldari, Cosima T.

    2014-01-01

    ABSTRACT T cell activation requires sustained signaling at the immune synapse, a specialized interface with the antigen-presenting cell (APC) that assembles following T cell antigen receptor (TCR) engagement by major histocompatibility complex (MHC)-bound peptide. Central to sustained signaling is the continuous recruitment of TCRs to the immune synapse. These TCRs are partly mobilized from an endosomal pool by polarized recycling. We have identified IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, as a central regulator of TCR recycling to the immune synapse. Here, we have investigated the interplay of IFT20 with the Rab GTPase network that controls recycling. We found that IFT20 forms a complex with Rab5 and the TCR on early endosomes. IFT20 knockdown (IFT20KD) resulted in a block in the recycling pathway, leading to a build-up of recycling TCRs in Rab5+ endosomes. Recycling of the transferrin receptor (TfR), but not of CXCR4, was disrupted by IFT20 deficiency. The IFT components IFT52 and IFT57 were found to act together with IFT20 to regulate TCR and TfR recycling. The results provide novel insights into the mechanisms that control TCR recycling and immune synapse assembly, and underscore the trafficking-related function of the IFT system beyond ciliogenesis. PMID:24554435

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

    Science.gov (United States)

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

    2009-01-01

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

  20. Back-propagation operation for analog neural network hardware with synapse components having hysteresis characteristics.

    Directory of Open Access Journals (Sweden)

    Michihito Ueda

    Full Text Available To realize an analog artificial neural network hardware, the circuit element for synapse function is important because the number of synapse elements is much larger than that of neuron elements. One of the candidates for this synapse element is a ferroelectric memristor. This device functions as a voltage controllable variable resistor, which can be applied to a synapse weight. However, its conductance shows hysteresis characteristics and dispersion to the input voltage. Therefore, the conductance values vary according to the history of the height and the width of the applied pulse voltage. Due to the difficulty of controlling the accurate conductance, it is not easy to apply the back-propagation learning algorithm to the neural network hardware having memristor synapses. To solve this problem, we proposed and simulated a learning operation procedure as follows. Employing a weight perturbation technique, we derived the error change. When the error reduced, the next pulse voltage was updated according to the back-propagation learning algorithm. If the error increased the amplitude of the next voltage pulse was set in such way as to cause similar memristor conductance but in the opposite voltage scanning direction. By this operation, we could eliminate the hysteresis and confirmed that the simulation of the learning operation converged. We also adopted conductance dispersion numerically in the simulation. We examined the probability that the error decreased to a designated value within a predetermined loop number. The ferroelectric has the characteristics that the magnitude of polarization does not become smaller when voltages having the same polarity are applied. These characteristics greatly improved the probability even if the learning rate was small, if the magnitude of the dispersion is adequate. Because the dispersion of analog circuit elements is inevitable, this learning operation procedure is useful for analog neural network hardware.

  1. A Machine Learning Method for the Prediction of Receptor Activation in the Simulation of Synapses

    Science.gov (United States)

    Montes, Jesus; Gomez, Elena; Merchán-Pérez, Angel; DeFelipe, Javier; Peña, Jose-Maria

    2013-01-01

    Chemical synaptic transmission involves the release of a neurotransmitter that diffuses in the extracellular space and interacts with specific receptors located on the postsynaptic membrane. Computer simulation approaches provide fundamental tools for exploring various aspects of the synaptic transmission under different conditions. In particular, Monte Carlo methods can track the stochastic movements of neurotransmitter molecules and their interactions with other discrete molecules, the receptors. However, these methods are computationally expensive, even when used with simplified models, preventing their use in large-scale and multi-scale simulations of complex neuronal systems that may involve large numbers of synaptic connections. We have developed a machine-learning based method that can accurately predict relevant aspects of the behavior of synapses, such as the percentage of open synaptic receptors as a function of time since the release of the neurotransmitter, with considerably lower computational cost compared with the conventional Monte Carlo alternative. The method is designed to learn patterns and general principles from a corpus of previously generated Monte Carlo simulations of synapses covering a wide range of structural and functional characteristics. These patterns are later used as a predictive model of the behavior of synapses under different conditions without the need for additional computationally expensive Monte Carlo simulations. This is performed in five stages: data sampling, fold creation, machine learning, validation and curve fitting. The resulting procedure is accurate, automatic, and it is general enough to predict synapse behavior under experimental conditions that are different to the ones it has been trained on. Since our method efficiently reproduces the results that can be obtained with Monte Carlo simulations at a considerably lower computational cost, it is suitable for the simulation of high numbers of synapses and it is

  2. A biogenic amine-synapse mechanism for mental retardation and developmental disabilities.

    Science.gov (United States)

    Okado, N; Narita, M; Narita, N

    2001-12-01

    Recent studies have demonstrated that biogenic amines have a function of facilitating formation and maintenance of synapses in diverse regions of the central nervous system in developing and adult animals. The normal number of synapses maintained by biogenic amines are crucial to acquire learning and memory. The level of biogenic amines was reported to decrease in the brain by several neurodevelopmental disorders associated with mental retardation and developmental disabilities such as Rett syndrome, autism and Down syndrome. Taken into consideration this fact together with the function of biogenic amines for synapses, the density of synapses appears to decrease considerably in the brains of patients suffered from the neurodevelopmental disorders. The synaptic overproduction during the critical period of development especially 1 year after birth has been considered as a background mechanism to provide plasticity for the developing brain. Synaptic overproduction does not appear to occur in the brains of patients suffered from the neurodevelopmental disorders, which they are observed mental retardation occurring in the first 1 year after birth. Along with the neurodevelopmental disorders, environmental factors (stress, drugs and nutrition) during pre- and post-natal critical developmental periods are known to change levels of biogenic amines in the brain. In fact, maternal stress has been shown to decrease the levels of serotonin and the density of synapses in the hippocampus of the offspring, and they showed developmental disabilities in the spatial learning and memory. A cascade appears to exist from either the child neurological disorders or the environmental factors to mental retardation and developmental disabilities by decreases in the levels of biogenic amines and synaptic density.

  3. Despite disorganized synapse structure, Th2 cells maintain directional delivery of CD40L to antigen-presenting B cells.

    Science.gov (United States)

    Gardell, Jennifer L; Parker, David C

    2017-01-01

    Upon recognition of peptide displayed on MHC molecules, Th1 and Th2 cells form distinct immunological synapse structures. Th1 cells have a bull's eye synapse structure with TCR/ MHC-peptide interactions occurring central to a ring of adhesion molecules, while Th2 cells have a multifocal synapse with small clusters of TCR/MHC interactions throughout the area of T cell/antigen-presenting cell interaction. In this study, we investigated whether this structural difference in the immunological synapse affects delivery of T cell help. The immunological synapse is thought to ensure antigen-specific delivery of cytolytic granules and killing of target cells by NK cells and cytolytic T cells. In helper T cells, it has been proposed that the immunological synapse may direct delivery of other effector molecules including cytokines. CD40 ligand (CD40L) is a membrane-bound cytokine essential for antigen-specific T cell help for B cells in the antibody response. We incubated Th1 and Th2 cells overnight with a mixture of antigen-presenting and bystander B cells, and the delivery of CD40L to B cells and subsequent B cell responses were compared. Despite distinct immunological synapse structures, Th1 and Th2 cell do not differ in their ability to deliver CD40L and T cell help in an antigen-specific fashion, or in their susceptibility to inhibition of help by a blocking anti-CD40L antibody.

  4. The Enhanced Rise and Delayed Fall of Memory in a Model of Synaptic Integration: Extension to Discrete State Synapses.

    Science.gov (United States)

    Elliott, Terry

    2016-09-01

    Integrate-and-express models of synaptic plasticity propose that synapses may act as low-pass filters, integrating synaptic plasticity induction signals in order to discern trends before expressing synaptic plasticity. We have previously shown that synaptic filtering strongly controls destabilizing fluctuations in developmental models. When applied to palimpsest memory systems that learn new memories by forgetting old ones, we have also shown that with binary-strength synapses, integrative synapses lead to an initial memory signal rise before its fall back to equilibrium. Such an initial rise is in dramatic contrast to nonintegrative synapses, in which the memory signal falls monotonically. We now extend our earlier analysis of palimpsest memories with synaptic filters to consider the more general case of discrete state, multilevel synapses. We derive exact results for the memory signal dynamics and then consider various simplifying approximations. We show that multilevel synapses enhance the initial rise in the memory signal and then delay its subsequent fall by inducing a plateau-like region in the memory signal. Such dynamics significantly increase memory lifetimes, defined by a signal-to-noise ratio (SNR). We derive expressions for optimal choices of synaptic parameters (filter size, number of strength states, number of synapses) that maximize SNR memory lifetimes. However, we find that with memory lifetimes defined via mean-first-passage times, such optimality conditions do not exist, suggesting that optimality may be an artifact of SNRs.

  5. Noradrenergic actions in the basolateral complex of the amygdala modulate Arc expression in hippocampal synapses and consolidation of aversive and non-aversive memory.

    Science.gov (United States)

    McReynolds, Jayme R; Anderson, Kelly M; Donowho, Kyle M; McIntyre, Christa K

    2014-11-01

    The basolateral complex of the amygdala (BLA) plays a role in the modulation of emotional memory consolidation through its interactions with other brain regions. In rats, memory enhancing infusions of the β-adrenergic receptor agonist clenbuterol into the BLA immediately after training enhances expression of the protein product of the immediate early gene Arc in the dorsal hippocampus and memory-impairing intra-BLA treatments reduce hippocampal Arc expression. We have proposed that the BLA may modulate memory consolidation through an influence on the local translation of synaptic plasticity proteins, like Arc, in recently active synapses in efferent brain regions. To date, all work related to this hypothesis is based on aversive memory tasks such as inhibitory avoidance (IA). To determine whether BLA modulation of hippocampal Arc protein expression is specific to plasticity associated with inhibitory avoidance memory, or a common mechanism for multiple types of memory, we tested the effect of intra-BLA infusions of clenbuterol on memory and hippocampal synaptic Arc expression following IA or object recognition training. Results indicate that intra-BLA infusions of clenbuterol enhance memory for both tasks; however, Arc expression in hippocampal synaptoneurosomes was significantly elevated only in rats trained on the aversive IA task. These findings suggest that regulation of Arc expression in hippocampal synapses may depend on co-activation of arousal systems. To test this hypothesis, a "high arousal" version of the OR task was used where rats were not habituated to the testing conditions. Posttraining intra-BLA infusions of clenbuterol enhanced consolidation of the high-arousing version of the task and significantly increased Arc protein levels in dorsal hippocampus synaptic fractions. These findings suggest that the BLA modulates multiple forms of memory and affects the synaptic plasticity-associated protein Arc in synapses of the dorsal hippocampus when

  6. Maternal dietary loads of alpha-tocopherol increase synapse density and glial synaptic coverage in the hippocampus of adult offspring

    Directory of Open Access Journals (Sweden)

    S. Salucci

    2014-05-01

    Full Text Available An increased intake of the antioxidant α-Tocopherol (vitamin E is recommended in complicated pregnancies, to prevent free radical damage to mother and fetus. However, the anti-PKC and antimitotic activity of α-Tocopherol raises concerns about its potential effects on brain development. Recently, we found that maternal dietary loads of α-Tocopherol through pregnancy and lactation cause developmental deficit in hippocampal synaptic plasticity in rat offspring. The defect persisted into adulthood, with behavioral alterations in hippocampus-dependent learning. Here, using the same rat model of maternal supplementation, ultrastructural morphometric studies were carried out to provide mechanistic interpretation to such a functional impairment in adult offspring by the occurrence of long-term changes in density and morphological features of hippocampal synapses. Higher density of axo-spinous synapses was found in CA1 stratum radiatum of α-Tocopherol-exposed rats compared to controls, pointing to a reduced synapse pruning. No morphometric changes were found in synaptic ultrastructural features, i.e., perimeter of axon terminals, length of synaptic specializations, extension of bouton-spine contact. Glia-synapse anatomical relationship was also affected. Heavier astrocytic coverage of synapses was observed in Tocopherol-treated offspring, notably surrounding axon terminals; moreover, the percentage of synapses contacted by astrocytic endfeet at bouton-spine interface (tripartite synapses was increased. These findings indicate that gestational and neonatal exposure to supranutritional tocopherol intake can result in anatomical changes of offspring hippocampus that last through adulthood. These include a surplus of axo-spinous synapses and an aberrant glia-synapse relationship, which may represent the morphological signature of previously described alterations in synaptic plasticity and hippocampus-dependent learning.

  7. The human PDZome: a gateway to PSD95-Disc large-zonula occludens (PDZ)-mediated functions.

    Science.gov (United States)

    Belotti, Edwige; Polanowska, Jolanta; Daulat, Avais M; Audebert, Stéphane; Thomé, Virginie; Lissitzky, Jean-Claude; Lembo, Frédérique; Blibek, Karim; Omi, Shizue; Lenfant, Nicolas; Gangar, Akanksha; Montcouquiol, Mireille; Santoni, Marie-Josée; Sebbagh, Michael; Aurrand-Lions, Michel; Angers, Stéphane; Kodjabachian, Laurent; Reboul, Jérome; Borg, Jean-Paul

    2013-09-01

    Protein-protein interactions organize the localization, clustering, signal transduction, and degradation of cellular proteins and are therefore implicated in numerous biological functions. These interactions are mediated by specialized domains able to bind to modified or unmodified peptides present in binding partners. Among the most broadly distributed protein interaction domains, PSD95-disc large-zonula occludens (PDZ) domains are usually able to bind carboxy-terminal sequences of their partners. In an effort to accelerate the discovery of PDZ domain interactions, we have constructed an array displaying 96% of the human PDZ domains that is amenable to rapid two-hybrid screens in yeast. We have demonstrated that this array can efficiently identify interactions using carboxy-terminal sequences of PDZ domain binders such as the E6 oncoviral protein and protein kinases (PDGFRβ, BRSK2, PCTK1, ACVR2B, and HER4); this has been validated via mass spectrometry analysis. Taking advantage of this array, we show that PDZ domains of Scrib and SNX27 bind to the carboxy-terminal region of the planar cell polarity receptor Vangl2. We also have demonstrated the requirement of Scrib for the promigratory function of Vangl2 and described the morphogenetic function of SNX27 in the early Xenopus embryo. The resource presented here is thus adapted for the screen of PDZ interactors and, furthermore, should facilitate the understanding of PDZ-mediated functions.

  8. Pharmacological Rescue of Long-Term Potentiation in Alzheimer Diseased Synapses.

    Science.gov (United States)

    Prieto, G Aleph; Trieu, Brian H; Dang, Cindy T; Bilousova, Tina; Gylys, Karen H; Berchtold, Nicole C; Lynch, Gary; Cotman, Carl W

    2017-02-01

    Long-term potentiation (LTP) is an activity-dependent and persistent increase in synaptic transmission. Currently available techniques to measure LTP are time-intensive and require highly specialized expertise and equipment, and thus are not well suited for screening of multiple candidate treatments, even in animal models. To expand and facilitate the analysis of LTP, here we use a flow cytometry-based method to track chemically induced LTP by detecting surface AMPA receptors in isolated synaptosomes: fluorescence analysis of single-synapse long-term potentiation (FASS-LTP). First, we demonstrate that FASS-LTP is simple, sensitive, and models electrically induced LTP recorded in intact circuitries. Second, we conducted FASS-LTP analysis in two well-characterized Alzheimer's disease (AD) mouse models (3xTg and Tg2576) and, importantly, in cryopreserved human AD brain samples. By profiling hundreds of synaptosomes, our data provide the first direct evidence to support the idea that synapses from AD brain are intrinsically defective in LTP. Third, we used FASS-LTP for drug evaluation in human synaptosomes. Testing a panel of modulators of cAMP and cGMP signaling pathways, FASS-LTP identified vardenafil and Bay-73-6691 (phosphodiesterase-5 and -9 inhibitors, respectively) as potent enhancers of LTP in synaptosomes from AD cases. These results indicate that our approach could provide the basis for protocols to study LTP in both healthy and diseased human brains, a previously unattainable goal. Learning and memory depend on the ability of synapses to strengthen in response to activity. Long-term potentiation (LTP) is a rapid and persistent increase in synaptic transmission that is thought to be affected in Alzheimer's disease (AD). However, direct evidence of LTP deficits in human AD brain has been elusive, primarily due to methodological limitations. Here, we analyze LTP in isolated synapses from AD brain using a novel approach that allows testing LTP in cryopreserved

  9. Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats.

    Science.gov (United States)

    Zamberletti, Erica; Gabaglio, Marina; Grilli, Massimo; Prini, Pamela; Catanese, Alberto; Pittaluga, Anna; Marchi, Mario; Rubino, Tiziana; Parolaro, Daniela

    2016-09-01

    Cannabis use has been frequently associated with sex-dependent effects on brain and behavior. We previously demonstrated that adult female rats exposed to delta-9-tetrahydrocannabinol (THC) during adolescence develop long-term alterations in cognitive performances and emotional reactivity, whereas preliminary evidence suggests the presence of a different phenotype in male rats. To thoroughly depict the behavioral phenotype induced by adolescent THC exposure in male rats, we treated adolescent animals with increasing doses of THC twice a day (PND 35-45) and, at adulthood, we performed a battery of behavioral tests to measure affective- and psychotic-like symptoms as well as cognition. Poorer memory performance and psychotic-like behaviors were present after adolescent THC treatment in male rats, without alterations in the emotional component. At cellular level, the expression of the NMDA receptor subunit, GluN2B, as well as the levels of the AMPA subunits, GluA1 and GluA2, were significantly increased in hippocampal post-synaptic fractions from THC-exposed rats compared to controls. Furthermore, increases in the levels of the pre-synaptic marker, synaptophysin, and the post-synaptic marker, PSD95, were also present. Interestingly, KCl-induced [(3)H]D-ASP release from hippocampal synaptosomes, but not gliosomes, was significantly enhanced in THC-treated rats compared to controls. Moreover, in the same brain region, adolescent THC treatment also resulted in a persistent neuroinflammatory state, characterized by increased expression of the astrocyte marker, GFAP, increased levels of the pro-inflammatory markers, TNF-α, iNOS and COX-2, as well as a concomitant reduction of the anti-inflammatory cytokine, IL-10. Notably, none of these alterations was observed in the prefrontal cortex (PFC). Together with our previous findings in females, these data suggest that the sex-dependent detrimental effects induced by adolescent THC exposure on adult behavior may rely on its

  10. Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats

    Directory of Open Access Journals (Sweden)

    Lara Sedó-Cabezón

    2015-10-01

    Full Text Available Ototoxicity is known to cause permanent loss of vestibule function through degeneration of sensory hair cells (HCs. However, functional recovery has been reported during washout after chronic ototoxicity, although the mechanisms underlying this reversible dysfunction are unknown. Here, we study this question in rats chronically exposed to the ototoxic compound 3,3′-iminodipropionitrile (IDPN. Pronounced alterations in vestibular function appeared before significant loss of HCs or stereociliary coalescence became evident by ultrastructural analyses. This early dysfunction was fully reversible if the exposure was terminated promptly. In cristae and utricles, the distinct junctions formed between type I HCs (HCI and calyx endings were completely dismantled at these early stages of reversible dysfunction, and completely rebuilt during washout. Immunohistochemical observations revealed loss and recovery of the junction proteins CASPR1 and tenascin-C and RT-PCR indicated that their loss was not due to decreased gene expression. KCNQ4 was mislocalized during intoxication and recovered control-like localization after washout. At early stages of the intoxication, the calyces could be classified as showing intact or lost junctions, indicating that calyceal junction dismantlement is triggered on a calyx-by-calyx basis. Chronic toxicity also altered the presence of ribeye, PSD-95 and GluA2 puncta in the calyces. These synaptic alterations varied between the two types of calyx endings (formed by calyx-only or dimorphic afferents and some persisted at the end of the washout period. The present data reveal new forms of plasticity of the calyx endings in adult mammals, including a robust capacity for rebuilding the calyceal junction. These findings contribute to a better understanding of the phenomena involved in progressive vestibular dysfunction and its potential recovery during and after ototoxic exposure.

