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1
Evergren, Emma. "Coordination of endocytosis at the synaptic periactive zone /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-683-2/.
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Ho, Shu Xian. "Silent synapses and postnatal development of the mouse cerebellar cortex." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0604/document.
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Dans le cortex cérébelleux, au premier chef impliqué dans l’apprentissage moteur, chaque neurone de Purkinje reçoit des centaines de milliers d'entrées provenant de cellules granulaires. Etonnement, il a été suggéré qu'une grande majorité de ces connexions (synapses) sont silencieuses, c’est-à-dire qu’elles ne transmettent pas d’information détectable. Les propriétés et le rôle de ces synapses silencieuses restent mystérieux. Jouent-elles le rôle d’une réserve ou sont-elles le produit de l’apprentissage cérébelleux ? En combinant l’enregistrement électrique de la transmission synaptique et la cartographie des entrées synaptiques dans des tranches aigües de cervelet de souris, nous avons étudié l'évolution du pourcentage des synapses qui sont silencieuses entre deux âges : avant le sevrage et une fois que l’agilité d’adulte est acquise. Nous avons observé que le pourcentage de synapses qui sont silencieuses reste remarquablement stable malgré l’augmentation du nombre total de synapsesIn the cerebellar cortex, primarily involved in motor learning, any Purkinje neuron receives hundreds of thousands of inputs from granule cells. Disturbingly, it has been suggested that the vast majority of these connections (synapses) are silent, that is to say they do not transmit any detectable information. The properties and the role of these silent synapses remains mysterious. Do they serve as a reserve pool for additional information storage or are they a byproduct of cerebellar learning? Combining the electrical recording of synaptic transmission and the mapping of synaptic inputs in acute cerebellar slices from mice, we have studied how the percentage of synapses which are silent changes between two postnatal ages: before weaning and once adult agility is acquired. Our main finding is that the percentage of synapses which are silent remains remarkably stable despite the increase in the total number of synapses
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Couchman, Kiri. "Receptors and Synapses in the MSO." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-130529.
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Tan, Scott H. (Scott Howard). "Epitaxial SiGe synapses for neuromorphic arrays." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/118687.
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Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2018.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 59-68).
Intelligent machines could help to facilitate language translation, maximize attentive learning, and optimize medical care. However, hardware to train and deploy Al systems are power-hungry and too slow for many applications. Neuromorphic arrays could potentially offer better efficiency compared to conventional hardware by storing high-precision analog weights between digital processors. However, neuromorphic arrays have not experimentally demonstrated learning accuracy comparable to conventional hardware due to irreproducibility associated with existing artificial synapses. Large variation arises in conventional devices due to the stochastic nature of metal movement through an amorphous synapse. Hence, passive arrays have only been demonstrated as small-scale systems. In this thesis, I developed single-crystalline Silicon-Germanium (SiGe) artificial synapses that have suitable properties for large-scale neurormorphic arrays. In contrast to amorphous films, epitaxially-grown SiGe can confine metal filaments within widened threading dislocations for uniform conductance update thresholds. Metal confinement reduces temporal variation to as low as 1%, which is the lowest variation reported to date, to the extent of the author's knowledge. Dislocations are selectively etched to allow for high ON/OFF ratio, good retention, many cycles of endurance, and linear conductance change. Simulations accounting for non-ideal device properties suggest that SiGe synapses in passive crossbar arrays could perform supervised learning for handwriting digit recognition with up to 95.1% accuracy. Hence, SiGe synapses demonstrate great promise for large-scale neuromorphic arrays.
by Scott H. Tan.
S.M.
5
Wang, Xin-hao. "Modulation of developing synapses by neurotrophin /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1998. http://wwwlib.umi.com/cr/ucsd/fullcit?p9834974.
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May, Patrick B. Y. "Studies on the induction of short- and long-term synaptic potentiation in the hippocampus." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/26497.
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High frequency repetitive stimulation of an excitatory input in the hippocampus results in a post-tetanic potentiation (PTP) of short duration (about 3 min) that can be followed by a long-term synaptic potentiation (LTP) of the same excitatory input (Schwartzkroin and Wester, 1975; Andersen
et al., 1977). It has been reported that this tetanus-induced LTP cannot be
elicited in a Ca²⁺-free medium and is therefore a Ca²⁺-dependent process
(Dunwiddie et al., 1978; Dunwiddie and Lynch, 1979; Wigstrӧm et al., 1979).
Whether the induction of LTP is directly dependent upon Ca²⁺, or whether, Ca²⁺ is required because synaptic transmission is needed to initiate
certain postsynaptic process(es) (a postsynaptic depolarization, for
instance) leading to LTP, is unknown. Recent studies from this laboratory
showed that both short-term potentiation (STP; with a duration resembling
PTP) and LTP can be associatively induced if activation of a test input
co-occured with either a tetanic stimulation of separate excitatory inputs
or a sufficient depolarization of the postsynaptic neurone (Sastry et al.,
1985). In this study, experiments were performed to investigate (1) whether
associative STP could be induced when activation of the test input preceded
or followed the onset of the conditioning train and (2) whether LTP could be
induced in the absence of Ca²⁺ in the extracellular medium if sufficient depolarizations of the presynaptic terminals and postsynaptic neurones were provided.
All experiments were performed using the transversely sectioned hippocampal slice preparation. Test stimuli were delivered via an electrode located in the stratum radiatum while the conditioning tetani (100 Hz, 10 pulses per train) were delivered via another electrode located in the recorded from the apical dendritic area of CA₁ neurones. After the initial control stimulation period, 5 conditioning tetani were given at a frequency of 0.2 Hz. The test stimuli either preceded (-) or followed ( + ) the onset of each conditioning train by 0 to 100 ms. When the test stimulus followed the onset of each conditioning train, there was significant STP of the test EPSP up to a conditioning-test interval of +80 ms. When the test stimulus preceded the onset of each conditioning train, there was significant STP of the test EPSP up to a conditioning-test interval of -50 ms. Conditioning tetani that were given without co-activation of the test input resulted in a subsequent depression of the test EPSP. It is suggested that either the test or the conditioning input can initiate some postsynaptic process(es) which can in turn affect the activated presynaptic terminals to increase transmitter release or alter the subsynaptic dendritic properties.
For studying the possibility of the induction of LTP in the absence of
Ca²⁺ in the extracellular medium, population EPSPs were recorded from
apical dendritic area of CA₁ neurones in response to stratum radiatum
stimulation. After the control stimulation period, slices were exposed
either to Ca²⁺-containing or Ca²⁺-free (with Mn²⁺ and Mg²⁺ replacing
Ca²⁺) medium, with the concentration of KC1 at 10 to 80 mM. Long-term
potentiation of the population EPSPs was observed following the exposure to
high K⁺ in Ca²⁺-free media. Following a brief period of potentiation
initially, population EPSPs often exhibited a tendency toward depression
after exposure to high K⁺ in Ca²⁺-containing media. LTP induced by high
K⁺ in Ca²⁺-free medium could also be observed when a fixed number of axons were being activated, indicating that a recruitment of presynaptic fibres cannot entirely account for the potentiation. LTP of the depolarizing commands were paired with activation of the stratum radiatum
while the slices were exposed to Ca²⁺ -free medium (normal concentration of
KC1). These results suggest that extracellular Ca²⁺, synaptic transmission and thus subsynaptic receptor activation are not necessary for the induction of LTP as long as sufficient depolarizations of the presynaptic terminals and postsynaptic neurones are provided.Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate
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Javalet, Charlotte. "Rôle des exosomes comme nouvelle voie de communication entre les neurones." Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV028/document.
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Les exosomes sont des vésicules d’origine endosomale sécrétées par les cellules dans leur environnement après fusion à la membrane plasmique des endosomes multivésiculés. Les exosomes représentent un nouveau mode de communication entre les cellules en permettant un transfert direct de protéines, de lipides et d’ARN. L’objectif de ma thèse était d’étudier le rôle des exosomes dans la communication entre les neurones. Précédemment, le laboratoire a montré que les neurones sécrètent des exosomes de manière régulée par l’activité synaptique. Nous avons observé que les exosomes neuronaux ne sont endocytés que par les neurones. Après avoir montré qu’ils ne contiennent que des ARN courts, nous avons réalisé un séquençage complet de leurs microARN et observé que ces microARN étaient sélectivement exportés dans les exosomes. Nos observations suggèrent que les microARN contenus dans les exosomes peuvent modifier la physiologie des neurones receveurs. Nos résultats renforcent l’hypothèse du rôle des exosomes dans la communication entre les neurones via le transfert de microARNExosomes are vesicles of endocytic origin released by cells into their environment following fusion of multivesicular endosomes with the plasma membrane. Exosomes represent a novel mechanism of cell communication allowing direct transfer of proteins, lipids and RNA. The goal of my PhD thesis was to study that exosomes represent a novel way of interneuronal communication. Our team has previously reported that neurons release exosomes in a way tightly regulated by synaptic activity. We observed that exosomes released by neurons are only endocytosed by neurons. We found that exosomes contain only small RNA and did a deep sequencing of all their microRNA. MicroRNA are selectively exported into exosomes. It seems that exosomal microRNA can modify the physiology of receiving neurons. Our results strengthen the hypothesis of the role of exosomes in the interneuronal communication by the way of microARN transfert
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Chen, Yu. "Regulation of EphA4-dependent signaling at synapses /." View abstract or full-text, 2007. http://library.ust.hk/cgi/db/thesis.pl?BICH%202007%20CHEN.
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Gray, Gregory Clark. "Ultrastructure of the retinal synapses in cubozoans /." Electronic version (PDF), 2007. http://dl.uncw.edu/etd/2007-3/grayg/gregorygray.pdf.
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Sun, Yu. "Recruitment of synaptic vesicles to developing synapses." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/36445.
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Synapse formation begins with the recognition of appropriate targets and formation of incipient contacts, and culminates with the recruitment of pre- and postsynaptic proteins to points of cell-cell contact. It is still unclear how cell-cell contact translates into the recruitment of synaptic proteins. Previous studies have shown that the cadherin/β-catenin cell adhesion complex plays an important role in localizing synaptic vesicles to developing synapses. This dissertation discusses work elucidating the transduction pathway that is activated following cell-cell contact, leading to the recruitment and retention of synaptic vesicles to presynaptic compartments. Using rat and mouse primary hippocampal cultures as a model system, we have demonstrated that β-catenin mediates the localization of synaptic vesicles to synapses through its recruitment of the PDZ scaffold protein, scribble, and it’s subsequent recruitment of the Rac/Cdc42 guanine nucleotide exchange factor, β-pix. We further demonstrate that β-pix enhances actin polymerization at these discrete sites, which is important for the “trapping” of synaptic vesicles as they translocate along the axon. We have demonstrated that cadherin, β-catenin, scribble, and β-pix form a complex at developing synapses using immunohistochemistry coupled with immunoprecipitation assays using synaptosomal fractions. Knockdown of β-catenin, scribble or β-pix using RNA interference (RNAi) disrupts the appropriate localization of synaptic vesicles at synapses. We have ordered this pathway and have shown that β-catenin is important for the recruitment and clustering of scribble to synapses, but that scribble knockdown does not affect β-catenin localization. We have also demonstrated that scribble knockdown disrupts the clustering of β-pix at synaptic sites. This complex has shown to control vesicle localization through β-pix-mediated enhancement of actin polymerization at these discrete sites. Indeed, β-pix knockdown results in decreased actin polymerization at synapses. Importantly, restoring actin polymerization at synapses through cortactin overexpression rescues the mislocalization of synaptic vesicles. This work provides novel insights into the molecular and cellular mechanisms underlying the development presynaptic compartments.
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Royle, Stephen J., Björn Granseth, Benjamin Odermatt, Aude Derevier, and Leon Lagnado. "Imaging phluorin-based probes at hippocampal synapses." Linköpings universitet, Cellbiologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-53183.
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Wide-ranging selection of methods for mammalian and yeast cells Methods for in vivo and in vitro assays High-throughput genome-wide approaches using yeast cells Microscopic and biochemical methods Contains protocols for the study of protein translocation across or into membranes of the endoplasmic reticulum, mitochondria, and nucleus Provides protocols for characterization of vesicle-mediated transport between endoplasmic reticulum, Golgi, lysosomes, and plasma membrane Methods represent both classic and cutting-edge techniques As membrane trafficking research has expanded over the past thirty years, a remarkable convergence of information has been gained by using genetic approaches in yeast cells with biochemical approaches in mammalian cells. Membrane Trafficking reflects these advances by devoting one section of the book to yeast cells and the other to mammalian cells, with each section providing both classic and cutting-edge techniques to study macromolecular transport across the membranes. These protocols, contributed by top experts in the field, have been tested in laboratories all around world. As a volume of the highly successful Methods in Molecular Biology™ series, the chapters include step-by-step laboratory protocols, a list of necessary materials and reagents, and the greatly beneficial Notes section, which aids in troubleshooting and avoiding known pitfalls. Comprehensive and state-of-the-art, Membrane Trafficking is the ideal reference for both senior researchers experienced in the field and graduate students studying membrane trafficking for the first time.The original publication is available at www.springerlink.com: Stephen J Royle, Björn Granseth, Benjamin Odermatt, Aude Derevier and Leon Lagnado, Imaging phluorin-based probes at hippocampal synapses, 2008, Methods in Molecular Biology; Membrane Trafficking, (457), 293-303. http://dx.doi.org/10.1007/978-1-59745-261-8 Copyright: Humana Press http://www.springer.com/
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Majdi, Maryam. "Brain ageing : cognitive status and cortical synapses." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115704.
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This thesis focused on the spatiotemporal patterning of classical excitatory and inhibitory synaptic contacts accounting for the majority of cerebral cortical connections, in relation to ageing and cognitive status. These investigations tested the hypothesis that higher CNS functions depend on the balance between excitatory and inhibitory synaptic connections. Glutamatergic and GABAergic presynaptic bouton densities were determined in aged animals segregated according to their cognitive status into aged and cognitively unimpaired (AU) and aged and cognitively impaired (AI), using the Morris water maze. These two groups were compared in terms of behaviour and the pattern of excitatory and inhibitory synapses. It was evident that an excitatory and inhibitory presynaptic decline is associated with age-related cognitive impairments; whereby both glutamatergic and GABAergic boutons gradually diminish from young to AU to AI. Nevertheless, the balance between excitatory and inhibitory presynaptic inputs was maintained. To determine whether postsynaptic sites differed with respect to ageing and cognitive impairments, excitatory and inhibitory postsynaptic scaffold proteins were investigated in the same cohort of segregated aged animals. There was an imbalance in density ratio between immunoreactive sites of excitatory versus inhibitory postsynaptic scaffold proteins in AI animals. This resulted from a marked decrease in the density of excitatory postsynaptic sites. To further investigate ultrastructural aspects of excitatory synapses I carried out electron microscopical studies of cerebral cortex to measure the abundance of NR2 receptor subunits of the NMDA receptor- a receptor site directly associated with excitatory postsynaptic scaffold proteins. This study revealed that NR2 immunoreactive sites were largely preserved during age-related cognitive decline with an uneven profile distribution. Finally, protein expression of specific receptor subunits and key proteins representative of excitatory and inhibitory postsynaptic sites was investigated by semi-quantitative Western blot analyses in selected cortical areas. It was clear that many of these postsynaptic proteins are affected by age and cognitive status. The most striking change was a marked up-regulation in neuroligin-1 in AI animals, which may affect the delicate balance between excitatory versus inhibitory synaptic inputs. Another notable finding was the down-regulated expression of GluR2 receptor subunits in AI animals, which should have implications for neuronal Ca2+ regulation. In conclusion, we have demonstrated the greater vulnerability of excitatory postsynaptic sites in aged and cognitively impaired animals.
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Bremaud, Antoine. "Dynamic and stochastic behaviour of neocortical synapses." Thesis, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550980.
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The neocortex receives inputs from many other brain regions, it contains many different types of neurones in 6 layers and processes large volumes of information. This thesis deals with some of the properties of the local synaptic circuitry of the neocortex. Dual intracellular recordings with biocytin labelling were performed in slices of adult rat neocortex in vitro using conventional sharp micro-electrodes. Responses of postsynaptic cells to trains of presynaptic action potentials were recorded. Histological processing identified the cells recorded and laminar location. The amplitude of each excitatory postsynaptic potential (EPSP), in each sweep was measured. Subsets of measurements for which conditions were deemed to be stable were selected. For recordings that included multiple data subsets whose amplitudes differed primarily because of differences in presynaptic release probability (p), the binomial parameters n (number of synapses), p and q (quantal amplitude) were estimated by fitting relationships between EPSP coefficient of variation, variance or proportion of failures of release and mean amplitude, with equations based on simple binomial models. Striking differences in the binomial parameters estimated for different classes of connections were found. To determine how far the outcomes of this analysis depended on the assumption of a simple binomial model in which p and q are identical at all synapses, Monte-Carlo simulations of simple and more complex binomial models of synaptic release were generated. These models demonstrated the wide range of conditions under which analysis based on simple binomial models can provide reliable estimates of n, p and q. Computational models (NEURON) that integrate short term synaptic dynamics with a stochastic simulation of synaptic transmission were developed. These models display properties similar to those displayed by synapses, but not observed in traditional deterministic models of release. For example, recovery from synaptic depression has peaks and troughs superimposed on a smooth exponential decay.