  11. In vitro and in vivo effects of a novel dimeric inhibitor of PSD-95 on excitotoxicity and functional recovery after experimental traumatic brain injury

    DEFF Research Database (Denmark)

    Sommer, Jens Bak; Bach, Anders; Rytter, Hana Malá

    2017-01-01

    PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a nov...... studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration....

  12. Spontaneous glutamatergic activity induces a BDNF-dependent potentiation of GABAergic synapses in the newborn rat hippocampus

    Science.gov (United States)

    Kuczewski, Nicola; Langlois, Anais; Fiorentino, Hervé; Bonnet, Stéphanie; Marissal, Thomas; Diabira, Diabe; Ferrand, Nadine; Porcher, Christophe; Gaiarsa, Jean-Luc

    2008-01-01

    Spontaneous ongoing synaptic activity is thought to play an instructive role in the maturation of the neuronal circuits. However the type of synaptic activity involved and how this activity is translated into structural and functional changes is not fully understood. Here we show that ongoing glutamatergic synaptic activity triggers a long-lasting potentiation of γ-aminobutyric acid (GABA) mediated synaptic activity (LLPGABA-A) in the developing rat hippocampus. LLPGABA-A induction requires (i) the activation of AMPA receptors and L-type voltage-dependent calcium channels, (ii) the release of endogenous brain-derived neurotrophic factor (BDNF), and (iii) the activation of postsynaptic tropomyosin-related kinase receptors B (TrkB). We found that spontaneous glutamatergic activity is required to maintain a high level of native BDNF in the newborn rat hippocampus and that application of exogenous BDNF induced LLPGABA-A in the absence of glutamatergic activity. These results suggest that ongoing glutamatergic synaptic activity plays a pivotal role in the functional maturation of hippocampal GABAergic synapses by means of a cascade involving BDNF release and downstream signalling through postsynaptic TrkB receptor activation. PMID:18772203

  13. High Dynamics and Precision Optical Measurement Using a Position Sensitive Detector (PSD in Reflection-Mode: Application to 2D Object Tracking over a Smart Surface

    Directory of Open Access Journals (Sweden)

    Ioan Alexandru Ivan

    2012-12-01

    Full Text Available When related to a single and good contrast object or a laser spot, position sensing, or sensitive, detectors (PSDs have a series of advantages over the classical camera sensors, including a good positioning accuracy for a fast response time and very simple signal conditioning circuits. To test the performance of this kind of sensor for microrobotics, we have made a comparative analysis between a precise but slow video camera and a custom-made fast PSD system applied to the tracking of a diffuse-reflectivity object transported by a pneumatic microconveyor called Smart-Surface. Until now, the fast system dynamics prevented the full control of the smart surface by visual servoing, unless using a very expensive high frame rate camera. We have built and tested a custom and low cost PSD-based embedded circuit, optically connected with a camera to a single objective by means of a beam splitter. A stroboscopic light source enhanced the resolution. The obtained results showed a good linearity and a fast (over 500 frames per second response time which will enable future closed-loop control by using PSD.

  14. The contribution of electrical synapses to field potential oscillations in the hippocampal formation.

    Science.gov (United States)

    Posłuszny, Anna

    2014-01-01

    Electrical synapses are a type of cellular membrane junction referred to as gap junctions (GJs). They provide a direct way to exchange ions between coupled cells and have been proposed as a structural basis for fast transmission of electrical potentials between neurons in the brain. For this reason GJs have been regarded as an important component within the neuronal networks that underlie synchronous neuronal activity and field potential oscillations. Initially, GJs appeared to play a particularly key role in the generation of high frequency oscillatory patterns in field potentials. In order to assess the scale of neuronal GJs contribution to field potential oscillations in the hippocampal formation, in vivo and in vitro studies are reviewed here. These investigations have shown that blocking the main neuronal GJs, those containing connexin 36 (Cx36-GJs), or knocking out the Cx36 gene affect field potential oscillatory patterns related to awake active behavior (gamma and theta rhythm) but have no effect on high frequency oscillations occurring during silent wake and sleep. Precisely how Cx36-GJs influence population activity of neurons is more complex than previously thought. Analysis of studies on the properties of transmission through GJ channels as well as Cx36-GJs functioning in pairs of coupled neurons provides some explanations of the specific influence of Cx36-GJs on field potential oscillations. It is proposed here that GJ transmission is strongly modulated by the level of neuronal network activity and changing behavioral states. Therefore, contribution of GJs to field potential oscillatory patterns depends on the behavioral state. I propose here a model, based on large body of experimental data gathered in this field by several authors, in which Cx36-GJ transmission especially contributes to oscillations related to active behavior, where it plays a role in filtering and enhancing coherent signals in the network under high-noise conditions. In contrast

  15. Loss of asymmetric spine synapses in dorsolateral prefrontal cortex of cognitively-impaired phencyclidine-treated monkeys

    Science.gov (United States)

    Elsworth, John D.; Hajszan, Tibor; Leranth, Csaba; Roth, Robert H.

    2012-01-01

    Schizophrenic patients, long-term abusers of phencyclidine (PCP), and monkeys treated with PCP all exhibit enduring cognitive deficits. Evidence indicates that loss of prefrontal cortex spine synapses results in cognitive dysfunction, suggesting the presence of synaptic pathology in the monkey PCP model; however, there is no direct evidence of such changes. Here we use the monkey PCP model of schizophrenia to investigate at the ultrastructural level whether remodeling of dorsolateral prefrontal cortex (DLPFC) asymmetric spine synapses occurs following PCP. Subchronic PCP treatment resulted in a decrease in the number of asymmetric spine synapses, which was greater in layer II/III than V of DLPFC, compared to vehicle-treated controls. This decrease may contribute to PCP-induced cognitive dysfunction in the nonhuman primate model and perhaps in schizophrenia. Thus, the synapse loss in the PCP model provides a novel target for the development of potential treatments of cognitive dysfunction in this model and in schizophrenia. PMID:21733230

  16. Antigp41 antibodies fail to block early events of virological synapses but inhibit HIV spread between T cells

    National Research Council Canada - National Science Library

    Massanella, Marta; Puigdomènech, Isabel; Cabrera, Cecilia; Fernandez-Figueras, Maria Teresa; Aucher, Anne; Gaibelet, Gerald; Hudrisier, Denis; García, Elisabet; Bofill, Margarita; Clotet, Bonaventura; Blanco, Julià

    2009-01-01

    Compared with cell-free viral infection, virological synapses increase HIV capture by target cells, viral infectivity and cytopathicity, and are believed to be less sensitive to antibody neutralization...

  17. MTM-6, a phosphoinositide phosphatase, is required to promote synapse formation in Caenorhabditis elegans.

    Science.gov (United States)

    Ericson, Vivian R; Spilker, Kerri A; Tugizova, Madina S; Shen, Kang

    2014-01-01

    Forming the proper number of synapses is crucial for normal neuronal development. We found that loss of function of the phosphoinositide phosphatase mtm-6 results in a reduction in the number of synaptic puncta. The reduction in synapses is partially the result of MTM-6 regulation of the secretion of the Wnt ligand EGL-20 from cells in the tail and partially the result of neuronal action. MTM-6 shows relative specificity for EGL-20 over the other Wnt ligands. We suggest that the ability of MTM-6 to regulate EGL-20 secretion is a function of its expression pattern. We conclude that regulation of secretion of different Wnt ligands can use different components. Additionally, we present a novel neuronal function for MTM-6.

  18. Retrogradely Transported TrkA Endosomes Signal Locally within Dendrites to Maintain Sympathetic Neuron Synapses

    Directory of Open Access Journals (Sweden)

    Kathryn M. Lehigh

    2017-04-01

    Full Text Available Sympathetic neurons require NGF from their target fields for survival, axonal target innervation, dendritic growth and formation, and maintenance of synaptic inputs from preganglionic neurons. Target-derived NGF signals are propagated retrogradely, from distal axons to somata of sympathetic neurons via TrkA signaling endosomes. We report that a subset of TrkA endosomes that are transported from distal axons to cell bodies translocate into dendrites, where they are signaling competent and move bidirectionally, in close proximity to synaptic protein clusters. Using a strategy for spatially confined inhibition of TrkA kinase activity, we found that distal-axon-derived TrkA signaling endosomes are necessary within sympathetic neuron dendrites for maintenance of synapses. Thus, TrkA signaling endosomes have unique functions in different cellular compartments. Moreover, target-derived NGF mediates circuit formation and synapse maintenance through TrkA endosome signaling within dendrites to promote aggregation of postsynaptic protein complexes.

  19. The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice.

    Science.gov (United States)

    Sia, G M; Clem, R L; Huganir, R L

    2013-11-22

    Synapse formation in the developing brain depends on the coordinated activity of synaptogenic proteins, some of which have been implicated in a number of neurodevelopmental disorders. Here, we show that the sushi repeat-containing protein X-linked 2 (SRPX2) gene encodes a protein that promotes synaptogenesis in the cerebral cortex. In humans, SRPX2 is an epilepsy- and language-associated gene that is a target of the foxhead box protein P2 (FoxP2) transcription factor. We also show that FoxP2 modulates synapse formation through regulating SRPX2 levels and that SRPX2 reduction impairs development of ultrasonic vocalization in mice. Our results suggest FoxP2 modulates the development of neural circuits through regulating synaptogenesis and that SRPX2 is a synaptogenic factor that plays a role in the pathogenesis of language disorders.

  20. Mimicking Neurotransmitter Release in Chemical Synapses via Hysteresis Engineering in MoS2 Transistors.

    Science.gov (United States)

    Arnold, Andrew J; Razavieh, Ali; Nasr, Joseph R; Schulman, Daniel S; Eichfeld, Chad M; Das, Saptarshi

    2017-03-28

    Neurotransmitter release in chemical synapses is fundamental to diverse brain functions such as motor action, learning, cognition, emotion, perception, and consciousness. Moreover, improper functioning or abnormal release of neurotransmitter is associated with numerous neurological disorders such as epilepsy, sclerosis, schizophrenia, Alzheimer's disease, and Parkinson's disease. We have utilized hysteresis engineering in a back-gated MoS2 field effect transistor (FET) in order to mimic such neurotransmitter release dynamics in chemical synapses. All three essential features, i.e., quantal, stochastic, and excitatory or inhibitory nature of neurotransmitter release, were accurately captured in our experimental demonstration. We also mimicked an important phenomenon called long-term potentiation (LTP), which forms the basis of human memory. Finally, we demonstrated how to engineer the LTP time by operating the MoS2 FET in different regimes. Our findings could provide a critical component toward the design of next-generation smart and intelligent human-like machines and human-machine interfaces.

  1. Reciprocal synapses between mushroom body and dopamine neurons form a positive feedback loop required for learning.

    Science.gov (United States)

    Cervantes-Sandoval, Isaac; Phan, Anna; Chakraborty, Molee; Davis, Ronald L

    2017-05-10

    Current thought envisions dopamine neurons conveying the reinforcing effect of the unconditioned stimulus during associative learning to the axons of Drosophila mushroom body Kenyon cells for normal olfactory learning. Here, we show using functional GFP reconstitution experiments that Kenyon cells and dopamine neurons from axoaxonic reciprocal synapses. The dopamine neurons receive cholinergic input via nicotinic acetylcholine receptors from the Kenyon cells; knocking down these receptors impairs olfactory learning revealing the importance of these receptors at the synapse. Blocking the synaptic output of Kenyon cells during olfactory conditioning reduces presynaptic calcium transients in dopamine neurons, a finding consistent with reciprocal communication. Moreover, silencing Kenyon cells decreases the normal chronic activity of the dopamine neurons. Our results reveal a new and critical role for positive feedback onto dopamine neurons through reciprocal connections with Kenyon cells for normal olfactory learning.

  2. Simultaneous Membrane Capacitance Measurements and TIRF Microscopy to Study Granule Trafficking at Immune Synapses.

    Science.gov (United States)

    Sleiman, Marwa; Stevens, David R; Rettig, Jens

    2017-01-01

    Whole-cell capacitance measurements allow the direct measurement of exocytosis with high temporal resolution. An added benefit of the whole-cell configuration is the possibility to control the cytosolic free calcium concentration allowing examination of the role of intracellular calcium in a variety of processes. We have coupled this method with imaging of cytotoxic granule release using total internal reflection fluorescence microscopy (TIRFM) to identify the capacitance steps associated with cytotoxic granule release identified by TIRFM. This requires the use of fluorescent granule markers to identify cytotoxic granules and allows characterization of cytotoxic granule fusion and of the behavior of cytotoxic granules at the immune synapse prior to fusion. Combination of these methods enables the study of a number of processes relevant to the function of the immune synapse.

  3. Physical aspects of low power synapses based on phase change memory devices

    Science.gov (United States)

    Suri, Manan; Bichler, Olivier; Querlioz, Damien; Traoré, Boubacar; Cueto, Olga; Perniola, Luca; Sousa, Veronique; Vuillaume, Dominique; Gamrat, Christian; DeSalvo, Barbara

    2012-09-01

    In this work, we demonstrate how phase change memory (PCM) devices can be used to emulate biologically inspired synaptic functions in particular, potentiation and depression, important for implementing neuromorphic hardware. PCM devices with different chalcogenide materials are fabricated and characterized. The asymmetry between the potentiation and depression behaviors of the PCM is stressed. Detailed multi-physical simulations are performed to study the underlying physics of the synaptic behavior of PCM. A versatile behavioral model and a multi-level circuit-compatible model are developed for system and circuit-level neuromorphic simulations. We propose a unique low-power methodology named the 2-PCM Synapse, to use PCM devices as synapses in large scale neuromorphic systems. To show the strength of our proposed solution, we efficiently simulated fully connected feed-forward spiking neural network capable of complex visual pattern extraction from real world data.

  4. N-cofilin can compensate for the loss of ADF in excitatory synapses.

    Science.gov (United States)

    Görlich, Andreas; Wolf, Michael; Zimmermann, Anika-Maria; Gurniak, Christine B; Al Banchaabouchi, Mumna; Sassoè-Pognetto, Marco; Witke, Walter; Friauf, Eckhard; Rust, Marco B

    2011-01-01

    Actin plays important roles in a number of synaptic processes, including synaptic vesicle organization and exocytosis, mobility of postsynaptic receptors, and synaptic plasticity. However, little is known about the mechanisms that control actin at synapses. Actin dynamics crucially depend on LIM kinase 1 (LIMK1) that controls the activity of the actin depolymerizing proteins of the ADF/cofilin family. While analyses of mouse mutants revealed the importance of LIMK1 for both pre- and postsynaptic mechanisms, the ADF/cofilin family member n-cofilin appears to be relevant merely for postsynaptic plasticity, and not for presynaptic physiology. By means of immunogold electron microscopy and immunocytochemistry, we here demonstrate the presence of ADF (actin depolymerizing factor), a close homolog of n-cofilin, in excitatory synapses, where it is particularly enriched in presynaptic terminals. Surprisingly, genetic ablation of ADF in mice had no adverse effects on synapse structure or density as assessed by electron microscopy and by the morphological analysis of Golgi-stained hippocampal pyramidal cells. Moreover, a series of electrophysiological recordings in acute hippocampal slices revealed that presynaptic recruitment and exocytosis of synaptic vesicles as well as postsynaptic plasticity were unchanged in ADF mutant mice. The lack of synaptic defects may be explained by the elevated n-cofilin levels observed in synaptic structures of ADF mutants. Indeed, synaptic actin regulation was impaired in compound mutants lacking both ADF and n-cofilin, but not in ADF single mutants. From our results we conclude that n-cofilin can compensate for the loss of ADF in excitatory synapses. Further, our data suggest that ADF and n-cofilin cooperate in controlling synaptic actin content.

  5. N-cofilin can compensate for the loss of ADF in excitatory synapses.

    Directory of Open Access Journals (Sweden)

    Andreas Görlich

    Full Text Available Actin plays important roles in a number of synaptic processes, including synaptic vesicle organization and exocytosis, mobility of postsynaptic receptors, and synaptic plasticity. However, little is known about the mechanisms that control actin at synapses. Actin dynamics crucially depend on LIM kinase 1 (LIMK1 that controls the activity of the actin depolymerizing proteins of the ADF/cofilin family. While analyses of mouse mutants revealed the importance of LIMK1 for both pre- and postsynaptic mechanisms, the ADF/cofilin family member n-cofilin appears to be relevant merely for postsynaptic plasticity, and not for presynaptic physiology. By means of immunogold electron microscopy and immunocytochemistry, we here demonstrate the presence of ADF (actin depolymerizing factor, a close homolog of n-cofilin, in excitatory synapses, where it is particularly enriched in presynaptic terminals. Surprisingly, genetic ablation of ADF in mice had no adverse effects on synapse structure or density as assessed by electron microscopy and by the morphological analysis of Golgi-stained hippocampal pyramidal cells. Moreover, a series of electrophysiological recordings in acute hippocampal slices revealed that presynaptic recruitment and exocytosis of synaptic vesicles as well as postsynaptic plasticity were unchanged in ADF mutant mice. The lack of synaptic defects may be explained by the elevated n-cofilin levels observed in synaptic structures of ADF mutants. Indeed, synaptic actin regulation was impaired in compound mutants lacking both ADF and n-cofilin, but not in ADF single mutants. From our results we conclude that n-cofilin can compensate for the loss of ADF in excitatory synapses. Further, our data suggest that ADF and n-cofilin cooperate in controlling synaptic actin content.

  6. Natural Killer Cell Lytic Granule Secretion Occurs through a Pervasive Actin Network at the Immune Synapse

    OpenAIRE

    Brown, Alice C. N.; Stephane Oddos; Dobbie, Ian M.; Juha-Matti Alakoskela; Parton, Richard M.; Philipp Eissmann; Neil, Mark A. A.; Christopher Dunsby; French, Paul M. W.; Ilan Davis; Daniel M Davis

    2011-01-01

    Natural Killer (NK) cells are innate immune cells that secrete lytic granules to directly kill virus-infected or transformed cells across an immune synapse. However, a major gap in understanding this process is in establishing how lytic granules pass through the mesh of cortical actin known to underlie the NK cell membrane. Research has been hampered by the resolution of conventional light microscopy, which is too low to resolve cortical actin during lytic granule secretion. Here we use two h...

  7. Nonnociceptive afferent activity depresses nocifensive behavior and nociceptive synapses via an endocannabinoid-dependent mechanism.