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Nicholson, Martin William. "Diazepam-dependent modulation of GABAergic inhibitory synapses." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10046265/.
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Diazepam is an allosteric modulator of GABAA receptors which potentiates GABAA receptor activity resulting in enhanced inhibitory synaptic transmission. Diazepam is used to treat anxiety, insomnia and seizures, however, its use is limited due to the development of tolerance. Here I show that prolonged treatment of cortical neurones with diazepam triggers endocytosis and subsequent downregulation of cell-surface GABAA receptors. Using pharmacological reagents, I have demonstrated that diazepam triggers PLC-dependent release of calcium from the endoplasmic reticulum which activates the phosphatase calcineurin resulting in dephosphorylation of the γ2 subunit of GABAA receptors and their endocytosis. This was elucidated using a combination of biochemical and cell biological approaches. In addition, I have developed HEK293 cell lines stably expressing various subtypes of GABAA receptors to investigate further diazepam and isoguvacine-dependent regulation of GABAA receptors. The same calcium-dependent signalling pathway that regulates cell-surface stability of GABAA receptors in neurones was found to operate in HEK293 cells. Subsequently, I focused on a key component of this signalling pathway; PLCδ1. Using biochemical techniques I have demonstrated that PLCδ1 binds directly to the GABAA receptor β3 subunit at two independent sites. This binding was confirmed by coimmunoprecipitation of PLCδ1 and GABAA receptors from cortical neuronal lysates. Interestingly, upon diazepam treatments, PLCδ1 was shown to dissociate from GABAA receptors, thus leading to mobilisation of calcium from the intracellular stores and activation of calcineurin. To assess how changes in cell-surface expression of GABAA receptors affect the stability of GABAergic synapses, I characterised the size and number of post-synaptic GABAA receptor clusters and the number of presynaptic GABA-releasing terminals following chronic diazepam treatment. I observed a reduction in the size and number of post-synaptic GABAA receptor clusters and a reduction in the number of GABA-releasing terminals. These data are consistent with the loss of cell-surface GABAA receptors following long-term treatments of cortical neurones with diazepam. These changes correlated with an increase in the expression of the early apoptosis marker, cleaved-caspase 3, in glutamatergic neurones suggesting indirect cytotoxic effects of diazepam treatments. The loss of inhibitory GABAergic synapses following chronic diazepam treatment may contribute to the well-known development of tolerance to these clinically important therapies for stress- and anxiety- related neurological disorders.
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Guillet, Marie. "Cytosquelette, synapses à ruban et neuropathies auditives." Thesis, Montpellier, 2015. http://www.theses.fr/2015MONT3504.
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Les cellules ciliées sont les cellules sensorielles de la cochlée, l’organe de l’audition, et assurent la transduction des stimulations acoustiques en message nerveux compréhensible par le système nerveux central. Nous avons étudié le rôle du cytosquelette dans le transfert synaptique et dans le cadre d’une neuropathie auditive.La première partie de cette thèse a consisté à déterminer le rôle des filaments d’actine dans l’exocytose des cellules ciliées. Pour ce faire, nous avons infusé des toxines connues pour dépolymériser les filaments d’actine directement dans les cellules ciliées internes. Après 10 minutes d’infusion, nous avons mesuré l’exocytose des cellules ciliées à partir de l’enregistrement de la capacité membranaire, indice de la fusion vésiculaire. Dans nos expériences, la dépolymérisation de l’actine provoquait une augmentation de l’exocytose. De plus nos résultats suggèrent qu’une fraction des vésicules éloignées des canaux calciques se rapproche des sites de libération après dépolymérisation du réseau d’actine. Ces travaux ont donc permis d’identifier une sous-population de vésicules synaptiques dont la disponibilité aux sites de fusion est dépendante des filaments d’actine. La seconde partie de cette thèse porte sur les mécanismes à l’origine d’une neuropathie auditive, la surdité AUNA1. Cette dernière se caractérise par la surexpression cytoplasmique de la protéine Diaph3, dont la fonction est de réguler la nucléation de l'actine et des microtubules. Pour étudier AUNA1, nous avons montré que les souris transgéniques qui surexpriment la protéine Diap3 (protéine murine) développent une surdité progressive, similaire à la neuropathie auditive AUNA1 : soit une élévation des seuils auditifs et des otoémissions normales, témoins de l’activité des cellules ciliées externes (qui ont pour rôle d’amplifier les stimulations sonores). En outre, le potentiel de sommation, qui reflète l’activité in vivo des cellules ciliées internes est altéré chez les souris transgéniques. L’observation des cellules ciliées internes en microscopie électronique à balayage montre un gonflement de la plaque cuticulaire, qui est une plateforme dense en actine servant à ancrer les stétéocils. L’observation en microscopie confocale du réseau de microtubules montre que ce dernier entoure la plaque cuticulaire chez les souris sauvages. A l’inverse, les microtubules envahissent la plaque cuticulaire chez les souris transgéniques. L’ensemble de ces résultats a donc permis de montrer un défaut d’adressage des microtubules à l’origine de la surdité AUNA1Inner hair cells transduce sound stimulation into neurotransmitter release onto the afferent auditory nerve fibers. Here, we studied how cytoskeleton modulates the transduction capabilities of the inner hair cells. Exocytosis at the inner hair cell ribbon synapse is achieved through the coupling between calcium channels and glutamate-filled synaptic vesicles. Using membrane capacitance measurements, we probed whether the actin filament network regulates the exocytosis of synaptic vesicles at the auditory hair cell. Our results suggest that actin network disruption increases exocytosis and that actin filaments may spatially organize a sub-fraction of synaptic vesicles with respect to the calcium channel.The auditory neuropathy 1 (AUNA1) is a form of human deafness, which results from a point mutation in the 5’untranslated region of the Diaphanous homolog 3 (DIAPH3) gene. Strikingly, the DIAPH3 mutation leads to the overexpression of the Diaph3 protein, a formin family member involved in the cytoskeleton nucleation and stabilization. Here, we examined in further details the anatomical, functional and molecular mechanisms that account for AUNA1. We found out that the Diap3-overexpressing transgenic mice show a progressive threshold shift associated to a defect in the inner hair cells. While synaptic function was not affected, Diap3-overexpression results into a selective and early-onset alteration of the inner hair cells cuticular plate, a dense plateform anchoring the stereocilia bundle. Molecular dissection of the apical components revealed that the microtubule meshwork undergoes an aberrant targeting into the cuticular plate of the transgenics’ inner hair cells at early onset, leading to the inabilities of these sensory cells to transduce incoming sound stimulation at later stages
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Williams, James H. ""Kiss and run" exocytosis at hippocampal synapses /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2000. http://wwwlib.umi.com/cr/ucsd/fullcit?p9970661.
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Mahesh, Iyer Keerthana. "The role of complement system related genes in synapse formation and specificity in the olivo-cerebellar network." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066406.