    Science.gov (United States)

    Yuan, Sharleen; Burrell, Brian D

    2013-12-01

    Previously, low-frequency stimulation (LFS) of a nonnociceptive touch-sensitive neuron has been found to elicit endocannabinoid-dependent long-term depression (eCB-LTD) in nociceptive synapses in the leech central nervous system (CNS) that requires activation of a presynaptic transient receptor potential vanilloid (TRPV)-like receptor by postsynaptically synthesized 2-arachidonoyl glycerol (2-AG). This capacity of nonnociceptive afferent activity to reduce nociceptive signaling resembles gate control of pain, albeit longer lasting in these synaptic experiments. Since eCB-LTD has been observed at a single sensory-motor synapse, this study examines the functional relevance of this mechanism, specifically whether this form of synaptic plasticity has similar effects at the behavioral level in which additional, intersegmental neural circuits are engaged. Experiments were carried out using a semi-intact preparation that permitted both synaptic recordings and monitoring of the leech whole body shortening, a defensive withdrawal reflex that was elicited via intracellular stimulation of a single nociceptive neuron (the N cell). The same LFS of a nonnociceptive afferent that induced eCB-LTD in single synapses also produced an attenuation of the shortening reflex. Similar attenuation of behavior was also observed when 2-AG was applied. LFS-induced behavioral and synaptic depression was blocked by tetrahydrolipstatin (THL), a diacylglycerol lipase inhibitor, and by SB366791, a TRPV1 antagonist. The effects of both THL and SB366791 were observed following either bath application of the drug or intracellular injection into the presynaptic (SB366791) or postsynaptic (THL) neuron. These findings demonstrate a novel, endocannabinoid-based mechanism by which nonnociceptive afferent activity may modulate nocifensive behaviors via action on primary afferent synapses.

  8. Flavonoid Hesperidin Induces Synapse Formation and Improves Memory Performance through the Astrocytic TGF-β1

    Directory of Open Access Journals (Sweden)

    Isadora Matias

    2017-06-01

    Full Text Available Synapse formation and function are critical events for the brain function and cognition. Astrocytes are active participants in the control of synapses during development and adulthood, but the mechanisms underlying astrocyte synaptogenic potential only began to be better understood recently. Currently, new drugs and molecules, including the flavonoids, have been studied as therapeutic alternatives for modulation of cognitive processes in physiological and pathological conditions. However, the cellular targets and mechanisms of actions of flavonoids remain poorly elucidated. In the present study, we investigated the effects of hesperidin on memory and its cellular and molecular targets in vivo and in vitro, by using a short-term protocol of treatment. The novel object recognition test (NOR was used to evaluate memory performance of mice intraperitoneally treated with hesperidin 30 min before the training and again before the test phase. The direct effects of hesperidin on synapses and astrocytes were also investigated using in vitro approaches. Here, we described hesperidin as a new drug able to improve memory in healthy adult mice by two main mechanisms: directly, by inducing synapse formation and function between hippocampal and cortical neurons; and indirectly, by enhancing the synaptogenic ability of cortical astrocytes mainly due to increased secretion of transforming growth factor beta-1 (TGF-β1 by these cells. Our data reinforces the known neuroprotective effect of hesperidin and, by the first time, characterizes its synaptogenic action on the central nervous system (CNS, pointing astrocytes and TGF-β1 signaling as new cellular and molecular targets of hesperidin. Our work provides not only new data regarding flavonoid’s actions on the CNS but also shed light on possible new therapeutic alternative based on astrocyte biology.

  9. Flavonoid Hesperidin Induces Synapse Formation and Improves Memory Performance through the Astrocytic TGF-β1

    Science.gov (United States)

    Matias, Isadora; Diniz, Luan P.; Buosi, Andrea; Neves, Gilda; Stipursky, Joice; Gomes, Flávia Carvalho Alcantara

    2017-01-01

    Synapse formation and function are critical events for the brain function and cognition. Astrocytes are active participants in the control of synapses during development and adulthood, but the mechanisms underlying astrocyte synaptogenic potential only began to be better understood recently. Currently, new drugs and molecules, including the flavonoids, have been studied as therapeutic alternatives for modulation of cognitive processes in physiological and pathological conditions. However, the cellular targets and mechanisms of actions of flavonoids remain poorly elucidated. In the present study, we investigated the effects of hesperidin on memory and its cellular and molecular targets in vivo and in vitro, by using a short-term protocol of treatment. The novel object recognition test (NOR) was used to evaluate memory performance of mice intraperitoneally treated with hesperidin 30 min before the training and again before the test phase. The direct effects of hesperidin on synapses and astrocytes were also investigated using in vitro approaches. Here, we described hesperidin as a new drug able to improve memory in healthy adult mice by two main mechanisms: directly, by inducing synapse formation and function between hippocampal and cortical neurons; and indirectly, by enhancing the synaptogenic ability of cortical astrocytes mainly due to increased secretion of transforming growth factor beta-1 (TGF-β1) by these cells. Our data reinforces the known neuroprotective effect of hesperidin and, by the first time, characterizes its synaptogenic action on the central nervous system (CNS), pointing astrocytes and TGF-β1 signaling as new cellular and molecular targets of hesperidin. Our work provides not only new data regarding flavonoid’s actions on the CNS but also shed light on possible new therapeutic alternative based on astrocyte biology. PMID:28659786

  10. Three-terminal ferroelectric synapse device with concurrent learning function for artificial neural networks

    Energy Technology Data Exchange (ETDEWEB)

    Nishitani, Y.; Kaneko, Y.; Ueda, M.; Fujii, E. [Advanced Technology Research Laboratories, Panasonic Corporation, Seika, Kyoto 619-0237 (Japan); Morie, T. [Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Wakamatsu-ku, Kitakyushu 808-0196 (Japan)

    2012-06-15

    Spike-timing-dependent synaptic plasticity (STDP) is demonstrated in a synapse device based on a ferroelectric-gate field-effect transistor (FeFET). STDP is a key of the learning functions observed in human brains, where the synaptic weight changes only depending on the spike timing of the pre- and post-neurons. The FeFET is composed of the stacked oxide materials with ZnO/Pr(Zr,Ti)O{sub 3} (PZT)/SrRuO{sub 3}. In the FeFET, the channel conductance can be altered depending on the density of electrons induced by the polarization of PZT film, which can be controlled by applying the gate voltage in a non-volatile manner. Applying a pulse gate voltage enables the multi-valued modulation of the conductance, which is expected to be caused by a change in PZT polarization. This variation depends on the height and the duration of the pulse gate voltage. Utilizing these characteristics, symmetric and asymmetric STDP learning functions are successfully implemented in the FeFET-based synapse device by applying the non-linear pulse gate voltage generated from a set of two pulses in a sampling circuit, in which the two pulses correspond to the spikes from the pre- and post-neurons. The three-terminal structure of the synapse device enables the concurrent learning, in which the weight update can be performed without canceling signal transmission among neurons, while the neural networks using the previously reported two-terminal synapse devices need to stop signal transmission for learning.

  11. A matter of balance: role of neurexin and neuroligin at the synapse.

    Science.gov (United States)

    Bang, Marie Louise; Owczarek, Sylwia

    2013-06-01

    Neurexins and neuroligins are synaptic cell adhesion molecules. Neurexins are primary located on the presynaptic membrane, whereas neuroligins are strictly postsynaptic proteins. Since their discovery, the knowledge of neurexins and neuroligins has expanded, implicating them in various neuronal processes, including the differentiation, maturation, stabilization, and plasticity of both inhibitory and excitatory synapses. Here, we review the most recent results regarding the structure and function of these cell adhesion molecules.

  12. Selective block of postsynaptic kainate receptors reveals their function at hippocampal mossy fiber synapses.

    Science.gov (United States)

    Pinheiro, Paulo S; Lanore, Frédéric; Veran, Julien; Artinian, Julien; Blanchet, Christophe; Crépel, Valérie; Perrais, David; Mulle, Christophe

    2013-02-01

    Progress in understanding the roles of kainate receptors (KARs) in synaptic integration, synaptic networks, and higher brain function has been hampered by the lack of selective pharmacological tools. We have found that UBP310 and related willardiine derivatives, previously characterized as selective GluK1 and GluK3 KAR antagonists, block postsynaptic KARs at hippocampal mossy fiber (MF) CA3 synapses while sparing AMPA and NMDA receptors. We further show that UBP310 is an antagonist of recombinant GluK2/GluK5 receptors, the major population of KARs in the brain. Postsynaptic KAR receptor blockade at MF synapses significantly reduces the sustained depolarization, which builds up during repetitive activity, and impacts on spike transmission mediated by heterosynaptic signals. In addition, KARs present in aberrant MF synapses in the epileptic hippocampus were also blocked by UBP310. Our results support a specific role for postsynaptic KARs in synaptic integration of CA3 pyramidal cells and describe a tool that will be instrumental in understanding the physiopathological role of KARs in the brain.

  13. Automated detection of synapses in serial section transmission electron microscopy image stacks.

    Directory of Open Access Journals (Sweden)

    Anna Kreshuk

    Full Text Available We describe a method for fully automated detection of chemical synapses in serial electron microscopy images with highly anisotropic axial and lateral resolution, such as images taken on transmission electron microscopes. Our pipeline starts from classification of the pixels based on 3D pixel features, which is followed by segmentation with an Ising model MRF and another classification step, based on object-level features. Classifiers are learned on sparse user labels; a fully annotated data subvolume is not required for training. The algorithm was validated on a set of 238 synapses in 20 serial 7197×7351 pixel images (4.5×4.5×45 nm resolution of mouse visual cortex, manually labeled by three independent human annotators and additionally re-verified by an expert neuroscientist. The error rate of the algorithm (12% false negative, 7% false positive detections is better than state-of-the-art, even though, unlike the state-of-the-art method, our algorithm does not require a prior segmentation of the image volume into cells. The software is based on the ilastik learning and segmentation toolkit and the vigra image processing library and is freely available on our website, along with the test data and gold standard annotations (http://www.ilastik.org/synapse-detection/sstem.

  14. Automated detection of synapses in serial section transmission electron microscopy image stacks.

    Science.gov (United States)

    Kreshuk, Anna; Koethe, Ullrich; Pax, Elizabeth; Bock, Davi D; Hamprecht, Fred A

    2014-01-01

    We describe a method for fully automated detection of chemical synapses in serial electron microscopy images with highly anisotropic axial and lateral resolution, such as images taken on transmission electron microscopes. Our pipeline starts from classification of the pixels based on 3D pixel features, which is followed by segmentation with an Ising model MRF and another classification step, based on object-level features. Classifiers are learned on sparse user labels; a fully annotated data subvolume is not required for training. The algorithm was validated on a set of 238 synapses in 20 serial 7197×7351 pixel images (4.5×4.5×45 nm resolution) of mouse visual cortex, manually labeled by three independent human annotators and additionally re-verified by an expert neuroscientist. The error rate of the algorithm (12% false negative, 7% false positive detections) is better than state-of-the-art, even though, unlike the state-of-the-art method, our algorithm does not require a prior segmentation of the image volume into cells. The software is based on the ilastik learning and segmentation toolkit and the vigra image processing library and is freely available on our website, along with the test data and gold standard annotations (http://www.ilastik.org/synapse-detection/sstem).

  15. The central role of the cytoskeleton in mechanisms and functions of the NK cell immune synapse.

    Science.gov (United States)

    Lagrue, Kathryn; Carisey, Alex; Oszmiana, Anna; Kennedy, Philippa R; Williamson, David J; Cartwright, Adam; Barthen, Charlotte; Davis, Daniel M

    2013-11-01

    Natural killer (NK) cells discriminate between healthy and unhealthy target cells through a balance of activating and inhibitory signals at direct intercellular contacts called immune synapses. Rearrangements in the cellular cytoskeleton have long been known to be critical in assembly of immune synapses. Here, through bringing together the vast literature on this subject, the number of different ways in which the cytoskeleton is important becomes evident. The dynamics of filamentous actin are critical in (i) creating the nanometer-scale organization of NK cell receptors, (ii) establishing cellular polarity, (iii) coordinating immune receptor and integrin-mediated signaling, and (iv) directing secretion of lytic granules and cytokines. The microtubule network also is important in the delivery of lytic granules and vesicles containing cytokines to the immune synapse. Together, these data establish that the cytoskeleton acts as a central regulator of this complex and dynamic process - and an enormous amount of NK cell biology is controlled through the cytoskeleton. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses

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    Tanaka Mika

    2013-01-01

    Full Text Available Abstract Background Neuronal activity alters calcium ion (Ca2+ dynamics in astrocytes, but the physiologic relevance of these changes is controversial. To examine this issue further, we generated an inducible transgenic mouse model in which the expression of an inositol 1,4,5-trisphosphate absorbent, “IP3 sponge”, attenuates astrocytic Ca2+ signaling. Results Attenuated Ca2+ activity correlated with reduced astrocytic coverage of asymmetric synapses in the hippocampal CA1 region in these animals. The decreased astrocytic ‘protection’ of the synapses facilitated glutamate ‘spillover’, which was reflected by prolonged glutamate transporter currents in stratum radiatum astrocytes and enhanced N-methyl-D-aspartate receptor currents in CA1 pyramidal neurons in response to burst stimulation. These mice also exhibited behavioral impairments in spatial reference memory and remote contextual fear memory, in which hippocampal circuits are involved. Conclusions Our findings suggest that IP3-mediated astrocytic Ca2+ signaling correlates with the formation of functional tripartite synapses in the hippocampus.

  17. The Demise of the Synapse As the Locus of Memory: A Looming Paradigm Shift?

    Science.gov (United States)

    Trettenbrein, Patrick C

    2016-01-01

    Synaptic plasticity is widely considered to be the neurobiological basis of learning and memory by neuroscientists and researchers in adjacent fields, though diverging opinions are increasingly being recognized. From the perspective of what we might call "classical cognitive science" it has always been understood that the mind/brain is to be considered a computational-representational system. Proponents of the information-processing approach to cognitive science have long been critical of connectionist or network approaches to (neuro-)cognitive architecture, pointing to the shortcomings of the associative psychology that underlies Hebbian learning as well as to the fact that synapses are practically unfit to implement symbols. Recent work on memory has been adding fuel to the fire and current findings in neuroscience now provide first tentative neurobiological evidence for the cognitive scientists' doubts about the synapse as the (sole) locus of memory in the brain. This paper briefly considers the history and appeal of synaptic plasticity as a memory mechanism, followed by a summary of the cognitive scientists' objections regarding these assertions. Next, a variety of tentative neuroscientific evidence that appears to substantiate questioning the idea of the synapse as the locus of memory is presented. On this basis, a novel way of thinking about the role of synaptic plasticity in learning and memory is proposed.

  18. ELKS2α/CAST Deletion Selectively Increases Neurotransmitter Release at Inhibitory Synapses

    Science.gov (United States)

    Kaeser, Pascal S.; Deng, Lunbin; Chávez, Andrés E.; Liu, Xinran; Castillo, Pablo E.; Südhof, Thomas C.

    2009-01-01

    SUMMARY The presynaptic active zone is composed of a protein-network that contains ELKS2α (a.k.a. CAST) as a central component. Here we demonstrate that in mice, deletion of ELKS2α caused a large increase in inhibitory but not excitatory neurotransmitter release, and potentiated the size, but not the properties, of the readily-releasable pool of vesicles at inhibitory synapses. Quantitative electron-microscopy revealed that the ELKS2α deletion did not change the number of docked vesicles or other ultrastructural parameters of synapses, except for a small decrease in synaptic vesicle numbers. The ELKS2α deletion did, however, alter the excitatory/inhibitory balance and exploratory behaviors, possibly as a result of the increased synaptic inhibition. Thus, different from previous studies indicating that ELKS2α is essential for mediating neurotransmitter release, our results suggest that ELKS2α normally restricts release and limits the size of the readily-releasable pool of synaptic vesicles at the active zone of inhibitory synapses. PMID:19874790

  19. ELKS2alpha/CAST deletion selectively increases neurotransmitter release at inhibitory synapses.

    Science.gov (United States)

    Kaeser, Pascal S; Deng, Lunbin; Chávez, Andrés E; Liu, Xinran; Castillo, Pablo E; Südhof, Thomas C

    2009-10-29

    The presynaptic active zone is composed of a protein network that contains ELKS2alpha (a.k.a. CAST) as a central component. Here we demonstrate that in mice, deletion of ELKS2alpha caused a large increase in inhibitory, but not excitatory, neurotransmitter release, and potentiated the size, but not the properties, of the readily-releasable pool of vesicles at inhibitory synapses. Quantitative electron microscopy revealed that the ELKS2alpha deletion did not change the number of docked vesicles or other ultrastructural parameters of synapses, except for a small decrease in synaptic vesicle numbers. The ELKS2alpha deletion did, however, alter the excitatory/inhibitory balance and exploratory behaviors, possibly as a result of the increased synaptic inhibition. Thus, as opposed to previous studies indicating that ELKS2alpha is essential for mediating neurotransmitter release, our results suggest that ELKS2alpha normally restricts release and limits the size of the readily-releasable pool of synaptic vesicles at the active zone of inhibitory synapses.

  20. The role of MuSK in synapse formation and neuromuscular disease.

    Science.gov (United States)

    Burden, Steven J; Yumoto, Norihiro; Zhang, Wei

    2013-05-01

    Muscle-specific kinase (MuSK) is essential for each step in neuromuscular synapse formation. Before innervation, MuSK initiates postsynaptic differentiation, priming the muscle for synapse formation. Approaching motor axons recognize the primed, or prepatterned, region of muscle, causing motor axons to stop growing and differentiate into specialized nerve terminals. MuSK controls presynaptic differentiation by causing the clustering of Lrp4, which functions as a direct retrograde signal for presynaptic differentiation. Developing synapses are stabilized by neuronal Agrin, which is released by motor nerve terminals and binds to Lrp4, a member of the low-density lipoprotein receptor family, stimulating further association between Lrp4 and MuSK and increasing MuSK kinase activity. In addition, MuSK phosphorylation is stimulated by an inside-out ligand, docking protein-7 (Dok-7), which is recruited to tyrosine-phosphorylated MuSK and increases MuSK kinase activity. Mutations in MuSK and in genes that function in the MuSK signaling pathway, including Dok-7, cause congenital myasthenia, and autoantibodies to MuSK, Lrp4, and acetylcholine receptors are responsible for myasthenia gravis.

  1. The extracellular region of Lrp4 is sufficient to mediate neuromuscular synapse formation.

    Science.gov (United States)

    Gomez, Andrea M; Burden, Steven J

    2011-12-01

    Neuromuscular synapse formation requires an exchange of signals between motor neurons and muscle. Agrin, supplied by motor neurons, binds to Lrp4 in muscle, stimulating phosphorylation of MuSK and recruitment of a signaling complex essential for synapse-specific transcription and anchoring of key proteins in the postsynaptic membrane. Lrp4, like the LDLR and other Lrp-family members, contains an intracellular region with motifs that can regulate receptor trafficking, as well as assembly of an intracellular signaling complex. Here, we show that the intracellular region of Lrp4 is dispensable for Agrin to stimulate MuSK phosphorylation and clustering of acetylcholine receptors in cultured myotubes. Moreover, muscle-selective expression of a Lrp4-CD4 chimera, composed of the extracellular and transmembrane regions of Lrp4 and the intracellular region of CD4, rescues neuromuscular synapse formation and the neonatal lethality of lrp4 mutant mice, demonstrating that Lrp4, lacking the Lrp4 intracellular region, is sufficient for presynaptic and postsynaptic differentiation. Copyright © 2011 Wiley Periodicals, Inc.

  2. The demise of the synapse as the locus of memory: A looming paradigm shift?

    Directory of Open Access Journals (Sweden)

    Patrick C. Trettenbrein

    2016-11-01

    Full Text Available Synaptic plasticity is widely considered to be the neurobiological basis of learning and memory by neuroscientists and researchers in adjacent fields, though diverging opinions are increasingly being recognised. From the perspective of what we might call classical cognitive science it has always been understood that the mind/brain is to be considered a computational-representational system. Proponents of the information-processing approach to cognitive science have long been critical of connectionist or network approaches to (neuro-cognitive architecture, pointing to the shortcomings of the associative psychology that underlies Hebbian learning as well as to the fact that synapses are practically unfit to implement symbols. Recent work on memory has been adding fuel to the fire and current findings in neuroscience now provide first tentative neurobiological evidence for the cognitive scientists’ doubts about the synapse as the (sole locus of memory in the brain. This paper briefly considers the history and appeal of synaptic plasticity as a memory mechanism, followed by a summary of the cognitive scientists’ objections regarding these assertions. Next, a variety of tentative neuroscientific evidence that appears to substantiate questioning the idea of the synapse as the locus of memory is presented. On this basis, a novel way of thinking about the role of synaptic plasticity in learning and memory is proposed.

  3. Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses

    Directory of Open Access Journals (Sweden)

    Paola eZacchi

    2014-04-01

    Full Text Available Gephyrin is a multifunctional scaffold protein essential for the postsynaptic accumulation of inhibitory glycine and GABAA receptors at synaptic sites. The molecular events involved in gephyrin-dependent GABAA receptor clustering are still unclear. Evidence has been recently provided that gephyrin phosphorylation plays a key role in these processes. By impinging upon its post-synaptic scaffolding properties as well as its stability, gephyrin post-translational modifications have been shown to impact on the structural remodeling of GABAergic synapses leading to synaptic plasticity. In addition, not only gephyrin phosphorylation per se but also the subsequent phosphorylation-dependent recruitment of the chaperone molecule Pin1 represents an emerging mechanism to regulate GABAergic signaling. Extensively characterized as pivotal enzyme controlling cell proliferation and differentiation, the prolyl-isomerase activity of Pin1 has been shown to regulate protein synthesis necessary to sustain the late phase of long-term potentiation at excitatory synapses, thus suggesting its involvement at synaptic sites. In this review we will summarize the current state of knowledge on the signaling pathways responsible for gephyrin post-translational modifications. We will also outline future lines of research that might contribute to better unveil the molecular mechanisms by which gephyrin regulates synaptic plasticity processes at GABAergic synapses.

  4. Recurrent synapses and circuits in the CA3 region of the hippocampus: an associative network.

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    Richard eMiles

    2014-01-01

    Full Text Available In the CA3 region of the hippocampus, pyramidal cells excite other pyramidal cells and interneurons. The axons of CA3 pyramidal cells spread throughout most of the region to form an associative network. These connections were first drawn by Cajal and Lorente de No. Their physiological properties were explored to understand epileptiform discharges generated in the region. Synapses between pairs of pyramidal cells involve one or few release sites and are weaker than connections made by mossy fibres on CA3 pyramidal cells. Synapses with interneurons are rather effective, as needed to control unchecked excitation. We examine contributions of recurrent synapses to epileptiform synchrony, to the genesis of sharp waves in the CA3 region and to population oscillations at theta and gamma frequencies. Recurrent connections in CA3, as other associative cortices, have a lower connectivity spread over a larger area than in primary sensory cortices. This sparse, but wide-ranging connectivity serves the functions of an associative network, including acquisition of neuronal representations as activity in groups of CA3 cells and completion involving the recall from partial cues of these ensemble firing patterns.

  5. [Morphometric studies of biological changes in synapses of the human caudate nucleus].

    Science.gov (United States)

    Eggers, R; Knebel, G; Haug, H

    1991-01-01

    In the adult the caudate nucleus decreases with increasing age. Light microscopic measurements result in smaller sized neurons and a reduced neuropil in the aged. Comparable to a sintering, nerve cells move nearer, and in consequence, their density increases. The total number of nerve cells, however, does not change remarkably. Using electronmicroscopic methods the aging of synapses was morphometrically examined: Blocks of the caudate nucleus were cut out of formalin-fixed brains from 43 males who had died between the 22nd and 102nd year of age without any neurological symptoms. The blocks were contrasted with EPTA (ethanolic phosphotungstic acid) and embedded in araldite. Though the whole tissue was autolytic, presynaptic and postsynaptic densities were well-preserved and clearly visible. Their numbers and sizes were measured with semiautomatic procedures. The regression analysis shows a significant decrease of the density of synapses with increasing age. The aging of the human caudate nucleus is characterized by a decrease of its volume, by a reduction of the size of neuronal perikarya, and a diminution of the number of synapses per neuron. But the total number of nerve cells remains nearly constant.

  6. Acyl Ghrelin Improves Synapse Recovery in an In Vitro Model of Postanoxic Encephalopathy.

    Science.gov (United States)

    Stoyanova, Irina I; Hofmeijer, Jeannette; van Putten, Michel J A M; le Feber, Joost

    2016-11-01

    Comatose patients after cardiac arrest have a poor prognosis. Approximately half never awakes as a result of severe diffuse postanoxic encephalopathy. Several neuroprotective agents have been tested, however without significant effect. In the present study, we used cultured neuronal networks as a model system to study the general synaptic damage caused by temporary severe hypoxia and the possibility to restrict it by ghrelin treatment. Briefly, we applied hypoxia (pO 2 lowered from 150 to 20 mmHg) during 6 h in 55 cultures. Three hours after restoration of normoxia, half of the cultures were treated with ghrelin for 24 h, while the other, non-supplemented, were used as a control. All cultures were processed immunocytochemically for detection of the synaptic marker synaptophysin. We observed that hypoxia led to drastic decline of the number of synapses, followed by some recovery after return to normoxia, but still below the prehypoxic level. Additionally, synaptic vulnerability was selective: large- and small-sized neurons were more susceptible to synaptic damage than the medium-sized ones. Ghrelin treatment significantly increased the synapse density, as compared with the non-treated controls or with the prehypoxic period. The effect was detected in all neuronal subtypes. In conclusion, exogenous ghrelin has a robust impact on the recovery of cortical synapses after hypoxia. It raises the possibility that ghrelin or its analogs may have a therapeutic potential for treatment of postanoxic encephalopathy.

  7. Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity.

    Science.gov (United States)

    Davenport, A J; Cross, R S; Watson, K A; Liao, Y; Shi, W; Prince, H M; Beavis, P A; Trapani, J A; Kershaw, M H; Ritchie, D S; Darcy, P K; Neeson, P J; Jenkins, M R

    2018-02-12

    Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell. Copyright © 2018 the Author(s). Published by PNAS.

  8. Spiking Neural Networks based on OxRAM Synapses for Real-time Unsupervised Spike Sorting

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    Thilo Werner

    2016-11-01

    Full Text Available In this paper, we present an alternative approach to perform spike sorting of complex brain signals based on spiking neural networks (SNN. The proposed architecture is suitable for hardware implementation by using RRAM technology for the implementation of synapses whose low latency (< 1μs enable real-time spike sorting. This offers promising advantagesto conventional spike sorting techniques for brain-computer interface and neural prosthesis applications. Moreover, the ultralow power consumption of the RRAM synapses of the spiking neural network (nW range may enable the design of autonomous implantable devices for rehabilitation purposes. We demonstrate an original methodology to use Oxide based RRAM (OxRAM as easy to program and low power (< 75 pJ synapses. Synaptic weights are modulated through the application of an online learning strategy inspired by biological Spike Timing Dependent Plasticity. Real spiking data have been recorded both intraand extracellularly from an in-vitro preparation of the Crayfish sensory-motor system and used for validation of the proposed OxRAM based SNN. This artificial SNN is able to identify, learn, recognize and distinguish between different spike shapes in the input signal with a recognition rate about 90% without any supervision.

  9. Physiological and chemical analysis of neurotransmitter candidates at a fast excitatory synapse in the jellyfish Cyanea capillata (Cnidaria, Scyphozoa).

    Science.gov (United States)

    Anderson, Peter A V; Trapido-Rosenthal, H G

    2009-12-01

    Motor nerve net (MNN) neurons in the jellyfish Cyanea capillata communicate with one another by way of fast, bidirectional excitatory chemical synapses. As is the case with almost all identified chemical synapses in cnidarians, the identity of the neurotransmitter at these synapses is unclear. MNN neurons are large enough for stable intracellular recordings. This, together with the fact that they can be exposed, providing unlimited access to them and to their synapses, prompted a study of the action of a variety of neurotransmitter candidates, including those typically associated with fast synapses in higher animals. Only the amino acids taurine and beta-alanine produced physiological responses consistent with those of the normal EPSP in these cells. Moreover, chemical analysis revealed that both taurine and beta-alanine are present in the neurons and released by depolarization. These various findings strongly suggest that either or both of these amino acids, or a closely related compound is the neurotransmitter at the fast chemical synapses between MNN neurons.

  10. Monoacylated Cellular Prion Proteins Reduce Amyloid-β-Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Damage

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    Ewan West

    2015-06-01

    Full Text Available Alzheimer’s disease (AD is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ and the loss of synapses. Aggregation of the cellular prion protein (PrPC by Aβ oligomers induced synapse damage in cultured neurons. PrPC is attached to membranes via a glycosylphosphatidylinositol (GPI anchor, the composition of which affects protein targeting and cell signaling. Monoacylated PrPC incorporated into neurons bound “natural Aβ”, sequestering Aβ outside lipid rafts and preventing its accumulation at synapses. The presence of monoacylated PrPC reduced the Aβ-induced activation of cytoplasmic phospholipase A2 (cPLA2 and Aβ-induced synapse damage. This protective effect was stimulus specific, as treated neurons remained sensitive to α-synuclein, a protein associated with synapse damage in Parkinson’s disease. In synaptosomes, the aggregation of PrPC by Aβ oligomers triggered the formation of a signaling complex containing the cPLA2.a process, disrupted by monoacylated PrPC. We propose that monoacylated PrPC acts as a molecular sponge, binding Aβ oligomers at the neuronal perikarya without activating cPLA2 or triggering synapse damage.

  11. Changes in Properties of Auditory Nerve Synapses following Conductive Hearing Loss.

    Science.gov (United States)

    Zhuang, Xiaowen; Sun, Wei; Xu-Friedman, Matthew A

    2017-01-11

    Auditory activity plays an important role in the development of the auditory system. Decreased activity can result from conductive hearing loss (CHL) associated with otitis media, which may lead to long-term perceptual deficits. The effects of CHL have been mainly studied at later stages of the auditory pathway, but early stages remain less examined. However, changes in early stages could be important because they would affect how information about sounds is conveyed to higher-order areas for further processing and localization. We examined the effects of CHL at auditory nerve synapses onto bushy cells in the mouse anteroventral cochlear nucleus following occlusion of the ear canal. These synapses, called endbulbs of Held, normally show strong depression in voltage-clamp recordings in brain slices. After 1 week of CHL, endbulbs showed even greater depression, reflecting higher release probability. We observed no differences in quantal size between control and occluded mice. We confirmed these observations using mean-variance analysis and the integration method, which also revealed that the number of release sites decreased after occlusion. Consistent with this, synaptic puncta immunopositive for VGLUT1 decreased in area after occlusion. The level of depression and number of release sites both showed recovery after returning to normal conditions. Finally, bushy cells fired fewer action potentials in response to evoked synaptic activity after occlusion, likely because of increased depression and decreased input resistance. These effects appear to reflect a homeostatic, adaptive response of auditory nerve synapses to reduced activity. These effects may have important implications for perceptual changes following CHL. Normal hearing is important to everyday life, but abnormal auditory experience during development can lead to processing disorders. For example, otitis media reduces sound to the ear, which can cause long-lasting deficits in language skills and verbal

  12. Aging alters the molecular dynamics of synapses in a sexually dimorphic pattern in zebrafish (Danio rerio).

    Science.gov (United States)

    Karoglu, Elif Tugce; Halim, Dilara Ozge; Erkaya, Bahriye; Altaytas, Ferda; Arslan-Ergul, Ayca; Konu, Ozlen; Adams, Michelle M

    2017-06-01

    The zebrafish has become a popular model for studying normal brain aging due to its large fecundity, conserved genome, and available genetic tools; but little data exists about neurobiological age-related alterations. The current study tested the hypothesis of an association between brain aging and synaptic protein loss across males and females. Western blot analysis of synaptophysin (SYP), a presynaptic vesicle protein, and postsynaptic density-95 (PSD-95) and gephyrin (GEP), excitatory and inhibitory postsynaptic receptor-clustering proteins, respectively, was performed in young, middle-aged, and old male and female zebrafish (Danio rerio) brains. Univariate and multivariate analyses demonstrated that PSD-95 significantly increased in aged females and SYP significantly decreased in males, but GEP was stable. Thus, these key synaptic proteins vary across age in a sexually dimorphic manner, which has been observed in other species, and these consequences may represent selective vulnerabilities for aged males and females. These data expand our knowledge of normal aging in zebrafish, as well as further establish this model as an appropriate one for examining human brain aging. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Centriole polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems

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    Arico Maurizo

    2011-06-01

    Full Text Available Abstract Background Cytolytic cells of the immune system destroy pathogen-infected cells by polarised exocytosis of secretory lysosomes containing the pore-forming protein perforin. Precise delivery of this lethal hit is essential to ensuring that only the target cell is destroyed. In cytotoxic T lymphocytes (CTLs, this is accomplished by an unusual movement of the centrosome to contact the plasma membrane at the centre of the immunological synapse formed between killer and target cells. Secretory lysosomes are directed towards the centrosome along microtubules and delivered precisely to the point of target cell recognition within the immunological synapse, identified by the centrosome. We asked whether this mechanism of directing secretory lysosome release is unique to CTL or whether natural killer (NK and invariant NKT (iNKT cytolytic cells of the innate immune system use a similar mechanism to focus perforin-bearing lysosome release. Results NK cells were conjugated with B-cell targets lacking major histocompatibility complex class I 721.221 cells, and iNKT cells were conjugated with glycolipid-pulsed CD1-bearing targets, then prepared for thin-section electron microscopy. High-resolution electron micrographs of the immunological synapse formed between NK and iNKT cytolytic cells with their targets revealed that in both NK and iNKT cells, the centrioles could be found associated (or 'docked' with the plasma membrane within the immunological synapse. Secretory clefts were visible within the synapses formed by both NK and iNKT cells, and secretory lysosomes were polarised along microtubules leading towards the docked centrosome. The Golgi apparatus and recycling endosomes were also polarised towards the centrosome at the plasma membrane within the synapse. Conclusions These results reveal that, like CTLs of the adaptive immune system, the centrosomes of NK and iNKT cells (cytolytic cells of the innate immune system direct secretory lysosomes to

  14. Synapse associated protein 102 (SAP102 binds the C-terminal part of the scaffolding protein neurobeachin.

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    Juliane Lauks

    Full Text Available Neurobeachin (Nbea is a multidomain scaffold protein abundant in the brain, where it is highly expressed during development. Nbea-null mice have severe defects in neuromuscular synaptic transmission resulting in lethal paralysis of the newborns. Recently, it became clear that Nbea is important also for the functioning of central synapses, where it is suggested to play a role in trafficking membrane proteins to both, the pre- and post-synaptic sites. So far, only few binding partners of Nbea have been found and the precise mechanism of their trafficking remains unclear. Here, we used mass spectrometry to identify SAP102, a MAGUK protein implicated in trafficking of the ionotropic glutamate AMPA- and NMDA-type receptors during synaptogenesis, as a novel Nbea interacting protein in mouse brain. Experiments in heterologous cells confirmed this interaction and revealed that SAP102 binds to the C-terminal part of Nbea that contains the DUF, PH, BEACH and WD40 domains. Furthermore, we discovered that introducing a mutation in Nbea's PH domain, which disrupts its interaction with the BEACH domain, abolishes this binding, thereby creating an excellent starting point to further investigate Nbea-SAP102 function in the central nervous system.

  15. Class 1 neural excitability, conventional synapses, weakly connected networks, and mathematical foundations of pulse-coupled models.

    Science.gov (United States)

    Izhikevich, E M

    1999-01-01

    Many scientists believe that all pulse-coupled neural networks are toy models that are far away from the biological reality. We show here, however, that a huge class of biophysically detailed and biologically plausible neural-network models can be transformed into a canonical pulse-coupled form by a piece-wise continuous, possibly noninvertible, change of variables. Such transformations exist when a network satisfies a number of conditions; e.g., it is weakly connected; the neurons are Class 1 excitable (i.e., they can generate action potentials with an arbitrary small frequency); and the synapses between neurons are conventional (i.e., axo-dendritic and axo-somatic). Thus, the difference between studying the pulse-coupled model and Hodgkin-Huxley-type neural networks is just a matter of a coordinate change. Therefore, any piece of information about the pulse-coupled model is valuable since it tells something about all weakly connected networks of Class 1 neurons. For example, we show that the pulse-coupled network of identical neurons does not synchronize in-phase. This confirms Ermentrout's result that weakly connected Class 1 neurons are difficult to synchronize, regardless of the equations that describe dynamics of each cell.

  16. Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo

    Directory of Open Access Journals (Sweden)

    Sandkühler Jürgen

    2008-05-01

    Full Text Available Abstract Inflammation, trauma or nerve injury trigger low-level activity in C-fibres and may cause long-lasting hyperalgesia. Long-term potentiation (LTP at synapses of primary afferent C-fibres is considered to underlie some forms of hyperalgesia. In previous studies, high- but not low-frequency conditioning stimulation of C-fibres has, however, been used to induce LTP in pain pathways. Recently we could show that also conditioning low-frequency stimulation (LFS at C-fibre intensity induces LTP in vitro as well as in the intact animal, i.e. with tonic descending inhibition fully active. In the slice preparation, this form of LTP requires a rise in postsynaptic Ca2+-concentration and activation of Ca2+-dependent signalling pathways. Here, we investigated the signalling mechanisms underlying this novel form of LTP in vivo. We found that the signal transduction pathways causing LFS-induced LTP in vivo include activation of neurokinin 1 and N-methyl-D-aspartate receptors, rise of [Ca2+]i from intracellular stores and via T-type voltage-dependent Ca2+ channels, activation of phospholipase C, protein kinase C and Ca2+-calmodulin dependent kinase II. These pathways match those leading to hyperalgesia in behaving animals and humans. We thus propose that LTP induced by low-level activity in C-fibres may underlie some forms of hyperalgesia.

  17. Does metabolic failure at the synapse cause Alzheimer's disease?

    Science.gov (United States)

    Engel, Peter A

    2014-12-01

    Alzheimer's disease (AD) a neurodegenerative disorder of widely distributed cortical networks evolves over years while A beta (Aβ) oligomer neurotoxicity occurs within seconds to minutes. This disparity combined with disappointing outcomes of anti-amyloid clinical trials challenges the centrality of Aβ as principal mediator of neurodegeneration. Reconsideration of late life AD as the end-product of intermittent regional failure of the neuronal support system to meet the needs of vulnerable brain areas offers an alternative point of view. This model introduces four ideas: (1) That Aβ is a synaptic signaling peptide that becomes toxic in circumstances of metabolic stress. (2) That intense synaptic energy and maintenance requirements of cortical hubs may exceed resources during peak demand initiating a neurotoxic cascade in these selectively vulnerable regions. (3) That axonal transport to and from neuron soma cannot account fully for high mitochondrial densities and other requirements of distant terminal axons. (4) That neurons as specialists in information management, delegate generic support functions to astrocytes and other cell types. Astrocytes use intercellular transport by exosomes and tunneling nanotubes (TNTs) to deliver mitochondria, substrates and protein reprocessing services to axonal sites distant from neuronal soma. This viewpoint implicates the brain's support system and its disruption by various age and disease-related insults as significant mediators of neurodegenerative disease. A better understanding of this system should broaden concepts of neurodegeneration and facilitate development of effective treatments. Published by Elsevier Ltd.