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La synaptogenèse est un processus précis : chaque type d'afférences innerve des domaines subcellulaires post-synaptiques spécifiques sur leur cible neuronale. Pour tester si cette spécificité est contrôlée par une combinaison unique de molécules à chaque synapse, j'ai utilisé le système olivo-cérébelleux comme modèle. Deux afférences excitatrices, les fibres parallèles issues des grains et les fibres grimpantes issues des neurones de l'olive inférieure, innervent des territoires distincts sur la même cible, la cellule de Purkinje. Une analyse comparative des profils d'expressions génique des grains et des neurones olivaires a montré que ces derniers expriment une plus grande diversité de protéines membranaires et sécrétées liées au système immunitaire. De plus, chaque type d'afférences exprime une combinaison spécifique de gènes liés à la voie du complément du système immunitaire inné. Parmi ceux-ci, la protéine sécrétée C1QL1, de la famille C1Q, joue un rôle instructif pour l'établissement du territoire d'innervation des fibres grimpantes sur les cellules de Purkinje. La protéine membranaire liée au complément SUSD4 assure, quant à elle, la maturation fonctionnelle et la stabilisation de ces synapses. Sachant que la protéine CBLN1 de la famille C1Q contrôle la synaptogenèse des fibres parallèles, ces résultats montrent que les différents membres de la famille C1Q sont des déterminants importants de l'identité et de la connectivité spécifique de chaque synapse excitatrice dans le cortex cérébelleux. Cette étude porte un nouvel éclairage sur l'hypothèse de la " chemoaffinité " et de sa participation à la formation de circuits neuronaux spécifiques et précisSynapse connectivity occurs in a precise manner such that no two types of afferents innervate the same postsynaptic subcellular domain. To test whether this specificity is controlled by a unique combination of molecules at each synapse, I used the olivo-cerebellar circuit as a model. There, two excitatory inputs, the Parallel fibers originating from granule cells and Climbing fibers originating from inferior olivary neurons, innervate distinct territories on the same target neuron, the Purkinje cell. Comparative gene expression analysis of these two inputs showed that the inferior olivary neurons express a greater diversity of genes encoding membrane and secreted proteins belonging to immune system-related pathways. Moreover, each input expresses a specific combination of complement-related genes. Among these, I identified the functional roles of two novel candidate genes specifically expressed by inferior olivary neurons. Secreted C1Q-related protein C1QL1 plays an instructive role in specifying Climbing fiber innervation territory on Purkinje cells, while membrane-bound complement control-related protein SUSD4 ensures the acquisition of proper functional properties of Climbing fiber synapses and their long-term stability. Given that C1Q-related CBLN1 promotes Parallel fiber synaptogenesis, these results show that different members of the C1Q family are important determinants of the identity and specific connectivity of each excitatory synapse in the cerebellar cortex. This study provides novel insights into the “chemoaffinity code” that controls subcellular specificity at each synapse type during the formation of neural circuits
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Eggers, Erika Dawn. "Ethanol modulation of glycine receptors from hypoglossal motoneurons /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/10555.
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Wiedemann, Aurélie. "Les Synapses Immunologiques sont des structures dynamiques présentant de multiples rôles fonctionnels." Toulouse 3, 2006. http://www.theses.fr/2006TOU30156.
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Les synapses immunologiques (SI) sont des domaines de signalisation spécialisés formés au site de contact entre les cellules du système immunitaire. Elles sont caractérisées par la réorganisation et la ségrégation des molécules de surface et des composants de la signalisation. Dans ce travail nous avons étudié le rôle fonctionnel de la SI formée entre des lymphocytes T et des cellules présentatrices d’antigène. Dans une première étude, nous avons tenté de savoir si la SI pouvait être impliquée dans le processus d’atténuation de l’activation des cellules T. Nous avons montré que la SI est un site important d’ubiquitination, processus pouvant être impliqué dans la dégradation de protéines. Dans une seconde étude, nous avons étudié la dynamique moléculaire se déroulant au site de contact entre des lymphocytes T cytotoxiques (CTL) et des cellules cibles. Nous avons pu montrer qu’un CTL est capable d’éliminer plusieurs cibles rencontrées simultanément. L’élimination de plusieurs cibles résulte d’un découplage spatio-temporel entre la formation de la synapse immunologique mature (synapse activatrice) et la sécrétion polarisée des granules lytiques (synapse lytique). Ce mécanisme de réponse à des contacts multiples par « des synapses découplées » assure la remarquable efficacité de la fonction cytotoxique.
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Bates, Susan Elizabeth. "Aspects of neurotransmitter release at insect glutamatergic synapses." Thesis, University of Nottingham, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238239.
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Spencer, Jonathan Paul. "Long-term changes in neurotransmission at corticostriatal synapses." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620598.
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Mahaman, Bachir Dodo Sahia. "Identification de nouvelles protéines des synapses à ruban." Thesis, Montpellier 1, 2014. http://www.theses.fr/2014MON1T018.
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Les cellules sensorielles auditives, les cellules ciliées internes (CCI), transforment les ondes sonores en message nerveux. Les synapses des CCI se distinguent de celles du système nerveux par leur anatomie. En effet, les synapses des CCI sont dotées d'un organite appelé ruban synaptique. Ce dernier a pour fonction de concentrer les vésicules synaptiques à proximité des zones actives. Il est important de souligner qu'un déficit de la libération synaptique à la première synapse auditive est à l'origine de surdités chez l'homme. Si la physiologie des synapses à rubans des cellules ciliées a été intensivement étudiée, la composition moléculaire des ces synapses reste en grande partie inconnue. L'objectif de cette thèse était donc d'isoler les protéines clefs de la machinerie synaptique. Pour ce faire, nous avons utilisé la technique du double hybride à partir d'une banque d'ADN complémentaire de cochlée et de la protéine Ribeye, composant majeur des rubans, comme appât. La difficulté majeure de notre étude provient de la structure de Ribeye, qui est constitué par deux domaines A et B. Tandis que le domaine A est dirigé vers le cœur du ruban synaptique et aurait une fonction structurale, le domaine B est fortement homologue au facteur de transcription Ctbp2. Ainsi, nous avons identifié plusieurs candidats comme étant des facteurs de transcription. Ces derniers interagissent probablement avec Ctbp2 dans le noyau. Nos résultats obtenus soulignent la difficulté d'identifier des protéines d'interactions, inhérente à l'utilisation de Ribeye comme appât. Parmi les autres candidats, nous avons isolés des composants du système de l'ubiquitine, suggérant une régulation ubiquitine-dépendante de l'activité ou de la structure des rubans synaptiquesInner hair cells (IHCs) are the sensory cells of the cochlea, the organ of hearing. IHCs transduce sound stimulation into the release of glutamate onto the afferent auditory nerve fibers. To achieve this task, IHCs harbor at their presynaptic side a large organelle, the so-called synaptic ribbon, surrounded by a monolayer of glutamate-filled synaptic vesicles. Exocytosis of glutamate at the hair cell ribbon synapse seems to be unconventional as the synaptic machinery, depicted so far, differs from most of the nervous system synapses. The goal of this work was to identify new members of the synaptic machinery of the hair cell ribbon synapse. To do so, we took advantage of the yeast two-hybrid system using a cochlea cDNA library as the prey and Ribeye (the major ribbon component) as the bait. Transcription factors were highly represented in our screening assay, most probably because Ribeye is highly homologous to the transcription factor Ctbp2. They probably interact with Ctbp2 in the nucleus. Our results underlined the difficulty to identify protein interactions because of the nature of Ribeye itself. However, we found ubiquitin system components among the other candidates, suggesting an ubiquitin-dependent regulation of the activity and/or structure of synaptic ribbons
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Hoy, Jennifer Lyn 1981. "The Development of Excitatory Synapses and Complex Behavior." Thesis, University of Oregon, 2011. http://hdl.handle.net/1794/12068.
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xi, 111 p. : ill. (some col.)Excitatory glutamatergic synapses facilitate important aspects of communication between the neurons that govern complex forms of behavior. Accordingly, small differences in the molecular composition of glutamatergic synapses have been suggested to underlie neurodevelopment disorders, drive evolutionary changes in brain function and behavior, and enhance specific aspects of cognition in mammals. The appropriate development and later function of these structures in the adult involves the wellcoordinated activities of hundreds of molecules. Therefore, an important goal in neuroscience is to identify and characterize how specific molecules contribute to the development of excitatory synapses as well as how manipulations of their function impact neural systems and behavior throughout life. This dissertation describes two important contributions toward this effort, (1) that the newly discovered molecule, Synaptic Cell Adhesion Molecule 1 (SynCAM1) specifically contributes to the early stages of glutamatergic synapse formation and (2) that Neuroligin1 (NL1) contributes to the mature function of glutamatergic synapses and mature forms of behavior in vivo. In the first set of experiments, I developed an in vitro cell based assay in order to determine the minimal molecular components necessary to recruit developmentally relevant glutamate receptor subtypes to sites of adhesion mediated by SynCAM1. In these experiments we discovered that protein 4.1B interacted with SynCAM1 in order to cause the specific recruitment of the NMDA type glutamate receptor containing the NR2B subunit. In the second set of experiments, we show that expression of NL1 missing the terminal 55 amino acids enhanced short term learning and flexibility in behaving mice while increasing the number of immature excitatory postsynaptic structures. Interestingly, this behavioral profile had components more consistent with 1 month old juvenile controls than age matched control littermates. In contrast, full length NL1 overexpression impaired learning and enhanced perseverance while yielding an increase in the proportion of synapses with mature characteristics. These results suggest that NL1's C-terminus drives the synaptic maturation process that shapes the development of complex behavior. Both studies bolster our understanding of how specific molecules impact the development of excitatory synapses and complex behavior. This dissertation includes both my previously published and unpublished co-authored material.
Committee in charge: William Roberts, Chairperson; Philip Washbourne, Advisor; Victoria Herman, Member; Michael Wehr, Member; Judith Eisen, Member; Clifford Kentros, Outside Member
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Liu, Xiaoying. "Pattern of synapse loss in neurodegenerative disorders a comparison between frontal lobe degeneration of non-Alzheimer type and Alzheimer's disease /." Lund : Dept. of Neuropathology, Institute of Pathology, Lund University, 1995. http://catalog.hathitrust.org/api/volumes/oclc/39783697.html.
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林綺鈴 and Yee-ling Lam. "Proheparanase action at excitatory synapses : implication on synaptic plasticity." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/193096.
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Synaptic plasticity is the activity-dependent modification of the strength of synaptic transmission. It is important for learning and memory. One of the mechanisms mediating synaptic plasticity at glutamatergic synapses is regulation of the postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor (AMPAR), which governs excitatory synaptic transmission. Perineuronal heparan sulfates (HS) have been implicated in controlling the open-state of AMPARs. Earlier findings in our laboratory showed heparanase expression and secretion of proheparanase by hippocampal neurons. Recombinant proheparanase triggered neuronal co-internalization of HS-proteoglycans and AMPAR subunits; this led to decreases in basal synaptic strength and long term potention of synaptic transmission at Schaffer collateral synapses of the hippocampus. The findings suggested proheparanase acting as a negative regulator of synaptic plasticity but the underlying mechanism remained unclear. We hypothesized that neuronal secretion of proheparanase is localized toperi-synaptic regions such that proheparanase mediates clustering of peri-synaptic HS-proteoglycans and AMPARs for internalization of the protein cluster.
To address this, protein kinase C-mediated secretion of proheparanase was enhanced by phorbol ester treatment of hippocampal slices. Synaptosome preparations from the treated slices indicated enrichment in proheparanase, suggesting that proheparanase was directed to synaptic terminals for localized secretion. With use of the hippocampal synaptosomes, pull-down experiments targeting syndecan-3and heparanase found AMPAR subunits, both GluR1 and GluR2/3, indicating that they formed clusters in the peri-synaptic area. Heparitinase pre-treated hippocampal neurons in culture led to lower levels of internalized AMPAR subunits, both GluR1 and GluR2/3,upon recombinant proheparanase treatment. This suggested that HS moieties were critical for proheparanase-mediated AMPAR internalization. Recombinant proheparanase treatment of the neuronal cultures also led to decreases in glutamate-induced calcium influx, in terms of both the number of responsive cells and the change in intracellular calcium level, consistent with proheparanase-mediated neuronal internalization of AMPARs. Taken together, these results support our hypothesis and highlight dependence on the HS moiety for proheparanase-mediated neuronal internalization of AMPARs.
We further investigated if proheparanase action at synapses can be found in other brain regions. The finding of neuronal heparanase expression in vestibular nucleus (VN) microexplant culture led us to study the role of proheparanase in synaptic plasticity in the VN. PKC activation enhanced heparanase expression in VN microexplant cultures. Recombinant proheparanase also triggered the uptake of HS and led to decreases in glutamate-induced calcium influxin VN microexplant cultures. These results support that proheparanase plays a role in synaptic plasticity in the VN but the effect and mechanism of action of proheparanase in VN neurons remain to be elucidated.
This study demonstrated that neuronal secretion of proheparanase at synaptic terminals regulates AMPAR internalization, resets peri-synaptic HS levels and lowers calcium dependent signaling in responsive cells. This work has revealed a novel role of neuronal proheparanase in synaptic plasticity.published_or_final_version
Biochemistry
Master
Master of Philosophy
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Kittler, Josef Thomas Jacques. "Molecular mechanics of GABAâ†A receptor anchoring and trafficking." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247083.
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Grant, James Roger. "Nitrergic signalling in the nervous system." Thesis, University of Sussex, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249111.
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Dykes, Iain Mackenzie. "A molecular study of regeneration in the CNS of the leech, Hirudo medicinalis." Thesis, University of Sussex, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249092.
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Binns, Malcolm David. "A large area optoelectronic neural network." Thesis, University of Cambridge, 1996. https://www.repository.cam.ac.uk/handle/1810/272597.
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Houdart, Florent. "La sous-unité régulatrice de la phosphodiestérase photo-activable : interaction avec des protéines à domaine SH3 et localisation synaptique dans les photorécepteurs." Poitiers, 2005. http://www.theses.fr/2005POIT2319.
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Dans les photorécepteurs, la phosphodiestérase 6 (PDE6) est régulée par le transfert de sa sous-unité régulatrice (P). Des études récentes indiquent que P peut interagir avec des domaines SH3. Nous avons donc recherché les protéines contenant des domaines SH3 capables d'interagir avec P dans les photorécepteurs de rat. Une étude en double-hybride et GST " Pull-Down " nous a permis d'identifier cinq partenaires potentiels de P : deux protéines impliquées dans l'endocytose (l'amphiphysine et la PACSINE) et trois protéines impliquées dans la signalisation des récepteurs tyrosine kinases (Src, Grb2 et la P85-PI3K). Trois de ces protéines (l'amphiphysine, la PACSINE et la P85-PI3K) sont clairement exprimées dans les photorécepteurs. Cependant, seule la PACSINE s'est montrée capable d'interagir in vivo avec Pau niveau des segments internes et des pédicules synaptiques des photorécepteurs, cette localisation est régulée par la lumière. Une étude portant sur le développement de la rétine de rat, nous a permis de détecter une expression de P dans les pédicules basaux des photorécepteurs sur des rats nouveaux nés (P0 à P5). Pour rechercher les possibles rôles de P dans la mise en place des synapses et la différenciation du photorécepteur, nous avons examiné les rétines de souris Prod -/-. Les observations en microscopie électronique révèlent une diminution de triades de bâtonnets correctement formées dans la plexiforme externe des souris P rod -/-. L'ensemble de ces résultats suggèrent que l'interaction P -PACSINE peut être impliquée dans l'endocytose au niveau des rubans synaptiques et que P est nécessaire à la différenciation des synapses des bâtonnetIn photoreceptors, phosphodiesterase 6 (PDE6) is regulated, due to the shuttling of its regulatory subunit (P). Recent studies have indicated that P can interact with SH3 domains and that it can alter MAPK signalling. Therefore, we sought to identify SH3-containing proteins that might interact with P in rat photoreceptors. A yeast two-hybrid and GST “Pull-Down” assay allowed us to identify two proteins involved in endocytosis (amphiphysin and PACSIN) and three proteins involved in receptor tyrosine kinase signalling (Src, GRB2 and P85-PI3K), as putative partners of P. Three of these proteins (amphiphysin, PACSIN and P85-PI3K) were clearly expressed in photoreceptors. However, only PACSIN was found to interact in vivo with P in inner segments and synaptic pedicles of photoreceptors and that P concentration in synaptic pedicles increases in response to light. A developmental study allowed us to detect P expression in the retina of newborn rats (P0). At the early stages of retinogenesis (P0 to P5), P immunodetection was confined to basal pedicles of photoreceptors. A result suggesting that P might play a role in the establishment of photoreceptor synapses. To investigate the possible roles of P in photoreceptor differentiation, retinas of P rod -/- mice were examined. Electron microscopic observations revealed a deficit of well-defined rod triads in the outer plexiform layer of P rod-/- mice. Together, the data suggest that P-pacsin interaction may contribute to specific characteristics of the endocytic mechanism at the ribbon synapse of photoreceptors and that P is required for optimal differentiation of rod synapses
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Descombes, Séverine. "Comparaison de l'inhibition synaptique médiée par l'adénosine dans l'aire CA3 de l'hippocampe de rats adultes et immatures." Sherbrooke : Université de Sherbrooke, 1998.
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Paul, Maëla. "Unraveling the mechanisms of climbing fiber synapse specificity in the cerebellum." Electronic Thesis or Diss., Sorbonne université, 2023. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2023SORUS109.pdf.