  18. Correlated alterations in serotonergic and dopaminergic modulations at the hippocampal mossy fiber synapse in mice lacking dysbindin.

    Directory of Open Access Journals (Sweden)

    Katsunori Kobayashi

    Full Text Available Dysbindin-1 (dystrobrevin-binding protein 1, DTNBP1 is one of the promising schizophrenia susceptibility genes. Dysbindin protein is abundantly expressed in synaptic regions of the hippocampus, including the terminal field of the mossy fibers, and this hippocampal expression of dysbindin is strongly reduced in patients with schizophrenia. In the present study, we examined the functional role of dysbindin in hippocampal mossy fiber-CA3 synaptic transmission and its modulation using the sandy mouse, a spontaneous mutant with deletion in the dysbindin gene. Electrophysiological recordings were made in hippocampal slices prepared from adult male sandy mice and their wild-type littermates. Basic properties of the mossy fiber synaptic transmission in the mutant mice were generally normal except for slightly reduced frequency facilitation. Serotonin and dopamine, two major neuromodulators implicated in the pathophysiology of schizophrenia, can potentiate mossy fiber synaptic transmission probably via an increase in cAMP levels. Synaptic potentiation induced by serotonin and dopamine was very variable in magnitude in the mutant mice, with some mice showing prominent enhancement as compared with the wild-type mice. In addition, the magnitude of potentiation induced by these monoamines significantly correlated with each other in the mutant mice, indicating that a subpopulation of sandy mice has marked hypersensitivity to both serotonin and dopamine. While direct activation of the cAMP cascade by forskolin induced robust synaptic potentiation in both wild-type and mutant mice, this forskolin-induced potentaition correlated in magnitude with the serotonin-induced potentiation only in the mutant mice, suggesting a possible change in coupling of receptor activation to downstream signaling. These results suggest that the dysbindin deficiency could be an essential genetic factor that causes synaptic hypersensitivity to dopamine and serotonin. The altered

  19. Altered power spectral density in the resting-state sensorimotor network in patients with myotonic dystrophy type 1.

    Science.gov (United States)

    Park, Jin-Sung; Seo, Jeehye; Cha, Hyunsil; Song, Hui-Jin; Lee, Sang-Hoon; Jang, Kyung Eun; Lee, Hui Joong; Park, Juyoung; Lee, Ho-Won; Chang, Yongmin

    2018-01-17

    Myotonic dystrophy type 1 (DM1) is a multisystemic disease that involves the brain with several neurological symptoms. Although there were few imaging studies on DM1, no studies have investigated functional alterations in the sensorimotor network at rest in patients with DM1. In the current study, a power spectral density (PSD) analysis of resting-state fMRI data was performed to assess possible alteration in spontaneous neural activity of the sensorimotor network in patients with DM1. Compared to healthy controls, patients with DM1 showed higher PSD responses in the orbitofrontal cortex, parahippocampus and basal ganglia (corrected P < 0.05). Patients with DM1 showed higher PSD responses in white matter structures associated with motor function (corrected P < 0.05). Furthermore, correlation analysis indicated that the brain regions showing PSD differences were correlated with measures of motor performance (P < 0.05). In gray matter, our findings suggest that motor disability in DM1 is not an isolated deterioration of the motor power but a multimodal dysfunction that also involves the visual system. In addition, the widespread PSD alteration in white matter structures suggest that motor deficits in DM1 involve motor movement structures as well as structures important for its coordination and regulation.

  20. Binaural noise reduction via cue-preserving MMSE filter and adaptive-blocking-based noise PSD estimation

    Science.gov (United States)

    Azarpour, Masoumeh; Enzner, Gerald

    2017-12-01

    Binaural noise reduction, with applications for instance in hearing aids, has been a very significant challenge. This task relates to the optimal utilization of the available microphone signals for the estimation of the ambient noise characteristics and for the optimal filtering algorithm to separate the desired speech from the noise. The additional requirements of low computational complexity and low latency further complicate the design. A particular challenge results from the desired reconstruction of binaural speech input with spatial cue preservation. The latter essentially diminishes the utility of multiple-input/single-output filter-and-sum techniques such as beamforming. In this paper, we propose a comprehensive and effective signal processing configuration with which most of the aforementioned criteria can be met suitably. This relates especially to the requirement of efficient online adaptive processing for noise estimation and optimal filtering while preserving the binaural cues. Regarding noise estimation, we consider three different architectures: interaural (ITF), cross-relation (CR), and principal-component (PCA) target blocking. An objective comparison with two other noise PSD estimation algorithms demonstrates the superiority of the blocking-based noise estimators, especially the CR-based and ITF-based blocking architectures. Moreover, we present a new noise reduction filter based on minimum mean-square error (MMSE), which belongs to the class of common gain filters, hence being rigorous in terms of spatial cue preservation but also efficient and competitive for the acoustic noise reduction task. A formal real-time subjective listening test procedure is also developed in this paper. The proposed listening test enables a real-time assessment of the proposed computationally efficient noise reduction algorithms in a realistic acoustic environment, e.g., considering time-varying room impulse responses and the Lombard effect. The listening test outcome

  1. Short-term synaptic plasticity at interneuronal synapses could sculpt rhythmic motor patterns

    Directory of Open Access Journals (Sweden)

    Yan eJia

    2016-02-01

    Full Text Available The output of a neuronal network depends on the organization and functional properties of its component cells and synapses. While the characterization of synaptic properties has lagged cellular analyses, a potentially important aspect in rhythmically active networks is how network synapses affect, and are in turn affected by, network activity. This could lead to a potential circular interaction where short-term activity-dependent synaptic plasticity is both influenced by and influences the network output. The analysis of synaptic plasticity in the lamprey locomotor network was extended here to characterize the short-term plasticity of connections between network interneurons and to try and address its potential network role. Paired recordings from identified interneurons in quiescent networks showed synapse-specific synaptic properties and plasticity that supported the presence of two hemisegmental groups that could influence bursting: depression in an excitatory interneuron group, and facilitation in an inhibitory feedback circuit. The influence of activity-dependent synaptic plasticity on network activity was investigated experimentally by changing Ringer Ca2+ levels, and in a simple computer model. A potential caveat of the experimental analyses was that changes in Ringer Ca2+ (and compensatory adjustments in Mg2+ in some cases could alter several other cellular and synaptic properties. Several of these properties were tested, and while there was some variability, these were not usually significantly affected by the Ringer changes. The experimental analyses suggested that depression of excitatory inputs had the strongest influence on the patterning of network activity. The simulation supported a role for this effect, and also suggested that the inhibitory facilitating group could modulate the influence of the excitatory synaptic depression. Short-term activity-dependent synaptic plasticity has not generally been considered in spinal cord

  2. Multisensory Bayesian Inference Depends on Synapse Maturation during Training: Theoretical Analysis and Neural Modeling Implementation.

    Science.gov (United States)

    Ursino, Mauro; Cuppini, Cristiano; Magosso, Elisa

    2017-03-01

    Recent theoretical and experimental studies suggest that in multisensory conditions, the brain performs a near-optimal Bayesian estimate of external events, giving more weight to the more reliable stimuli. However, the neural mechanisms responsible for this behavior, and its progressive maturation in a multisensory environment, are still insufficiently understood. The aim of this letter is to analyze this problem with a neural network model of audiovisual integration, based on probabilistic population coding-the idea that a population of neurons can encode probability functions to perform Bayesian inference. The model consists of two chains of unisensory neurons (auditory and visual) topologically organized. They receive the corresponding input through a plastic receptive field and reciprocally exchange plastic cross-modal synapses, which encode the spatial co-occurrence of visual-auditory inputs. A third chain of multisensory neurons performs a simple sum of auditory and visual excitations. The work includes a theoretical part and a computer simulation study. We show how a simple rule for synapse learning (consisting of Hebbian reinforcement and a decay term) can be used during training to shrink the receptive fields and encode the unisensory likelihood functions. Hence, after training, each unisensory area realizes a maximum likelihood estimate of stimulus position (auditory or visual). In cross-modal conditions, the same learning rule can encode information on prior probability into the cross-modal synapses. Computer simulations confirm the theoretical results and show that the proposed network can realize a maximum likelihood estimate of auditory (or visual) positions in unimodal conditions and a Bayesian estimate, with moderate deviations from optimality, in cross-modal conditions. Furthermore, the model explains the ventriloquism illusion and, looking at the activity in the multimodal neurons, explains the automatic reweighting of auditory and visual inputs

  3. Enhanced Transmission at the Calyx of Held Synapse in a Mouse Model for Angelman Syndrome

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    Tiantian Wang

    2018-01-01

    Full Text Available The neurodevelopmental disorder Angelman syndrome (AS is characterized by intellectual disability, motor dysfunction, distinct behavioral aspects, and epilepsy. AS is caused by a loss of the maternally expressed UBE3A gene, and many of the symptoms are recapitulated in a Ube3a mouse model of this syndrome. At the cellular level, changes in the axon initial segment (AIS have been reported, and changes in vesicle cycling have indicated the presence of presynaptic deficits. Here we studied the role of UBE3A in the auditory system by recording synaptic transmission at the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB through in vivo whole cell and juxtacellular recordings. We show that MNTB principal neurons in Ube3a mice exhibit a hyperpolarized resting membrane potential, an increased action potential (AP amplitude and a decreased AP half width. Moreover, both the pre- and postsynaptic AP in the calyx of Held synapse of Ube3a mice showed significantly faster recovery from spike depression. An increase in AIS length was observed in the principal MNTB neurons of Ube3a mice, providing a possible substrate for these gain-of-function changes. Apart from the effect on APs, we also observed that EPSPs showed decreased short-term synaptic depression (STD during long sound stimulations in AS mice, and faster recovery from STD following these tones, which is suggestive of a presynaptic gain-of-function. Our findings thus provide in vivo evidence that UBE3A plays a critical role in controlling synaptic transmission and excitability at excitatory synapses.

  4. Single calcium channel domain gating of synaptic vesicle fusion at fast synapses; analysis by graphic modeling

    Science.gov (United States)

    Stanley, Elise F

    2015-01-01

    At fast-transmitting presynaptic terminals Ca2+ enter through voltage gated calcium channels (CaVs) and bind to a synaptic vesicle (SV) -associated calcium sensor (SV-sensor) to gate fusion and discharge. An open CaV generates a high-concentration plume, or nanodomain of Ca2+ that dissipates precipitously with distance from the pore. At most fast synapses, such as the frog neuromuscular junction (NMJ), the SV sensors are located sufficiently close to individual CaVs to be gated by single nanodomains. However, at others, such as the mature rodent calyx of Held (calyx of Held), the physiology is more complex with evidence that CaVs that are both close and distant from the SV sensor and it is argued that release is gated primarily by the overlapping Ca2+ nanodomains from many CaVs. We devised a 'graphic modeling' method to sum Ca2+ from individual CaVs located at varying distances from the SV-sensor to determine the SV release probability and also the fraction of that probability that can be attributed to single domain gating. This method was applied first to simplified, low and high CaV density model release sites and then to published data on the contrasting frog NMJ and the rodent calyx of Held native synapses. We report 3 main predictions: the SV-sensor is positioned very close to the point at which the SV fuses with the membrane; single domain-release gating predominates even at synapses where the SV abuts a large cluster of CaVs, and even relatively remote CaVs can contribute significantly to single domain-based gating. PMID:26457441

  5. ON Cone Bipolar Cell Axonal Synapses in the OFF Inner Plexiform Layer of the Rabbit Retina

    Science.gov (United States)

    Lauritzen, J. Scott; Anderson, James R.; Jones, Bryan W.; Watt, Carl B.; Mohammed, Shoeb; Hoang, John V.; Marc, Robert E.

    2012-01-01

    Analysis of the rabbit retinal connectome RC1 reveals that the division between the ON and OFF inner plexiform layer (IPL) is not structurally absolute. ON cone bipolar cells make non-canonical axonal synapses onto specific targets and receive amacrine cell synapses in the nominal OFF layer, creating novel motifs, including inhibitory crossover networks. Automated transmission electron microscope (ATEM) imaging, molecular tagging, tracing, and rendering of ≈ 400 bipolar cells reveals axonal ribbons in 36% of ON cone bipolar cells, throughout the OFF IPL. The targets include GABA-positive amacrine cells (γACs), glycine-positive amacrine cells (GACs) and ganglion cells. Most ON cone bipolar cell axonal contacts target GACs driven by OFF cone bipolar cells, forming new architectures for generating ON-OFF amacrine cells. Many of these ON-OFF GACs target ON cone bipolar cell axons, ON γACs and/or ON-OFF ganglion cells, representing widespread mechanisms for OFF to ON crossover inhibition. Other targets include OFF γACs presynaptic to OFF bipolar cells, forming γAC-mediated crossover motifs. ON cone bipolar cell axonal ribbons drive bistratified ON-OFF ganglion cells in the OFF layer and provide ON drive to polarity-appropriate targets such as bistratified diving ganglion cells (bsdGCs). The targeting precision of ON cone bipolar cell axonal synapses shows that this drive incidence is necessarily a joint distribution of cone bipolar cell axonal frequency and target cell trajectories through a given volume of the OFF layer. Such joint distribution sampling is likely common when targets are sparser than sources and when sources are coupled, as are ON cone bipolar cells. PMID:23042441

  6. Short-Term Synaptic Plasticity at Interneuronal Synapses Could Sculpt Rhythmic Motor Patterns.

    Science.gov (United States)

    Jia, Yan; Parker, David

    2016-01-01

    The output of a neuronal network depends on the organization and functional properties of its component cells and synapses. While the characterization of synaptic properties has lagged cellular analyses, a potentially important aspect in rhythmically active networks is how network synapses affect, and are in turn affected by, network activity. This could lead to a potential circular interaction where short-term activity-dependent synaptic plasticity is both influenced by and influences the network output. The analysis of synaptic plasticity in the lamprey locomotor network was extended here to characterize the short-term plasticity of connections between network interneurons and to try and address its potential network role. Paired recordings from identified interneurons in quiescent networks showed synapse-specific synaptic properties and plasticity that supported the presence of two hemisegmental groups that could influence bursting: depression in an excitatory interneuron group, and facilitation in an inhibitory feedback circuit. The influence of activity-dependent synaptic plasticity on network activity was investigated experimentally by changing Ringer Ca(2+) levels, and in a simple computer model. A potential caveat of the experimental analyses was that changes in Ringer Ca(2+) (and compensatory adjustments in Mg(2+) in some cases) could alter several other cellular and synaptic properties. Several of these properties were tested, and while there was some variability, these were not usually significantly affected by the Ringer changes. The experimental analyses suggested that depression of excitatory inputs had the strongest influence on the patterning of network activity. The simulation supported a role for this effect, and also suggested that the inhibitory facilitating group could modulate the influence of the excitatory synaptic depression. Short-term activity-dependent synaptic plasticity has not generally been considered in spinal cord models. These

  7. [Effects of electroacupuncture at different acupoints on learning and memory ability and PSD-95 protein expression on hippocampus CA1 in rats with autism].

    Science.gov (United States)

    Zhang, Xue-Jun; Wu, Qiang

    2013-07-01

    To explore the effect mechanism of electroacupuncture (EA) at Changqiang (GV 1) or Baihui (GV 20) on autism based on molecular biology. The autism model was established by intraperitoneal injection of sodium valproate (VPA) in Wistar pregnant rats. Forty young rats with autism were selected and randomly divided into a model group, a non-acupoint group, an electroacupuncture at "Changqiang" (GV 1) (EAGV 1 for short) group and an electroacupuncture at "Baihui" (GV 20) (EAGV 20 for short) group. Another 10 normal young rats were selected as a blank group. In the EAGV 1 group, acupuncture was applied at Houhai [as Changqiang (GV 1)], then EA apparatus was connected with continuous wave, 2 Hz, 20 min, once a day for consecutive 20 days. The same EA manipulation as EAGV 1 group was used in the EAGV 20 group where "Baihui" (GV 20) was selected and non-acupoint group where non-acupoint in the right rib was selected. Blank group and model group were reared under the same conditions without any intervention. The escape latency and the ratio of swimming distance in platform quadrant to total swimming distance in each group were observed by using Morris water maze, and the PSD-95 protein expression in hippocampal CA 1 was measured by immunohistochemical techniques. Compared with the blank group, the escape latency in the model group and the non-acupoint group lengthened (both P swimming distance in platform quadrant to total swimming distance was decreased (both P swimming distance in platform quadrant to total swimming distance was increased, the PSD-95 protein expression was increased (both P swimming distance in platform quadrant to total swimming distance and the PSD-95 protein expression had no significant difference between EAGV 1 group and EAGV 20 group (P > 0.05). Electroacupuncture at Changqiang (GV 1) or Baihui (GV 20) can respectively improve learning and memory ability of rats with autism, which has no significant difference and the mechanism of action may be

  8. Estradiol modulates the efficacy of synaptic inhibition by decreasing the dwell time of GABAA receptors at inhibitory synapses.

    Science.gov (United States)

    Mukherjee, Jayanta; Cardarelli, Ross A; Cantaut-Belarif, Yasmine; Deeb, Tarek Z; Srivastava, Deepak P; Tyagarajan, Shiva K; Pangalos, Menelas N; Triller, Antoine; Maguire, Jamie; Brandon, Nicholas J; Moss, Stephen J

    2017-10-31

    Estrogen plays a critical role in many physiological processes and exerts profound effects on behavior by regulating neuronal excitability. While estrogen has been established to exert effects on dendritic morphology and excitatory neurotransmission its role in regulating neuronal inhibition is poorly understood. Fast synaptic inhibition in the adult brain is mediated by specialized populations of γ-c aA receptors (GABAARs) that are selectively enriched at synapses, a process dependent upon their interaction with the inhibitory scaffold protein gephyrin. Here we have assessed the role that estradiol (E2) plays in regulating the dynamics of GABAARs and stability of inhibitory synapses. Treatment of cultured cortical neurons with E2 reduced the accumulation of GABAARs and gephyrin at inhibitory synapses. However, E2 exposure did not modify the expression of either the total or the plasma membrane GABAARs or gephyrin. Mechanistically, single-particle tracking revealed that E2 treatment selectively reduced the dwell time and thereby decreased the confinement of GABAARs at inhibitory synapses. Consistent with our cell biology measurements, we observed a significant reduction in amplitude of inhibitory synaptic currents in both cultured neurons and hippocampal slices exposed to E2, while their frequency was unaffected. Collectively, our results suggest that acute exposure of neurons to E2 leads to destabilization of GABAARs and gephyrin at inhibitory synapses, leading to reductions in the efficacy of GABAergic inhibition via a postsynaptic mechanism. Published under the PNAS license.

  9. 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.

  10. How do horizontal cells 'talk' to cone photoreceptors? Different levels of complexity at the cone-horizontal cell synapse.

    Science.gov (United States)

    Chapot, Camille A; Euler, Thomas; Schubert, Timm

    2017-08-15

    The first synapse of the retina plays a fundamental role in the visual system. Due to its importance, it is critical that it encodes information from the outside world with the greatest accuracy and precision possible. Cone photoreceptor axon terminals contain many individual synaptic sites, each represented by a presynaptic structure called a 'ribbon'. These synapses are both highly sophisticated and conserved. Each ribbon relays the light signal to one ON cone bipolar cell and several OFF cone bipolar cells, while two dendritic processes from a GABAergic interneuron, the horizontal cell, modulate the cone output via parallel feedback mechanisms. The presence of these three partners within a single synapse has raised numerous questions, and its anatomical and functional complexity is still only partially understood. However, the understanding of this synapse has recently evolved, as a consequence of progress in understanding dendritic signal processing and its role in facilitating global versus local signalling. Indeed, for the downstream retinal network, dendritic processing in horizontal cells may be essential, as they must support important functional operations such as contrast enhancement, which requires spatial averaging of the photoreceptor array, while at the same time preserving accurate spatial information. Here, we review recent progress made towards a better understanding of the cone synapse, with an emphasis on horizontal cell function, and discuss why such complexity might be necessary for early visual processing. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

  11. Mixed Analog/Digital Matrix-Vector Multiplier for Neural Network Synapses

    DEFF Research Database (Denmark)

    Lehmann, Torsten; Bruun, Erik; Dietrich, Casper

    1996-01-01

    In this work we present a hardware efficient matrix-vector multiplier architecture for artificial neural networks with digitally stored synapse strengths. We present a novel technique for manipulating bipolar inputs based on an analog two's complements method and an accurate current rectifier....../sign detector. Measurements on a CMOS test chip are presented and validates the techniques. Further, we propose to use an analog extension, based on a simple capacitive storage, for enhancing weight resolution during learning. It is shown that the implementation of Hebbian learning and back-propagation learning...

  12. Modulation of Central Synapses by Astrocyte-Released ATP and Postsynaptic P2X Receptors

    Science.gov (United States)

    Pankratov, Yuriy

    2017-01-01

    Communication between neuronal and glial cells is important for neural plasticity. P2X receptors are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular ATP released by neurons and/or glia. Recent data show that postsynaptic P2X receptors underlie slow neuromodulatory actions rather than fast synaptic transmission at brain synapses. Here, we review these findings with a particular focus on the release of ATP by astrocytes and the diversity of postsynaptic P2X-mediated modulation of synaptic strength and plasticity in the CNS. PMID:28845311

  13. Incremental resistance programming of programmable metallization cells for use as electronic synapses

    Science.gov (United States)

    Mahalanabis, D.; Barnaby, H. J.; Gonzalez-Velo, Y.; Kozicki, M. N.; Vrudhula, S.; Dandamudi, P.

    2014-10-01

    In this work, we investigate the resistance switching behavior of Ag-Ge-Se based resistive memory (ReRAM) devices, otherwise known as programmable metallization cells (PMC). The devices studied are switched between high and low resistive states under externally applied electrical bias. The presence of multiple resistive states observed under both dc and pulse voltage application makes these devices promising candidates for use as electronic synapses in neuromorphic hardware implementations. Finally, the effect of varying pulse voltage magnitude and width on the change in resistance is observed through measurement.

  14. The human language and epilepsy associated gene SRPX2 regulates synapse formation and vocalization in mice

    OpenAIRE

    Sia, G.M.; Clem, R.L.; Huganir, R L

    2013-01-01

    Synapse formation in the developing brain depends on the coordinated activity of synaptogenic proteins, some which have been implicated in a number of neurodevelopmental disorders. Here, we show that the sushi repeat-containing domain protein X-linked 2 (SRPX2) gene encodes a protein that promotes synaptogenesis in the cerebral cortex. In humans, SRPX2 is an epilepsy- and language-associated gene that is a target of the foxhead box protein P2 (FoxP2) transcription factor. We also show that Fo...

  15. TLR-4 engagement of dendritic cells confers a BST-2/tetherin-mediated restriction of HIV-1 infection to CD4+ T cells across the virological synapse

    Directory of Open Access Journals (Sweden)

    Blanchet Fabien P

    2013-01-01

    Full Text Available Abstract Background Dendritic cells and their subsets, located at mucosal surfaces, are among the first immune cells to encounter disseminating pathogens. The cellular restriction factor BST-2/tetherin (also known as CD317 or HM1.24 potently restricts HIV-1 release by retaining viral particles at the cell surface in many cell types, including primary cells such as macrophages. However, BST-2/tetherin does not efficiently restrict HIV-1 infection in immature dendritic cells. Results We now report that BST-2/tetherin expression in myeloid (myDC and monocyte-derived dendritic cells (DC can be significantly up-regulated by IFN-α treatment and TLR-4 engagement with LPS. In contrast to HeLa or 293T cells, infectious HIV-1 release in immature DC and IFN-α–matured DC was only modestly affected in the absence of Vpu compared to wild-type viruses. Strikingly, immunofluorescence analysis revealed that BST-2/tetherin was excluded from HIV containing tetraspanin-enriched microdomains (TEMs in both immature DC and IFN-α–matured DC. In contrast, in LPS-mediated mature DC, BST-2/tetherin exerted a significant restriction in transfer of HIV-1 infection to CD4+ T cells. Additionally, LPS, but not IFN-α stimulation of immature DC, leads to a dramatic redistribution of cellular restriction factors to the TEM as well as at the virological synapse between DC and CD4+ T cells. Conclusions In conclusion, we demonstrate that TLR-4 engagement in immature DC significantly up-regulates the intrinsic antiviral activity of BST-2/tetherin, during cis-infection of CD4+ T cells across the DC/T cell virological synapse. Manipulating the function and potency of cellular restriction factors such as BST-2/tetherin to HIV-1 infection, has implications in the design of antiviral therapeutic strategies.

  16. Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGFδ/δ mouse model of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Lambrechts Diether

    2010-03-01

    Full Text Available Abstract Background Vascular endothelial growth factor (VEGF is an endothelial cell mitogen that stimulates vasculogenesis. It has also been shown to act as a neurotrophic factor in vitro and in vivo. Deletion of the hypoxia response element of the promoter region of the gene encoding VEGF in mice causes a reduction in neural VEGF expression, and results in adult-onset motor neurone degeneration that resembles amyotrophic lateral sclerosis (ALS. Investigating the molecular pathways to neurodegeneration in the VEGFδ/δ mouse model of ALS may improve understanding of the mechanisms of motor neurone death in the human disease. Results Microarray analysis was used to determine the transcriptional profile of laser captured spinal motor neurones of transgenic and wild-type littermates at 3 time points of disease. 324 genes were significantly differentially expressed in motor neurones of presymptomatic VEGFδ/δ mice, 382 at disease onset, and 689 at late stage disease. Massive transcriptional downregulation occurred with disease progression, associated with downregulation of genes involved in RNA processing at late stage disease. VEGFδ/δ mice showed reduction in expression, from symptom onset, of the cholesterol synthesis pathway, and genes involved in nervous system development, including axonogenesis, synapse formation, growth factor signalling pathways, cell adhesion and microtubule-based processes. These changes may reflect a reduced capacity of VEGFδ/δ mice for maintenance and remodelling of neuronal processes in the face of demands of neural plasticity. The findings are supported by the demonstration that in primary motor neurone cultures from VEGFδ/δ mice, axon outgrowth is significantly reduced compared to wild-type littermates. Conclusions Downregulation of these genes involved in axon outgrowth and synapse formation in adult mice suggests a hitherto unrecognized role of VEGF in the maintenance of neuronal circuitry. Dysregulation of

  17. Reduced synapse and axon numbers in the prefrontal cortex of rats subjected to a chronic stress model for depression

    DEFF Research Database (Denmark)

    Csabai, Dávid; Wiborg, Ove; Czéh, Boldizsár

    2018-01-01

    Stressful experiences can induce structural changes in neurons of the limbic system. These cellular changes contribute to the development of stress-induced psychopathologies like depressive disorders. In the prefrontal cortex of chronically stressed animals, reduced dendritic length and spine loss...... have been reported. This loss of dendritic material should consequently result in synapse loss as well, because of the reduced dendritic surface. But so far, no one studied synapse numbers in the prefrontal cortex of chronically stressed animals. Here, we examined synaptic contacts in rats subjected...... to an animal model for depression, where animals are exposed to a chronic stress protocol. Our hypothesis was that long term stress should reduce the number of axo-spinous synapses in the medial prefrontal cortex. Adult male rats were exposed to daily stress for 9 weeks and afterward we did a post mortem...

  18. Fast kinetics of exocytosis revealed by simultaneous measurements of presynaptic capacitance and postsynaptic currents at a central synapse.

    Science.gov (United States)

    Sun, J Y; Wu, L G

    2001-04-01

    The rate of release from nerve terminals depends on both the number of release sites and the rate of release at each site. The latter remains largely unknown at central synapses. We addressed this issue by simultaneously measuring the nerve terminal membrane capacitance and the postsynaptic current at single calyceal synapses in rat brainstem. We found that a 10 ms presynaptic step depolarization depleted a releasable pool containing 3300-5200 vesicles. Released vesicles were endocytosed with a time constant of a few seconds to tens of seconds. Release of only one third of this pool saturated both postsynaptic AMPA and NMDA receptors. A release site can release more than three vesicles in 10 ms (>300 vesicles per second). We conclude that both a large number of release sites and a fast release rate at each site enable synapses to release at a high rate.

  19. 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

  20. Decreased presence of perforated synapses in a triple-transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Bertoni-Freddari, Carlo; Sensi, Stefano L; Giorgetti, Belinda; Balietti, Marta; Di Stefano, Giuseppina; Canzoniero, Lorella M T; Casoli, Tiziana; Fattoretti, Patrizia

    2008-04-01

    Transgenic mouse models of Alzheimer's disease (AD) are useful tools to further our understanding of AD genotype-phenotype interaction. The triple transgenic mice harboring mutant forms of APP/PS1/Tau (3xTg-AD) exhibit beta-amyloid (Abeta) plaques (by 6 months of age) as well as neurofibrillary tangles (by 10-12 months of age). In this study, we characterized morphological alterations of hippocampal synapses obtained from 13-month-old 3xTg-AD and age-matched control (PS1-KI) mice. Numeric density of synapses (Nv, number of junctions/microm(3) of tissue), average synaptic contact area (S), and synaptic surface density (Sv, total synaptic contact area/microm(3) of tissue) were investigated by morphometric methods in the AD vulnerable CA1 pyramidal cell layer. Comparisons between 3xTg-AD and control mice showed no statistically significant differences in any of the three parameters; however, a significant decrease (by 28.5%) in the fraction of perforated junctional areas (PS) was observed in the 3xTg-AD mice. As PS is a reliably indirect index of synaptic plasticity, a decreased PS number might represent a subtle and early sign of synaptic dysfunction occurring in the 3xTg-AD mice, and lend support to the hypothesis that altered synaptic function is a critical feature of AD.

  1. Cholesterol Regulates Multiple Forms of Vesicle Endocytosis at a Mammalian Central Synapse

    Science.gov (United States)

    Yue, Hai-Yuan; Xu, Jianhua

    2015-01-01

    Endocytosis in synapses sustains neurotransmission by recycling vesicle membrane and maintaining the homeostasis of synaptic membrane. A role of membrane cholesterol in synaptic endocytosis remains controversial because of conflicting observations, technical limitations in previous studies, and potential interference from nonspecific effects after cholesterol manipulation. Furthermore, it is unclear whether cholesterol participates in distinct forms of endocytosis that function under different activity levels. In this study, applying the whole-cell membrane capacitance measurement to monitor endocytosis in real time at the rat calyx of Held terminals, we found that disrupting cholesterol with dialysis of cholesterol oxidase (COase) or methyl-β-cyclodextrin (MCD) impaired three different forms of endocytosis, i.e., slow endocytosis, rapid endocytosis, and endocytosis of the retrievable membrane that exists at the surface before stimulation. The effects were observed when disruption of cholesterol was mild enough not to change Ca2+ channel current or vesicle exocytosis, indicative of stringent cholesterol requirement in synaptic endocytosis. Extracting cholesterol with high concentrations of MCD reduced exocytosis, mainly by decreasing the readily releasable pool (RRP) and the vesicle replenishment after RRP depletion. Our study suggests that cholesterol is an important, universal regulator in multiple forms of vesicle endocytosis at mammalian central synapses. PMID:25893258

  2. The RNA-centred view of the synapse: non-coding RNAs and synaptic plasticity.

    Science.gov (United States)

    Smalheiser, Neil R

    2014-09-26

    If mRNAs were the only RNAs made by a neuron, there would be a simple mapping of mRNAs to proteins. However, microRNAs and other non-coding RNAs (ncRNAs; endo-siRNAs, piRNAs, BC1, BC200, antisense and long ncRNAs, repeat-related transcripts, etc.) regulate mRNAs via effects on protein translation as well as transcriptional and epigenetic mechanisms. Not only are genes ON or OFF, but their ability to be translated can be turned ON or OFF at the level of synapses, supporting an enormous increase in information capacity. Here, I review evidence that ncRNAs are expressed pervasively within dendrites in mammalian brain; that some are activity-dependent and highly enriched near synapses; and that synaptic ncRNAs participate in plasticity responses including learning and memory. Ultimately, ncRNAs can be viewed as the post-it notes of the neuron. They have no literal meaning of their own, but derive their functions from where (and to what) they are stuck. This may explain, in part, why ncRNAs differ so dramatically from protein-coding genes, both in terms of the usual indicators of functionality and in terms of evolutionary constraints. ncRNAs do not appear to be direct mediators of synaptic transmission in the manner of neurotransmitters or receptors, yet they orchestrate synaptic plasticity-and may drive species-specific changes in cognition.

  3. Cockayne syndrome-derived neurons display reduced synapse density and altered neural network synchrony.

    Science.gov (United States)

    Vessoni, Alexandre T; Herai, Roberto H; Karpiak, Jerome V; Leal, Angelica M S; Trujillo, Cleber A; Quinet, Annabel; Agnez Lima, Lucymara F; Menck, Carlos F M; Muotri, Alysson R

    2016-04-01

    Cockayne syndrome (CS) is a rare genetic disorder in which 80% of cases are caused by mutations in the Excision Repair Cross-Complementation group 6 gene (ERCC6). The encoded ERCC6 protein is more commonly referred to as Cockayne Syndrome B protein (CSB). Classical symptoms of CS patients include failure to thrive and a severe neuropathology characterized by microcephaly, hypomyelination, calcification and neuronal loss. Modeling the neurological aspect of this disease has proven difficult since murine models fail to mirror classical neurological symptoms. Therefore, a robust human in vitro cellular model would advance our fundamental understanding of the disease and reveal potential therapeutic targets. Herein, we successfully derived functional CS neural networks from human CS induced pluripotent stem cells (iPSCs) providing a new tool to facilitate studying this devastating disease. We identified dysregulation of the Growth Hormone/Insulin-like Growth Factor-1 (GH/IGF-1) pathway as well as pathways related to synapse formation, maintenance and neuronal differentiation in CSB neurons using unbiased RNA-seq gene expression analyses. Moreover, when compared to unaffected controls, CSB-deficient neural networks displayed altered electrophysiological activity, including decreased synchrony, and reduced synapse density. Collectively, our work reveals that CSB is required for normal neuronal function and we have established an alternative to previously available models to further study neural-specific aspects of CS. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. A Novel Chaotic Neural Network Using Memristive Synapse with Applications in Associative Memory

    Directory of Open Access Journals (Sweden)

    Xiaofang Hu

    2012-01-01

    Full Text Available Chaotic Neural Network, also denoted by the acronym CNN, has rich dynamical behaviors that can be harnessed in promising engineering applications. However, due to its complex synapse learning rules and network structure, it is difficult to update its synaptic weights quickly and implement its large scale physical circuit. This paper addresses an implementation scheme of a novel CNN with memristive neural synapses that may provide a feasible solution for further development of CNN. Memristor, widely known as the fourth fundamental circuit element, was theoretically predicted by Chua in 1971 and has been developed in 2008 by the researchers in Hewlett-Packard Laboratory. Memristor based hybrid nanoscale CMOS technology is expected to revolutionize the digital and neuromorphic computation. The proposed memristive CNN has four significant features: (1 nanoscale memristors can simplify the synaptic circuit greatly and enable the synaptic weights update easily; (2 it can separate stored patterns from superimposed input; (3 it can deal with one-to-many associative memory; (4 it can deal with many-to-many associative memory. Simulation results are provided to illustrate the effectiveness of the proposed scheme.

  5. The effects of congenital deafness on auditory nerve synapses and globular bushy cells in cats.

    Science.gov (United States)

    Redd, E E; Pongstaporn, T; Ryugo, D K

    2000-09-01

    It is well known that auditory deprivation affects the structure and function of the central nervous system. Congenital deafness represents one form of deprivation, and in the adult white cat, it has been shown to have a clear effect upon the synaptic interface between endbulbs of Held and spherical bushy cells. It is not known, however, whether all primary synapses are affected and/or whether they are affected in the same way and to the same extent. Thus, we studied a second neuronal circuit in the deaf white cat involving modified (small) endbulbs and globular bushy cells. Compared to normal hearing cats, modified endbulbs of congenitally deaf cats were 52.2% smaller but unchanged in structural complexity. There was also a striking loss of extracellular space between ending and cell body. The somata of postsynaptic globular bushy cells were 13.4% smaller and had enlarged postsynaptic densities. These data reveal that axosomatic synapses demonstrate abnormal structure as a consequence of deafness and that the extent of the abnormalities can vary with respect to the circuits involved. The implication of these observations is that synaptic anomalies would introduce differential delays within separate circuits, thereby desynchronizing neural activity from sound stimuli. This loss of synchronization could in turn disrupt temporal processing and compromise a host of related functions, including language comprehension.

  6. Electrical synapses between AII amacrine cells in the retina: Function and modulation.

    Science.gov (United States)

    Hartveit, Espen; Veruki, Margaret Lin

    2012-12-03

    Adaptation enables the visual system to operate across a large range of background light intensities. There is evidence that one component of this adaptation is mediated by modulation of gap junctions functioning as electrical synapses, thereby tuning and functionally optimizing specific retinal microcircuits and pathways. The AII amacrine cell is an interneuron found in most mammalian retinas and plays a crucial role for processing visual signals in starlight, twilight and daylight. AII amacrine cells are connected to each other by gap junctions, potentially serving as a substrate for signal averaging and noise reduction, and there is evidence that the strength of electrical coupling is modulated by the level of background light. Whereas there is extensive knowledge concerning the retinal microcircuits that involve the AII amacrine cell, it is less clear which signaling pathways and intracellular transduction mechanisms are involved in modulating the junctional conductance between electrically coupled AII amacrine cells. Here we review the current state of knowledge, with a focus on the recent evidence that suggests that the modulatory control involves activity-dependent changes in the phosphorylation of the gap junction channels between AII amacrine cells, potentially linked to their intracellular Ca(2+) dynamics. This article is part of a Special Issue entitled Electrical Synapses. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment.

    Science.gov (United States)

    Townes-Anderson, Ellen; Wang, Jianfeng; Halász, Éva; Sugino, Ilene; Pitler, Amy; Whitehead, Ian; Zarbin, Marco

    2017-06-01

    Retinal detachment disrupts the rod-bipolar synapse in the outer plexiform layer by retraction of rod axons. We showed that breakage is due to RhoA activation whereas inhibition of Rho kinase (ROCK), using Y27632, reduces synaptic damage. We test whether the ROCK inhibitor fasudil, used for other clinical applications, can prevent synaptic injury after detachment. Detachments were made in pigs by subretinal injection of balanced salt solution (BSS) or fasudil (1, 10 mM). In some animals, fasudil was injected intravitreally after BSS-induced detachment. After 2 to 4 hours, retinae were fixed for immunocytochemistry and confocal microscopy. Axon retraction was quantified by imaging synaptic vesicle label in the outer nuclear layer. Apoptosis was analyzed using propidium iodide staining. For biochemical analysis by Western blotting, retinal explants, detached from retinal pigmented epithelium, were cultured for 2 hours. Subretinal injection of fasudil (10 mM) reduced retraction of rod spherules by 51.3% compared to control detachments ( n = 3 pigs, P = 0.002). Intravitreal injection of 10 mM fasudil, a more clinically feasible route of administration, also reduced retraction (28.7%, n = 5, P ROCK, was decreased with 30 μM fasudil ( n = 8-10 explants, P ROCK signaling with fasudil reduced photoreceptor degeneration and preserved the rod-bipolar synapse after retinal detachment. These results support the possibility, previously tested with Y27632, that ROCK inhibition may attenuate synaptic damage in iatrogenic detachments.