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Le fonctionnement du cerveau repose sur la mise en place de réseaux neuronaux hautement stéréotypés via des contacts synaptiques précis mais variés. Comprendre ce qui contrôle la spécificité et l'identité des synapses est donc indispensable à la compréhension non seulement du cerveau mais aussi de l'étiologie des synaptopathies, comme les troubles du spectre autistique ou encore la schizophrénie. En 1963, Sperry propose l'hypothèse de chimio-affinité impliquant que chaque type de synapse exprime une combinaison moléculaire spécifique qui régule la connectivité du circuit. Cependant, l'existence et la nature de telles combinaisons restent toujours à démontrer. Afin de tester cette hypothèse, je me suis concentrée sur le réseau olivo-cérébelleux qui est impliqué dans de nombreux processus cognitifs ainsi que dans le contrôle des fonctions motrices. Dans ce système, les fibres grimpantes et les fibres parallèles se connectent au même neurone cible, la cellule de Purkinje, initialement sur un territoire commun, puis plus tard sur des territoires distincts. Ce modèle est ainsi idéal pour l'étude les mécanismes moléculaires à l'origine de la spécificité des synapses. Chaque afférence de la cellule de Purkinje exprime une protéine différente de la famille C1Q qui est nécessaire, mais pas suffisante, à la formation de leurs synapses sur leur cible. J'ai donc cherché à déterminer la nature de la combinaison moléculaire qui est à l'origine de l'identité de la synapse fibre grimpante/cellule de Purkinje. Pour cela, j'ai combiné des analyses de transcriptomiques et de bio-informatiques, avec des expériences de perte de fonction réalisées de manière neurone-spécifique chez la souris. J'ai identifié une combinaison de molécules présynaptiques qui sont sécrétées et qui sous-tendent l'identité de la synapse fibre grimpante/cellule de Purkinje. Étonnamment, j'ai découvert que ce code spécifique est généré, au cours du développement postnatal, à partir d'un code commun aux deux afférences. De plus, les fibres grimpantes spécifient activement leur identité moléculaire synaptique alors que les synapses des fibres parallèles conservent le "code commun" initial. Enfin, je suis actuellement en train de tester si cette spécification du code moléculaire est régulée par l'activité neuronale au cours du développement postnatal. Pour conclure, cette étude constitue une dissection sans précédent des mécanismes contrôlant le développement des circuits convergeant vers un seul type de neurone, et ouvrant la voie à notre compréhension de l'origine des troubles du neurodéveloppementBrain function is based on the establishment of highly stereotyped neuronal networks through precise and diverse synaptic contacts. Understanding what controls synapse specificity and identity is thus mandatory not only to understand brain functions but also the etiology of synaptopathies such as autism spectrum disorders or schizophrenia. While Sperry postulated the chemo-affinity hypothesis in the 1960s, implying a molecular combination for each synapse type in the assembly of neural circuits, the existence and nature of these combinations have not been demonstrated. To address this question, I focused on the olivo-cerebellar network involved in the control of motor function and cognitive processes. In this well characterized circuit, two different excitatory inputs, the climbing fibers and the parallel fibers, connect the same target neuron, the Purkinje cell, initially on the same territory and then on distinct and non-overlapping territories in the mature stage. It is therefore an ideal model to study the molecular basis of synapse identity. Based on previous data from our laboratory and others, the expression of a specific C1Q-related protein in each input is necessary, but not sufficient, for proper formation of climbing fibers and parallel fibers synapses on Purkinje cells. Loss of function of the specific C1Q-related protein at each input, CBLN1 at the parallel fibers and C1QL1 at the climbing fiber, result in the loss of about half of the respective synapses, suggesting the involvement of other molecules. Thus, I searched for the nature of this molecular combination, focusing on identifying the one coding for climbing fiber/Purkinje cell synapse identity. I combined neuron-specific transcriptomics and bioinformatics analyses followed by neuron-specific loss of function using genome editing in vivo during mouse development. I have identified a combination of presynaptic secreted molecules underlying the identity of the climbing fiber/Purkinje cell synapses. Surprisingly, I have also discovered that this specific code is generated, during postnatal development, in an afferent-specific manner starting from a common code. Climbing fibers actively and gradually specify their synaptic molecular identity while parallel fibers rely on the “original common code”. This result suggests that synapse molecular diversification follows input-specific molecular rules. Finally, I am currently testing whether the specification of the molecular code is regulated by neuronal activity during postnatal development. This study represents an unprecedented dissection of the mechanisms controlling circuit development at a single neuron type level with important consequences for our understanding of the etiology of neurodevelopmental disorders
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Chirwa, Sanika Samuel. "Studies on the asynchronous synaptic responses and endogenous potentiating substances of neurotransmission in the hippocampus." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/28641.
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In the hippocampus, transient tetanic stimulations of inputs, or brief simultaneous pairings of conditioning intracellular postsynaptic depolarizations
with activated presynaptic afferents at low stimulation frequencies, result in input specific long-term potentiation (LTP) of synaptic transmission.
LTP lasts for hours in vitro, or weeks in vivo, and it is thought to be involved in memory and learning. Experimental evidence in the literature suggests that postsynaptic mechanisms mediate LTP induction, whereas presynaptic
mechanisms are involved in its maintenance. Since LTP is thought to be generated by postsynaptic mechanisms and to be subsequently maintained by presynaptic processes, this suggests the presence of feedback interactions during LTP development, however, the experimental evidence for such interactions
is presently not available. Consequently, the present studies were conducted to examine possible feedback interactions between postsynaptic and presynaptic elements in the hippocampus. Furthermore, the experiments tested the hypothesis that substances released during tetanic stimulations caused the release of endogenous substances that interacted with activated afferents resulting in alterations in presynaptic functions and LTP production.
Experiments were conducted using transversely sectioned guinea pig hippocampal slices. Briefly, physiological medium containing 3.5 mNi Ba++ and 0.5 mM Ca (denoted as Ba medium) was used to induce the asynchronous
release of transmitters, observed as evoked miniature EPSPs (minEPSPs) in CA1b neurons after stimulation of the stratum radiatum. During transient Ba++ applications, short bursts of evoked minEPSPs were observed following stimulations of the stratum radiatum or conditioning depolarizing current injections into CA1b neurons. Moreover, the frequencies
of minEPSPs were significantly increased immediately after simultaneous stimulations of the stratum radiatum and conditioning depolarizing current injections into CA1b neurons. Significant increases in the frequencies of evoked minEPSPs were also observed during LTP induced by tetanic stimulations.
The above increases in the frequencies of evoked minEPSPs were attributed, in part, to presynaptic changes resulting in increases in transmitters
released. However, a thorough quanta! analysis is requirea to substantiate this conclusion.
In order to determine whether any substances released during tetanic stimulations were involved in the mooulation of presynaptic functions and induction of LTP, samples were collected from guinea pig hippocampus and rabbit neocortex. It was found that samples that were collected during tetanic stimulations of the guinea pig hippocampus in vivo or rabbit neocortex
in vivo produced LTP in the guinea pig hippocampal slice in vitro. Applications of these samples after heating and cooling failed to induce LTP. Subsequent studies demonstrated that PC-12 cells incubated in growth medium treated with samples collected during tetanic stimulations of the rabbit neocortex developed extensive neurite growths. In contrast, PC-12 cell cultures incubated in (1) heated and cooled samples, (2) samples collected in the absence of tetanic stimulations of the rabbit neocortex, or (3) plain growth medium, failed to develop neurite growths. In addition, PC-12 cell cultures that were incubatea in growth medium containing samples collected during tetanic stimulations plus saccharin (10 mM), a substance known to inhibit N6F-dependent neurite growth, failed to develop neurites. In separate experiments it was found that saccharin could block (1) the synaptic potentiating effects of the above collected and applied endogenous substances, and (2) LTP induced with tetanic stimulations, in the guinea pig hippocampus in vitro. The concentrations of saccharin used in these studies had insignificant effects on resting membrane potentials, input resistances, spontaneous or evoked responses of CA1b neurons. Furthermore, CA1b neuronal depolarizations induced by N-methyl-DL-aspartate (NMDA) or with tetanic stimulations of the stratum radiatum, were not altered by saccharin applications. In addition, saccharin had insignificant effects on paired-pulse facilitation, post-tetanic potentiations, minEPSP frequencies in CA1b neurons, and Schaffer collaterals terminal excitability. These results suggest that saccharin blocked LTP through mechanisms different from either non-specific alterations in CA1b cell properties or NMDA receptor activation. Perhaps the agent antagonized LTP at a step beyond NMDA receptor activation. That saccharin blocked LTP caused by the applied neocortical sample as well as by tetanic stimulation of the stratum radiatum,
and that saccharin also blocked neurite growth in PC-12 cells induced by the neocortical samples, raises the prospect that growth related substances are involved in LTP generation. In other control experiments, it was found that the potentiating effects of the collected endogenous substances were not antagonised by atropine or dihydro-e-erythroidine. Heated and then cooled solutions of glutamate (a putative transmitter at the Schaffer col laterals-CA1b synapses) still maintained their actions on the CA1b population spike. While brief applications of 2.5 μg/ml exogenous NGF (from Vipera lebetina) during low frequency stimulations of the stratum radiatum did not consistently induce LTP, this peptide significantly facilitated
the development of LTP when applied in association with tetanic stimulations
of weak inputs in the CA1b area. These weak inputs could not support LTP if tetanized in the absence of the exogenous NGF.