  8. Degradation of aggregated LDL occurs in complex extracellular sub-compartments of the lysosomal synapse.

    Science.gov (United States)

    Singh, Rajesh K; Barbosa-Lorenzi, Valéria C; Lund, Frederik W; Grosheva, Inna; Maxfield, Frederick R; Haka, Abigail S

    2016-03-01

    Monocyte-derived cells use an extracellular, acidic, lytic compartment (a lysosomal synapse) for initial degradation of large objects or species bound to the extracellular matrix. Akin to osteoclast degradation of bone, extracellular catabolism is used by macrophages to degrade aggregates of low density lipoprotein (LDL) similar to those encountered during atherogenesis. However, unlike osteoclast catabolism, the lysosomal synapse is a highly dynamic and intricate structure. In this study, we use high resolution three dimensional imaging to visualize compartments formed by macrophages to catabolize aggregated LDL. We show that these compartments are topologically complex, have a convoluted structure and contain sub-regions that are acidified. These sub-regions are characterized by a close apposition of the macrophage plasma membrane and aggregates of LDL that are still connected to the extracellular space. Compartment formation is dependent on local actin polymerization. However, once formed, compartments are able to maintain a pH gradient when actin is depolymerized. These observations explain how compartments are able to maintain a proton gradient while remaining outside the boundaries of the plasma membrane. © 2016. Published by The Company of Biologists Ltd.

  9. Artificial neuron synapse transistor based on silicon nanomembrane on plastic substrate

    Science.gov (United States)

    Liu, Minjie; Huang, Gaoshan; Feng, Ping; Guo, Qinglei; Shao, Feng; Tian, Ziao; Li, Gongjin; Wan, Qing; Mei, Yongfeng

    2017-06-01

    Silicon nanomembrane (SiNM) transistors gated by chitosan membrane were fabricated on plastic substrate to mimic synapse behaviors. The device has both a bottom proton gate (BG) and multiple side gates (SG). Electrical transfer properties of BG show hysteresis curves different from those of typical SiO2 gate dielectric. Synaptic behaviors and functions by linear accumulation and release of protons have been mimicked on this device: excitatory post-synaptic current (EPSC) and paired pulse facilitation behavior of biological synapses were mimicked and the paired-pulse facilitation index could be effectively tuned by the spike interval applied on the BG. Synaptic behaviors and functions, including short-term memory and long-term memory, were also experimentally demonstrated in BG mode. Meanwhile, spiking logic operation and logic modulation were realized in SG mode. Project supported by the National Natural Science Foundation of China (No. 51322201), the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20120071110025), and Science and Technology Commission of Shanghai Municipality (No. 14JC1400200).

  10. Introducing Autoimmunity at the Synapse by a Novel Animal Model of Experimental Autoimmune Myasthenia Gravis.

    Science.gov (United States)

    Wang, Jianwen; Xiao, Yatao; Zhang, Kejing; Luo, Benyan; Shen, Chengyong

    2018-02-06

    The neuromuscular junction (NMJ) is a peripheral synapse between motor neurons and skeletal muscle fibers that controls muscle contraction. The NMJ is the target of various disorders including myasthenia gravis (MG), an autoimmune disease in which auto-antibodies (auto-Abs) attack the synapse, and thus cause muscle weakness in patients. There are multiple auto-Abs in the MG patient sera, but not all the Abs are proven to be pathogenic, which increases the difficulties in clinical diagnoses and treatments. To establish the causative roles of auto-Abs in MG pathogenesis, the experimental autoimmune MG (EAMG) induced by the active immunization of auto-antigens (auto-Ags) or the passive transfer of auto-Abs is required. These models simulate many features of the human disease. To date, there are three kinds of EAMG models reported, of which AChR-EAMG and MuSK-EAMG are well characterized, while the recent LRP4-EAMG is much less studied. Here, we report a current summary of LRP4-EAMG and its pathogenic mechanisms. The features of LRP4-EAMG are more similar to those of AChR-EAMG, indicating a similar clinical treatment for LRP4- and AChR-positive MG patients, compared to MuSK-positive MG patients. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Cholesterol regulates multiple forms of vesicle endocytosis at a mammalian central synapse.

    Science.gov (United States)

    Yue, Hai-Yuan; Xu, Jianhua

    2015-07-01

    Endocytosis in synapses sustains neurotransmission by recycling vesicle membrane and maintaining the homeostasis of synaptic membrane. A role of membrane cholesterol in synaptic endocytosis remains controversial because of conflicting observations, technical limitations in previous studies, and potential interference from non-specific effects after cholesterol manipulation. Furthermore, it remains unclear whether cholesterol participates in distinct forms of endocytosis that function under different activity levels. In this study, applying the whole-cell membrane capacitance measurement to monitor endocytosis in real time at the rat calyx of Held terminals, we found that disrupting cholesterol with dialysis of cholesterol oxidase or methyl-β-cyclodextrin impaired three different forms of endocytosis, including slow endocytosis, rapid endocytosis, and endocytosis of the retrievable membrane that exists at the surface before stimulation. The effects were observed when disruption of cholesterol was mild enough not to change Ca(2+) channel current or vesicle exocytosis, indicative of stringent cholesterol requirement in synaptic endocytosis. Extracting cholesterol with high concentrations of methyl-β-cyclodextrin reduced exocytosis, mainly by decreasing the readily releasable pool and the vesicle replenishment after readily releasable pool depletion. Our study suggests that cholesterol is an important, universal regulator in multiple forms of vesicle endocytosis at mammalian central synapses. © 2015 International Society for Neurochemistry.

  12. Fast, Temperature-Sensitive and Clathrin-Independent Endocytosis at Central Synapses.

    Science.gov (United States)

    Delvendahl, Igor; Vyleta, Nicholas P; von Gersdorff, Henrique; Hallermann, Stefan

    2016-05-04

    The fusion of neurotransmitter-filled vesicles during synaptic transmission is balanced by endocytotic membrane retrieval. Despite extensive research, the speed and mechanisms of synaptic vesicle endocytosis have remained controversial. Here, we establish low-noise time-resolved membrane capacitance measurements that allow monitoring changes in surface membrane area elicited by single action potentials and stronger stimuli with high-temporal resolution at physiological temperature in individual bona-fide mature central synapses. We show that single action potentials trigger very rapid endocytosis, retrieving presynaptic membrane with a time constant of 470 ms. This fast endocytosis is independent of clathrin but mediated by dynamin and actin. In contrast, stronger stimuli evoke a slower mode of endocytosis that is clathrin, dynamin, and actin dependent. Furthermore, the speed of endocytosis is highly temperature dependent with a Q10 of ∼3.5. These results demonstrate that distinct molecular modes of endocytosis with markedly different kinetics operate at central synapses. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Presynaptic GABAB Receptors Regulate Hippocampal Synapses during Associative Learning in Behaving Mice.

    Directory of Open Access Journals (Sweden)

    M Teresa Jurado-Parras

    Full Text Available GABAB receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the central nervous system. Pharmacological activation of GABAB receptors regulates neurotransmission and neuronal excitability at pre- and postsynaptic sites. Electrophysiological activation of GABAB receptors in brain slices generally requires strong stimulus intensities. This raises the question as to whether behavioral stimuli are strong enough to activate GABAB receptors. Here we show that GABAB1a-/- mice, which constitutively lack presynaptic GABAB receptors at glutamatergic synapses, are impaired in their ability to acquire an operant learning task. In vivo recordings during the operant conditioning reveal a deficit in learning-dependent increases in synaptic strength at CA3-CA1 synapses. Moreover, GABAB1a-/- mice fail to synchronize neuronal activity in the CA1 area during the acquisition process. Our results support that activation of presynaptic hippocampal GABAB receptors is important for acquisition of a learning task and for learning-associated synaptic changes and network dynamics.

  14. Multiple forms of metaplasticity at a single hippocampal synapse during late postnatal development

    Directory of Open Access Journals (Sweden)

    Daniel G. McHail

    2015-04-01

    Full Text Available Metaplasticity refers to adjustment in the requirements for induction of synaptic plasticity based on the prior history of activity. Numerous forms of developmental metaplasticity are observed at Schaffer collateral synapses in the rat hippocampus at the end of the third postnatal week. Emergence of spatial learning and memory at this developmental stage suggests possible involvement of metaplasticity in the final maturation of the hippocampus. Three distinct metaplastic phenomena are apparent. (1 As transmitter release probability increases with increasing age, presynaptic potentiation is reduced. (2 Alterations in the composition and channel conductance properties of AMPARs facilitate the induction of postsynaptic potentiation with increasing age. (3 Low frequency stimulation inhibits subsequent induction of potentiation in animals older but not younger than 3 weeks of age. Thus, many forms of plasticity expressed at SC-CA1 synapses are different in rats younger and older than 3 weeks of age, illustrating the complex orchestration of physiological modifications that underlie the maturation of hippocampal excitatory synaptic transmission. This review paper describes three late postnatal modifications to synaptic plasticity induction in the hippocampus and attempts to relate these metaplastic changes to developmental alterations in hippocampal network activity and the maturation of contextual learning.

  15. Correlations induced by depressing synapses in critically self-organized networks with quenched dynamics

    Science.gov (United States)

    Campos, João Guilherme Ferreira; Costa, Ariadne de Andrade; Copelli, Mauro; Kinouchi, Osame

    2017-04-01

    In a recent work, mean-field analysis and computer simulations were employed to analyze critical self-organization in networks of excitable cellular automata where randomly chosen synapses in the network were depressed after each spike (the so-called annealed dynamics). Calculations agree with simulations of the annealed version, showing that the nominal branching ratio σ converges to unity in the thermodynamic limit, as expected of a self-organized critical system. However, the question remains whether the same results apply to the biological case where only the synapses of firing neurons are depressed (the so-called quenched dynamics). We show that simulations of the quenched model yield significant deviations from σ =1 due to spatial correlations. However, the model is shown to be critical, as the largest eigenvalue of the synaptic matrix approaches unity in the thermodynamic limit, that is, λc=1 . We also study the finite size effects near the critical state as a function of the parameters of the synaptic dynamics.

  16. Anterior cingulate synapses in prefrontal areas 10 and 46 suggest differential influence in cognitive control.

    Science.gov (United States)

    Medalla, Maria; Barbas, Helen

    2010-12-01

    Dorsolateral prefrontal areas 46 and 10 are involved in distinct aspects of cognition. Area 46 has a key role in working memory tasks, and frontopolar area 10 is recruited in complex multitask operations. Both areas are innervated by the anterior cingulate cortex (ACC), a region associated with emotions and memory but is also important for attentional control through unknown synaptic mechanisms. Here, we found that in rhesus monkeys (Macaca mulatta) most axon terminals labeled from tracers injected into ACC area 32 innervated spines of presumed excitatory neurons, but ∼20-30% formed mostly large synapses with dendritic shafts of presumed inhibitory neurons in the upper layers (I-IIIa) of dorsolateral areas 10, 46, and 9. Moreover, area 32 terminals targeted preferentially calbindin and, to a lesser extent, calretinin neurons, which are thought to be inhibitory neurons that modulate the gain of task-relevant activity during working memory tasks. Area 46 was distinguished as a recipient of more (by ∼40%) area 32 synapses on putative inhibitory neurons. Area 10 stood apart as recipient of significantly larger (by ∼40% in volume) area 32 terminals on spines of putative excitatory neurons. These synaptic specializations suggest that area 32 has complementary roles, potentially enhancing inhibition in area 46 and strengthening excitation in area 10, which may help direct attention to new tasks while temporarily holding in memory another task.

  17. Employment of Molecularly Imprinted Polymers to High-Throughput Screen nNOS-PSD-95 Interruptions: Structure and Dynamics Investigations on Monomer-Template Complexation.

    Science.gov (United States)

    Wang, Yongwei; Zhao, Ting; Dai, Peng; Jiang, Nan; Li, Fei

    2016-03-16

    Molecularly imprinted polymers (MIPs) are employed to screen nNOS-PSD-95 (neuronal nitric oxide synthase post-synaptic density protein-95) interruptions. 5-(3,5-Dichloro-2-hydroxybenzylamino)-2-hydroxybenzoic acid (ZL006; a potential drug candidate for the treatment of stroke, depression, and pain) is employed as a template. Four kinds of functional monomers (2-VP: 2-vinylpyridine; 4-VP: 4-vinylpyridine; MMA: methyl methacrylate; and MAAM: methacrylamide) are designed, and their complexation with ZL006 in various solvents (methanol, acetonitrile, toluene, chloroform) is investigated by molecular dynamics simulations and quantum mechanics calculations. Both 4-VP and MAAM have stronger interactions with ZL006 than those of 2-VP and MMA. The appropriate ratio of monomer to template is 3:1. Intermolecular hydrogen bonds play a dominant role in monomer-template complexation. Ideal solvents are toluene and chloroform, and the solvation effect on monomer-template complexation is revealed. Both molecular modeling and adsorption experiments demonstrate that as-synthesized ZL006-MIP with 4-VP as a monomer has better selectivity than that employing MAAM to screen for nNOS-PSD-95 interruptions. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Repetitive activation of the corticospinal pathway by means of rTMS may reduce the efficiency of corticomotoneuronal synapses

    DEFF Research Database (Denmark)

    Taube, Wolfgang; Leukel, Christian; Nielsen, Jens Bo

    2015-01-01

    Low-frequency rTMS applied to the primary motor cortex (M1) may produce depression of motor-evoked potentials (MEPs). This depression is commonly assumed to reflect changes in cortical circuits. However, little is known about rTMS-induced effects on subcortical circuits. Therefore, the present......-either at M1 and/or the CM synapse. As the early facilitation reflects activation of direct CM projections, the most likely site of action is the synapse of the CM neurons onto spinal motoneurons....

  19. Chronic early life lead (Pb2+) exposure alters presynaptic vesicle pools in hippocampal synapses.

    Science.gov (United States)

    Guariglia, Sara Rose; Stansfield, Kirstie H; McGlothan, Jennifer; Guilarte, Tomas R

    2016-11-02

    Lead (Pb2+) exposure has been shown to impair presynaptic neurotransmitter release in both in vivo and in vitro model systems. The mechanism by which Pb2+ impairs neurotransmitter release has not been fully elucidated. In previous work, we have shown that Pb2+ exposure inhibits vesicular release and reduces the number of fast-releasing sites in cultured hippocampal neurons. We have also shown that Pb2+ exposure inhibits vesicular release and alters the distribution of presynaptic vesicles in Shaffer Collateral - CA1 synapses of rodents chronically exposed to Pb2+ during development. In the present study, we used transmission electron microscopy to examine presynaptic vesicle pools in Mossy Fiber-CA3 synapses and in Perforant Path-Dentate Gyrus synapses of rats to determine if in vivo Pb2+ exposure altered presynaptic vesicle distribution in these hippocampal regions. Data were analyzed using T-test for each experimental endpoint. We found that Pb2+ exposure significantly reduced the number of vesicles in the readily releasable pool and recycling pool in Mossy Fiber-CA3 terminals. In both Mossy Fiber-CA3 terminals and in Perforant Path-Dentate Gyrus terminals, Pb2+ exposure significantly increased vesicle nearest neighbor distance in all vesicular pools (Rapidly Releasable, Recycling and Resting). We also found a reduction in the size of the postsynaptic densities of CA3 dendrites in the Pb2+ exposed group. In our previous work, we have demonstrated that Pb2+ exposure impairs vesicular release in Shaffer Collateral - CA1 terminals of the hippocampus and that the number of docked vesicles in the presynaptic active zone was reduced. Our current data shows that Pb2+ exposure reduces the number of vesicles that are in proximity to release sites in Mossy Fiber- CA3 terminals. Furthermore, Pb2+ exposure causes presynaptic vesicles to be further from one another, in both Mossy Fiber- CA3 terminals and in Perforant Pathway - Dentate Gyrus terminals, which may interfere with

  20. Compact electronic soma and synapse circuits fabricated using a low temperature approach

    Science.gov (United States)

    Subramaniam, Anand

    Digital circuits using the von Neumann architecture and complementary metal-oxide-semiconductor (CMOS) electronic devices dominate large-scale processing systems today and are extremely efficient at performing well-defined operations. However, these systems are less efficient at tasks which involve processing large amounts of imprecise information originating from the surrounding environment, such as pattern recognition and outcome prediction. The human brain is the best processor of such information sets, and consists of a large number of primitive elements (1010 neurons and 1014 synapses). Neuromorphic systems are a class of circuits that draw inspiration from the extremely parallel architecture of the brain. A major goal is thus to develop neuromorphic circuits using a large-area, low-power, and highly dense approach. The major focus of this work is the fabrication of a compact circuit which can implement a biologically realistic synaptic learning rule using low-temperature materials. Ambipolar nanocrystalline-silicon (nc-Si) thin-film transistors (TFTs) are selected as basic building blocks of spiking soma circuits. These TFTs are fabricated at the nanoscale using a CMOS-compatible fabrication process at a maximum temperature of 250 °C. High-κ gate dielectrics are incorporated to achieve lower subthreshold swings and threshold voltages. Soma circuits which consist of a few nc-Si TFTs and capacitors are fabricated and shown to display spiking behavior similar to biological neurons. Electronic synapses are fabricated using Au nanoparticle (NP) memory devices based on nc-Si TFTs and TiN/HfO2/TiN memristors. These are then integrated with the soma circuit to achieve an action potential pair-based learning rule, namely spike-timing-dependent plasticity (STDP). The STDP rule is experimentally demonstrated for the first time using simple rectangular voltage pulses alone. The soma circuits are shown to be capable of driving a significant number of synapses in a large

  1. The Extracellular and Cytoplasmic Domains of Syndecan Cooperate Postsynaptically to Promote Synapse Growth at the Drosophila Neuromuscular Junction.

    Science.gov (United States)

    Nguyen, Margaret U; Kwong, Jereen; Chang, Julia; Gillet, Victoria G; Lee, Rachel M; Johnson, Karl Gregory

    2016-01-01

    The heparan sulfate proteoglycan (HSPG) Syndecan (Sdc) is a crucial regulator of synapse development and growth in both vertebrates and invertebrates. In Drosophila, Sdc binds via its extracellular heparan sulfate (HS) sidechains to the receptor protein tyrosine phosphatase LAR to promote the morphological growth of the neuromuscular junction (NMJ). To date, however, little else is known about the molecular mechanisms by which Sdc functions to promote synapse growth. Here we show that all detectable Sdc found at the NMJ is provided by the muscle, strongly suggesting a post-synaptic role for Sdc. We also show that both the cytoplasmic and extracellular domains of Sdc are required to promote synapse growth or to rescue Sdc loss of function. We report the results of a yeast two-hybrid screen using the cytoplasmic domains of Sdc as bait, and identify several novel candidate binding partners for the cytoplasmic domains of Sdc. Together, these studies provide new insight into the mechanism of Sdc function at the NMJ, and provide enticing future directions for further exploring how Sdc promotes synapse growth.