The results of the studies in this thesis suggested that postsynaptic depolarizations modulated presynaptic functions in the hippocampus. Tetanic stimulations in hippocampus and neocortex caused the release of diffusible substances, which were probably growth related macromolecules, that interacted
with activated presynaptic afferents and/or subsynaptic dendritic elements resulting in LTP development. The precise locus of actions of these agents awaits further investigations.Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate
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Arsenault, Dany. "Remodelage développemental des synapses lemniscales dans le noyau ventral postérieur du thalamus." Thesis, Université Laval, 2007. http://www.theses.ulaval.ca/2007/24267/24267.pdf.
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Khimich, Darina. "Molecular physiology of the inner hair cell ribbon synapses." [S.l.] : [s.n.], 2005. http://webdoc.sub.gwdg.de/diss/2005/khimich.
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Shi, Yuanyuan. "Two dimensional materials based electronic synapses for neuromorphic applications." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663415.
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Electronic machines and computers have experienced a huge development during the last four decades, mainly thanks to the continuous scaling down of the hardware responsible of information processing and storage (i.e. transistors). However, as the size of these devices approaches inter-atomic distances, the fabrication costs increase exponentially. In order to solve this problem, the industry has started to consider new system architectures and hardware for processing and storing information. Inspired by nature, scientists and engineers have focused their attention on the human brain, which is the most powerful system known.
The human brain can easily perform an infinity of operations that computers cannot do, it can naturally learn by adapting its physical structure, and it consumes much less energy. The reason is that human brains use a very sophisticated and dense neural network that process and stores the information in parallel. This massive parallelism is the genuine feature that even the most powerful computers developed to date cannot match, as they all rely in an architecture that process and stores information independently, creating a bottleneck that limits their performance. Therefore, emulating the functioning of the human brain using electronic circuits is extremely important, and it has become an obsession for the biggest enterprises.
The first artificial neural networks for artificial intelligence (AI) systems relied on the use of field effect transistors, as they has been the basis of all modern electronic devices. However, recent studies indicate that memristors may be more suitable to emulate the interaction between neurons. More specifically, two neurons interact to each other through a synapse, which is a thin membrane that change its resistivity based on the electrical impulses released by the two neurons. The structure and working principle of synapses is strikingly similar to that of memristors, which moreover show the advantage of a simpler structure and a lower fabrication cost compared to transistors.
However, not all memristors are suitable for emulating biological synapses. Most traditional memristors change their resistivity between two different states when a specific electrical impulse is applied. However, synapses change their resistivity with the time in a dynamic way, following some specific learning rules. In this PhD thesis I carry out a deep study about resistive switching in different materials, and I fabricate memristive devices that can accurately resemble several synaptic behaviors. One of the most innovative aspect of my investigation is that I use a new dielectric material (called hexagonal boron nitride) that holds a layered structure, and thanks to it my memristors show several properties never observed before.
For example, Au/Ti/h-BN/Cu devices exhibit the coexistence of bipolar and threshold RS, which can be controlled by using different current limitations. The devices do not require forming process, due to the present of native defects in the h-BN stack during the growth. Doping the Cu substrate with Ni results in a lower amount of native defects, which reduces the current in high resistive state (but these devices require the use of a forming process). For both Cu and Ni-doped Cu electrodes, the current ON/OFF ratio can be improved by increasing the thickness of the h-BN stack. In Au/Ti/graphene/h-BN/graphene/Au devices the switching voltages increase and the currents in high resistive state are smaller than in the devices without graphene. The most probable reason for this observation is that multilayer graphene can block and slow down the migration of ions between the h-BN and the electrodes. Metal/h-BN/metal electronic synapses show an unprecedented relaxation process with very low variability in hundreds of cycles, and the power consumption is very low in both standby and volatile regime (i.e. 0.1 fW and 600 pW, respectively).El cerebro humano puede realizar de forma sencilla infinidad de operaciones que los ordenadores no pueden hacer, pueden aprender naturalmente adaptando su estructura física, y consumen mucho menos energía. La razón es que el cerebro humano usa una sofisticada y muy densa red neuronal que procesa y almacena la información en paralelo. Este masivo paralelismo es la genuina característica que los ordenadores no pueden igualar, ya que éstos procesan y almacenan la información en unidades distintas, creando un embudo que limita sus prestaciones. Por lo tanto, emular el funcionamiento del cerebro utilizando componentes electrónicos es extremadamente importante, y se ha convertido en la obsesión de las mayores empresas. Las primeras redes neuronales artificiales para el desarrollo de inteligencia artificial están basadas en transistores, ya que éstos han sido la base de todos los dispositivos electrónicos modernos. Sin embargo, estudios recientes indican que los memristores podrían ser más idóneos para emular la interacción entre neuronas. En concreto, dos neuronas interactúan entre ellas a través de sinapsis, es decir, finas membranas que cambian su resistividad dependiendo de los impulsos eléctricos emitidos por las dos neuronas. La estructura y principio de funcionamiento de una sinapsis es muy similar al de un memristor, el cual presenta la ventaja de tener una estructura más simple y un coste de fabricación más bajo que un transistor. En esta tesis doctoral hemos desarrollado memristores avanzados utilizando materiales bidimensionales, como el grafeno y, especialmente, el nitruto de boto hexagonal con estructura multicapa. Nuestros experimentos y simulaciones indican que los dispositivos metal/h-BN/metal pueden ser utilizados como sinapsis electrónicas, ya que muestran comportamientos sinápticos en un único dispositivo. En nuestros dispositivos hemos observado short term plasticity, long term plasticity, spike timing dependent plasticity, y synapse relaxation. El régimen de funcionamiento puede ser controlado modificando la amplitud, duración e intervalo entre los pulsos aplicados. Además, las sinapsis electrónicas hechas mediante estructuras metal/h-BN/metal muestran un proceso de relajación muy repetitivo y con una baja variabilidad nunca observada anteriormente. Además, el consumo de potencia es muy bajo tanto en reposo (0.1 fW) como en modo volátil (600 pW).
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Wong, Tak Pan 1968. "Age-related structural and functional modification of cortical synapses." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37623.
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Cortical synaptic atrophy with aging has long been regarded as the primary substrate of decline in cognitive function. However, little is known about the impact of this structural change on cortical synaptic function. The aim of this thesis was to investigate the functional consequence of age-related synaptic reductions in the parietal cortex. In the first study, I analyzed synaptic density in the parietal cortex and revealed significant age-related presynaptic reductions. Interestingly, I found a preferential disappearance of synapses in deep cortical layers. The functional impact of presynaptic reduction was tested in the second study. Whole cell patch clamp recording of spontaneous synaptic currents (sPSCs) onto layer V pyramidal neurons revealed no age-related change. In contrast, the frequency of action potential - independent miniature postsynaptic currents (mPSCs) was decreased, thus revealing an increase in action potential dependent activity (FrequencysPSCs - frequencymPscs) in aged brains. The third study focused on the ratio between excitation and inhibition in aged impaired and aged unimpaired rats that were divided on the basis of their performance in the Morris Water Maze. Interestingly, I found an imbalance between excitation and inhibition in both aged groups. Finally, to test whether similar age-related modifications occur in other neurotransmitter systems, the fourth study contrasted cholinergic vs. non-cholinergic inputs onto layer V pyramidal neurons. I found a preferential decline in cholinergic inputs onto pyramidal neurons with aging. These findings provide evidence of functional compensation for the lost of synaptic structures in aged brains. However, rather than a general decline in synaptic function, imbalance between different synaptic inputs may be an important cellular substrate for cognitive impairment.
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Forbes, C. A. "Properties of central neurones and synapses in cell culture." Thesis, University of Newcastle Upon Tyne, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378280.
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Mistry, Rajen Babubhai. "Frequency-dependent short-term plasticity at thalamic reticular synapses." Thesis, University of Bristol, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407031.