  2. The Extracellular and Cytoplasmic Domains of Syndecan Cooperate Postsynaptically to Promote Synapse Growth at the Drosophila Neuromuscular Junction.

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    Margaret U Nguyen

    Full Text Available The heparan sulfate proteoglycan (HSPG Syndecan (Sdc is a crucial regulator of synapse development and growth in both vertebrates and invertebrates. In Drosophila, Sdc binds via its extracellular heparan sulfate (HS sidechains to the receptor protein tyrosine phosphatase LAR to promote the morphological growth of the neuromuscular junction (NMJ. To date, however, little else is known about the molecular mechanisms by which Sdc functions to promote synapse growth. Here we show that all detectable Sdc found at the NMJ is provided by the muscle, strongly suggesting a post-synaptic role for Sdc. We also show that both the cytoplasmic and extracellular domains of Sdc are required to promote synapse growth or to rescue Sdc loss of function. We report the results of a yeast two-hybrid screen using the cytoplasmic domains of Sdc as bait, and identify several novel candidate binding partners for the cytoplasmic domains of Sdc. Together, these studies provide new insight into the mechanism of Sdc function at the NMJ, and provide enticing future directions for further exploring how Sdc promotes synapse growth.

  3. Complexin 3 Increases the Fidelity of Signaling in a Retinal Circuit by Regulating Exocytosis at Ribbon Synapses

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    Lena S. Mortensen

    2016-06-01

    Full Text Available Complexin (Cplx proteins modulate the core SNARE complex to regulate exocytosis. To understand the contributions of Cplx to signaling in a well-characterized neural circuit, we investigated how Cplx3, a retina-specific paralog, shapes transmission at rod bipolar (RB→AII amacrine cell synapses in the mouse retina. Knockout of Cplx3 strongly attenuated fast, phasic Ca2+-dependent transmission, dependent on local [Ca2+] nanodomains, but enhanced slower Ca2+-dependent transmission, dependent on global intraterminal [Ca2+] ([Ca2+]I. Surprisingly, coordinated multivesicular release persisted at Cplx3−/− synapses, although its onset was slowed. Light-dependent signaling at Cplx3−/− RB→AII synapses was sluggish, owing largely to increased asynchronous release at light offset. Consequently, propagation of RB output to retinal ganglion cells was suppressed dramatically. Our study links Cplx3 expression with synapse and circuit function in a specific retinal pathway and reveals a role for asynchronous release in circuit gain control.

  4. Durable Interactions of T Cells with T Cell Receptor Stimuli in the Absence of a Stable Immunological Synapse.

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    Mayya, Viveka; Judokusumo, Edward; Abu Shah, Enas; Peel, Christopher G; Neiswanger, Willie; Depoil, David; Blair, David A; Wiggins, Chris H; Kam, Lance C; Dustin, Michael L

    2018-01-09

    T cells engage in two modes of interaction with antigen-presenting surfaces: stable synapses and motile kinapses. Although it is surmised that durable interactions of T cells with antigen-presenting cells involve synapses, in situ 3D imaging cannot resolve the mode of interaction. We have established in vitro 2D platforms and quantitative metrics to determine cell-intrinsic modes of interaction when T cells are faced with spatially continuous or restricted stimulation. All major resting human T cell subsets, except memory CD8 T cells, spend more time in the kinapse mode on continuous stimulatory surfaces. Surprisingly, we did not observe any concordant relationship between the mode and durability of interaction on cell-sized stimulatory spots. Naive CD8 T cells maintain kinapses for more than 3 hr before leaving stimulatory spots, whereas their memory counterparts maintain synapses for only an hour before leaving. Thus, durable interactions do not require stable synapses. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  5. Cux1 and Cux2 regulate dendritic branching, spine morphology and synapses of the upper layer neurons of the cortex

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    Cubelos, Beatriz; Sebastián-Serrano, Alvaro; Beccari, Leonardo; Calcagnotto, Maria Elisa; Cisneros, Elsa; Kim, Seonhee; Dopazo, Ana; Alvarez-Dolado, Manuel; Redondo, Juan Miguel; Bovolenta, Paola; Walsh, Christopher A.; Nieto, Marta

    2010-01-01

    Summary Dendrite branching and spine formation determines the function of morphologically distinct and specialized neuronal subclasses. However, little is known about the programs instructing specific branching patterns in vertebrate neurons and whether such programs influence dendritic spines and synapses. Using knockout and knockdown studies combined with morphological, molecular and electrophysiological analysis we show that the homeobox Cux1 and Cux2 are intrinsic and complementary regulators of dendrite branching, spine development and synapse formation in layer II–III neurons of the cerebral cortex. Cux genes control the number and maturation of dendritic spines partly through direct regulation of the expression of Xlr3b and Xlr4b, chromatin remodeling genes previously implicated in cognitive defects. Accordingly, abnormal dendrites and synapses in Cux2−/− mice correlate with reduced synaptic function and defects in working memory. These demonstrate critical roles of Cux in dendritogenesis and highlight novel subclass-specific mechanisms of synapse regulation that contribute to the establishment of cognitive circuits. PMID:20510857

  6. On optical detection of densely labeled synapses in neuropil and mapping connectivity with combinatorially multiplexed fluorescent synaptic markers.

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    Yuriy Mishchenko

    Full Text Available We propose a new method for mapping neural connectivity optically, by utilizing Cre/Lox system Brainbow to tag synapses of different neurons with random mixtures of different fluorophores, such as GFP, YFP, etc., and then detecting patterns of fluorophores at different synapses using light microscopy (LM. Such patterns will immediately report the pre- and post-synaptic cells at each synaptic connection, without tracing neural projections from individual synapses to corresponding cell bodies. We simulate fluorescence from a population of densely labeled synapses in a block of hippocampal neuropil, completely reconstructed from electron microscopy data, and show that high-end LM is able to detect such patterns with over 95% accuracy. We conclude, therefore, that with the described approach neural connectivity in macroscopically large neural circuits can be mapped with great accuracy, in scalable manner, using fast optical tools, and straightforward image processing. Relying on an electron microscopy dataset, we also derive and explicitly enumerate the conditions that should be met to allow synaptic connectivity studies with high-resolution optical tools.

  7. Calcium-Activated Proteases Are Critical for Refilling Depleted Vesicle Stores in Cultured Sensory-Motor Synapses of "Aplysia"

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    Khoutorsky, Arkady; Spira, Micha E.

    2005-01-01

    "Aplysia" motoneurons cocultured with a presynaptic sensory neuron exhibit homosynaptic depression when stimulated at low frequencies. A single bath application of serotonin (5HT) leads within seconds to facilitation of the depressed synapse. The facilitation is attributed to mobilization of neurotransmitter-containing vesicles from a…

  8. The Nanoworld of the Tripartite Synapse: Insights from Super-Resolution Microscopy

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    Janosch P. Heller

    2017-11-01

    Full Text Available Synaptic connections between individual nerve cells are fundamental to the process of information transfer and storage in the brain. Over the past decades a third key partner of the synaptic machinery has been unveiled: ultrathin processes of electrically passive astroglia which often surround pre- and postsynaptic structures. The recent advent of super-resolution (SR microscopy has begun to uncover the dynamic nanoworld of synapses and their astroglial environment. Here we overview and discuss the current progress in our understanding of the synaptic nanoenvironment, as gleaned from the imaging methods that go beyond the diffraction limit of conventional light microscopy. We argue that such methods are essential to achieve a new level of comprehension pertinent to the principles of signal integration in the brain.

  9. The effect of desflurane on neuronal communication at a central synapse.

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    Mapelli, Jonathan; Gandolfi, Daniela; Giuliani, Enrico; Prencipe, Francesco P; Pellati, Federica; Barbieri, Alberto; D'Angelo, Egidio; Bigiani, Albertino

    2015-01-01

    Although general anesthetics are thought to modify critical neuronal functions, their impact on neuronal communication has been poorly examined. We have investigated the effect induced by desflurane, a clinically used general anesthetic, on information transfer at the synapse between mossy fibers and granule cells of cerebellum, where this analysis can be carried out extensively. Mutual information values were assessed by measuring the variability of postsynaptic output in relationship to the variability of a given set of presynaptic inputs. Desflurane synchronized granule cell firing and reduced mutual information in response to physiologically relevant mossy fibers patterns. The decrease in spike variability was due to an increased postsynaptic membrane excitability, which made granule cells more prone to elicit action potentials, and to a strengthened synaptic inhibition, which markedly hampered membrane depolarization. These concomitant actions on granule cells firing indicate that desflurane re-shapes the transfer of information between neurons by providing a less informative neurotransmission rather than completely silencing neuronal activity.

  10. Communication between the synapse and the nucleus in neuronal development, plasticity, and disease.

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    Cohen, Sonia; Greenberg, Michael E

    2008-01-01

    Sensory experience is critical for the proper development and plasticity of the brain throughout life. Successful adaptation to the environment is necessary for the survival of an organism, and this process requires the translation of specific sensory stimuli into changes in the structure and function of relevant neural circuits. Sensory-evoked activity drives synaptic input onto neurons within these behavioral circuits, initiating membrane depolarization and calcium influx into the cytoplasm. Calcium signaling triggers the molecular mechanisms underlying neuronal adaptation, including the activity-dependent transcriptional programs that drive the synthesis of the effector molecules required for long-term changes in neuronal function. Insight into the signaling pathways between the synapse and the nucleus that translate specific stimuli into altered patterns of connectivity within a circuit provides clues as to how activity-dependent programs of gene expression are coordinated and how disruptions in this process may contribute to disorders of cognitive function.

  11. Synapses with short-term plasticity are optimal estimators of presynaptic membrane potentials

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    Pfister, Jean-Pascal; Dayan, Peter; Lengyel, Máté

    2013-01-01

    The trajectory of the somatic membrane potential of a cortical neuron exactly reflects the computations performed on its afferent inputs. However, the spikes of such a neuron are a very low-dimensional and discrete projection of this continually evolving signal. We explored the possibility that the neuron’s efferent synapses perform the critical computational step of estimating the membrane potential trajectory from the spikes. We found that short-term changes in synaptic efficacy can be interpreted as implementing an optimal estimator of this trajectory. Short-term depression arose when presynaptic spiking was sufficiently intense as to reduce the uncertainty associated with the estimate; short-term facilitation reflected structural features of the statistics of the presynaptic neuron such as up and down states. Our analysis provides a unifying account of a powerful, but puzzling, form of plasticity. PMID:20852625

  12. Termination of the Activating NK Cell Immunological Synapse Is an Active and Regulated Process.

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    Netter, Petra; Anft, Moritz; Watzl, Carsten

    2017-10-01

    Cellular cytotoxicity is essential for the elimination of virus-infected and cancerous cells by NK cells. It requires a direct cellular contact through the establishment of an immunological synapse (IS) between the NK cell and the target cell. In this article, we show that not only the establishment of the IS, but also its maintenance is a highly regulated process. Ongoing receptor-proximal signaling events from activating NK cell receptors and actin dynamics were necessary to maintain a stable contact in an energy-dependent fashion, even after the IS was formed successfully. More importantly, the initiation of a contact to a new susceptible target cell resulted in accelerated detachment from an old target cell. We propose that the maintenance of an existing IS is a dynamic and regulated process to allow for effective serial killing of NK cells. Copyright © 2017 by The American Association of Immunologists, Inc.

  13. The role of microglia at synapses in the healthy CNS: novel insights from recent imaging studies.

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    Tremblay, Marie-Ève

    2011-02-01

    In the healthy brain, quiescent microglia continuously remodel their shape by extending and retracting highly motile processes. Despite a seemingly random sampling of their environment, microglial processes specifically interact with subsets of synaptic structures, as shown by recent imaging studies leading to proposed reciprocal interactions between microglia and synapses under non-pathological conditions. These studies revealed that various modalities of microglial dynamic behavior including their interactions with synaptic elements are regulated by manipulations of neurotransmission, neuronal activity and sensory experience. Conversely, these observations implied an unexpected role for quiescent microglia in the elimination of synaptic structures by specialized mechanisms that include the phagocytosis of axon terminals and dendritic spines. In light of these recent discoveries, microglia are now emerging as important effectors of neuronal circuit reorganization.

  14. Mechanisms of induction and maintenance of spike-timing dependent plasticity in biophysical synapse models.

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    Graupner, Michael; Brunel, Nicolas

    2010-01-01

    We review biophysical models of synaptic plasticity, with a focus on spike-timing dependent plasticity (STDP). The common property of the discussed models is that synaptic changes depend on the dynamics of the intracellular calcium concentration, which itself depends on pre- and postsynaptic activity. We start by discussing simple models in which plasticity changes are based directly on calcium amplitude and dynamics. We then consider models in which dynamic intracellular signaling cascades form the link between the calcium dynamics and the plasticity changes. Both mechanisms of induction of STDP (through the ability of pre/postsynaptic spikes to evoke changes in the state of the synapse) and of maintenance of the evoked changes (through bistability) are discussed.

  15. Impaired ubiquitin-proteasome system activity in the synapses of Huntington's disease mice.

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    Wang, Jianjun; Wang, Chuan-En; Orr, Adam; Tydlacka, Suzanne; Li, Shi-Hua; Li, Xiao-Jiang

    2008-03-24

    Huntington's disease (HD) is caused by the expansion of a polyglutamine tract in the N-terminal region of huntingtin (htt) and is characterized by selective neurodegeneration. In addition to forming nuclear aggregates, mutant htt accumulates in neuronal processes as well as synapses and affects synaptic function. However, the mechanism for the synaptic toxicity of mutant htt remains to be investigated. We targeted fluorescent reporters for the ubiquitin-proteasome system (UPS) to presynaptic or postsynaptic terminals of neurons. Using these reporters and biochemical assays of isolated synaptosomes, we found that mutant htt decreases synaptic UPS activity in cultured neurons and in HD mouse brains that express N-terminal or full-length mutant htt. Given that the UPS is a key regulator of synaptic plasticity and function, our findings offer insight into the selective neuronal dysfunction seen in HD and also establish a method to measure synaptic UPS activity in other neurological disease models.

  16. Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice

    Science.gov (United States)

    Wang, Jianjun; Wang, Chuan-En; Orr, Adam; Tydlacka, Suzanne; Li, Shi-Hua; Li, Xiao-Jiang

    2008-01-01

    Huntington's disease (HD) is caused by the expansion of a polyglutamine tract in the N-terminal region of huntingtin (htt) and is characterized by selective neurodegeneration. In addition to forming nuclear aggregates, mutant htt accumulates in neuronal processes as well as synapses and affects synaptic function. However, the mechanism for the synaptic toxicity of mutant htt remains to be investigated. We targeted fluorescent reporters for the ubiquitin–proteasome system (UPS) to presynaptic or postsynaptic terminals of neurons. Using these reporters and biochemical assays of isolated synaptosomes, we found that mutant htt decreases synaptic UPS activity in cultured neurons and in HD mouse brains that express N-terminal or full-length mutant htt. Given that the UPS is a key regulator of synaptic plasticity and function, our findings offer insight into the selective neuronal dysfunction seen in HD and also establish a method to measure synaptic UPS activity in other neurological disease models. PMID:18362179

  17. Angelman syndrome at the synapse: meeting report of the Angelman Syndrome Foundation's 2009 scientific symposium.

    Science.gov (United States)

    Williams, Charles; Franco, Lisa

    2010-02-01

    Angelman syndrome is caused by disruption of the ubiquitin-protein ligase E3A gene (UBE3A). The gene encodes an ubiquitinating protein that is widely expressed in the body but has tissue-specific expression in brain neurons, resulting in transcription from only the maternal allele. The normal function of this protein is beginning to be delineated, but its protein targets and role in various cellular pathways remain elusive. Angelman syndrome mouse models lacking the protein in the brain provide insight into neuronal cell dysfunction, particularly in hippocampal neurons where dendritic structure and synaptic function become disturbed. The Angelman Syndrome Foundation's 2009 symposium theme was thus ''Angelman Syndrome at the Synapse,'' and the event enabled neuroscientists and other researchers and clinicians to present their current research on the syndrome.

  18. The Pathophysiology of Fragile X (and What It Teaches Us about Synapses)

    Science.gov (United States)

    Bhakar, Asha L.; Dölen, Gül; Bear, Mark F.

    2014-01-01

    Fragile X is the most common known inherited cause of intellectual disability and autism, and it typically results from transcriptional silencing of FMR1 and loss of the encoded protein, FMRP (fragile X mental retardation protein). FMRP is an mRNA-binding protein that functions at many synapses to inhibit local translation stimulated by metabotropic glutamate receptors (mGluRs) 1 and 5. Recent studies on the biology of FMRP and the signaling pathways downstream of mGluR1/5 have yielded deeper insight into how synaptic protein synthesis and plasticity are regulated by experience. This new knowledge has also suggested ways that altered signaling and synaptic function can be corrected in fragile X, and human clinical trials based on this information are under way. PMID:22483044

  19. Multiple proviral integration events after virological synapse-mediated HIV-1 spread.

    Science.gov (United States)

    Russell, Rebecca A; Martin, Nicola; Mitar, Ivonne; Jones, Emma; Sattentau, Quentin J

    2013-08-15

    HIV-1 can move directly between T cells via virological synapses (VS). Although aspects of the molecular and cellular mechanisms underlying this mode of spread have been elucidated, the outcomes for infection of the target cell remain incompletely understood. We set out to determine whether HIV-1 transfer via VS results in productive, high-multiplicity HIV-1 infection. We found that HIV-1 cell-to-cell spread resulted in nuclear import of multiple proviruses into target cells as seen by fluorescence in-situ hybridization. Proviral integration into the target cell genome was significantly higher than that seen in a cell-free infection system, and consequent de novo viral DNA and RNA production in the target cell detected by quantitative PCR increased over time. Our data show efficient proviral integration across VS, implying the probability of multiple integration events in target cells that drive productive T cell infection. Copyright © 2013. Published by Elsevier Inc.

  20. Resolving dynamics of cell signaling via real-time imaging of the immunological synapse.

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    Stevens, Mark A.; Pfeiffer, Janet R. (University of New Mexico, Albuquerque, NM); Wilson, Bridget S. (University of New Mexico, Albuquerque, NM); Timlin, Jerilyn Ann; Thomas, James L. (University of New Mexico, Albuquerque, NM); Lidke, Keith A. (University of New Mexico, Albuquerque, NM); Spendier, Kathrin (University of New Mexico, Albuquerque, NM); Oliver, Janet M. (University of New Mexico, Albuquerque, NM); Carroll-Portillo, Amanda (University of New Mexico, Albuquerque, NM); Aaron, Jesse S.; Mirijanian, Dina T.; Carson, Bryan D.; Burns, Alan Richard; Rebeil, Roberto

    2009-10-01

    This highly interdisciplinary team has developed dual-color, total internal reflection microscopy (TIRF-M) methods that enable us to optically detect and track in real time protein migration and clustering at membrane interfaces. By coupling TIRF-M with advanced analysis techniques (image correlation spectroscopy, single particle tracking) we have captured subtle changes in membrane organization that characterize immune responses. We have used this approach to elucidate the initial stages of cell activation in the IgE signaling network of mast cells and the Toll-like receptor (TLR-4) response in macrophages stimulated by bacteria. To help interpret these measurements, we have undertaken a computational modeling effort to connect the protein motion and lipid interactions. This work provides a deeper understanding of the initial stages of cellular response to external agents, including dynamics of interaction of key components in the signaling network at the 'immunological synapse,' the contact region of the cell and its adversary.