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Cizeron, Mélissa. "Synaptome mapping of glutamatergic synapses across the mouse brain." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28739.
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Synapses are specialised contacts between neurons. At postsynaptic terminals of glutamatergic synapses, protein complexes process and transmit the information received from the presynaptic terminal. Scaffolding proteins, among which members of the disc large homologue (DLG) family are the most abundant, assemble the molecular machinery in the postsynaptic terminal. Recently, two members of the DLG family, postsynaptic density protein 95 (PSD95) and synapse associated protein 102 (SAP102), have been shown to form different types of complexes, thus giving the synapse different signalling capabilities. However, the spatial distribution of these synaptic markers in different synapses remains elusive due to technical challenges. This thesis presents the first applications of a new method, the Genes to Cognition Synaptome Mapping pipeline (G2CSynMapp), to map individual synapses at the whole-brain level, in a quantitative and unbiased manner. This method was used to generate PSD95 and SAP102 synaptome maps – i.e. comprehensive maps of PSD95 and SAP102 positive synapses – in the mouse brain and to achieve three aims: i) characterise PSD95 and SAP102 synapse diversity, ii) measure the trajectory of PSD95 and SAP102 synapse changes during the postnatal lifespan and iii) determine whether PSD95 synaptome is reorganised by mutation. First, I have used G2CSynMapp to generate the first synaptome maps in the adult mouse brain. This reference map of PSD95 and SAP102 positive synapses revealed a highly organised distribution pattern of glutamatergic synapses between anatomical regions. Moreover, it uncovered that synapse populations are very diverse within anatomical regions and can form patches, gradients and input-specific glomeruli. Second, the trajectories of PSD95 and SAP102 synaptomes were mapped across the mouse postnatal lifespan. At birth, synapse densities are low and increase rapidly during the first month of life. During ageing, the density of SAP102 and PSD95 positive synapses decrease gradually. Interestingly, different anatomical regions show different trajectories of synapse density and parameters across the lifespan. Moreover, the packing of PSD95 and SAP102 at synapses have specific pattern of changes. Third, the PSD95 synaptome was found to be reorganised differently in two disease models, PSD93 and SAP102 knock-out mice. In humans, mutations in the genes encoding PSD93 or SAP102 have been involved in schizophrenia and mental retardation, respectively. Of particular interest, opposite changes were identified in the neocortex of the two mutant lines that are reminiscent of their inverse behavioural phenotypes.
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Oddos, Stephane. "High-resolution imaging of natural killer cell immunological synapses." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6361.
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The first observations of the immunological synapse have demonstrated that immune-cell signalling in situ does not simply depend on protein structures and signalling pathways but also on temporal and spatial coordinates. With the advent of new live-cell, three-dimensional fluorescence microscopy techniques our understanding of the relationship between the formation of the immunological synapse and the development of an immune response has been greatly improved. Using artificial activating substrates as surrogate target cells or antigen presenting cells in conventional microscopes has so far been the state-of-the-art to obtain high-resolution images of immunological synapses. However, such artificial substrates may not fully recapitulate the complexity of intercellular interactions. Newly developed super-resolution techniques are very promising, but they remain inadequate for live-cell imaging. Technical improvements are therefore crucially needed to address these bottlenecks and improve our understanding of immune-cell signalling. In this report we achieve high-speed high-resolution imaging of live intercellular immunological synapses by combining confocal microscopy with optical tweezers. We design, build and demonstrate the performance and flexibility of the instrument by imaging a variety of molecules at T cell and NK cell synapses. NKG2D is an important receptor that allows NK cells to recognise and kill tumour cells. Due to the lack of suitable imaging technology, NKG2D signalling at the synapse remains unclear. We specifically use our new instrument to gain further understanding of NKG2D signalling, signal integration, and NKG2D-mediated cytotoxicity. For the first time at live intercellular NK-cell immunological synapses, we describe the formation and the dynamics of NKG2D microclusters. We show that these microclusters actively signal and that they coalesce around a secretory domain through which lytic secretions are delivered. Importantly, these results suggest that the physical distribution of NKG2D at the immunological synapse may play an important role in directing lytic-secretion delivery at the NK cell synapse.
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Gandhi, Sunil P. "Three modes of single-vesicle recycling in hippocampal synapses /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3091205.
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MARCOTULLI, DANIELE. "Levetiracetam influences downstream protein interactions at synapses expressing SV2A." Doctoral thesis, Università Politecnica delle Marche, 2019. http://hdl.handle.net/11566/263612.
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Although levetiracetam is one of the most widely prescribed antiepileptic drugs, its mechanism of action remains unknown beyond the binding to the synaptic vesicle protein SV2A.
SV2A is one of the three paralogs of the SV2 family. The function of SV2 has not been fully elucidated yet, however it is known that SV2A is involved in synaptic endocytosis and vesicle protein trafficking; in particular, it regulates vesicular levels of synaptotagmin, the calcium sensor for neurotransmitter release.
Here, we tested the hypothesis that levetiracetam affects synaptic vesicle composition.
Levetiracetam chronic treatment post-transcriptionally decreased several vesicular proteins and increased LRRK2, without any change in mRNA levels. Analysis of SV2A interactome indicated that the presynaptic proteins regulations induced by levetiracetam are mediated through protein-protein interactions.
Next, we asked whether levetiracetam affects the trafficking function and protein-protein interactions of SV2A. To this end, a new approach to isolate newly endocytosed vesicles was developed. Unbiased proteomics results revealed that levetiracetam changes the association of APT1 and complexin-1 (a synaptotagmin interactor) to newly endocytosed vesicles. Protein-protein interaction studies suggested that levetiracetam alters the interaction of synaptotagmin with SV2A and complexin. Importantly, levetiracetam effects predominated in the absence of SV2B, suggesting a possible mechanism of pharmacological specificity.
We propose that levetiracetam shapes the mechanism of neurotransmitter release by altering SV2A trafficking function and that SV2 paralogs’ expression pattern underlies pharmacological specificity.
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MOSCHETTA, MATTEO. "Removal of the calcium-dependent regulation of ATP binding in Synapsin I has distinct effects at excitatory and inhibitory synapses." Doctoral thesis, Università degli studi di Genova, 2020. http://hdl.handle.net/11567/993830.
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Synapsins are the most abundant family of neuro-specific phosphoproteins associated with the cytoplasmic surface of the synaptic vesicle membrane. These proteins actively regulate synaptic transmission at the level of the presynaptic terminal by controlling the storage and mobilization of synaptic vesicles within a reserve pool. However, it is hypothesized that synapsins could be involved in other stages of synaptic vesicle dynamics such as trafficking, docking, fusion with the plasma membrane and consequent recycling. Synapsin I (SynI) in particular is expressed two isoforms (Ia and Ib) at the presynaptic compartment of all neurons in the adult brain. Several studies suggest that SynI is also involved in axon elongation and synaptic vesicle fusion kinetics. In human, nonsense and missense mutations of SYN1 gene are related to several diseases such as epilepsy and autism spectrum disorder; in fact, SynI knockout (KO) mice show an epileptic and autism-like phenotype. To carry out its functions, SynI requires to bind ATP in a Ca2+-dependent manner thanks to the coordination of a glutamate residue (E373). As ATP binding regulates SynI oligomerization and SV clustering, we analyzed the effect of E373K mutation on neurotransmitter release and short-term plasticity in excitatory and inhibitory synapses. We coupled electrophysiology (patch-clamp recordings) with electron microscopy in primary SynI KO hippocampal neurons in which either the human wild type or the E373K mutant SynI were re-introduced by infection with lentiviral vectors. Our data indicate that E373K mutation affects predominantly excitatory synapses. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was enhanced, without changes in the amplitude and in the number of excitatory synapses. The increment of mEPSCs frequency was totally abolished after acute injection of BAPTA-AM (a specific Ca2+ chelator), suggesting a possible alteration of Ca2+ homeostasis at the presynaptic terminal. Excitatory E373K-Syn I neurons showed reduced evoked EPSC amplitude attributable to a reduction of the readily releasable pool (RRP), while, on the contrary, inhibitory E373K-Syn I neurons did not show any difference both in miniature, evoked IPSC amplitude and RRP size. While no effects in the dynamics and steady state of depression were detected, both excitatory and inhibitory E373K-Syn I neurons failed to recover after stimulation with long high-frequency trains. No mutation-induced changes were observed in network firing/bursting activity as determined with multi-electrode extracellular recordings. Our data suggest that the Ca2+-dependent regulation of ATP-binding to SynI plays important roles in spontaneous and evoked neurotransmitter release that differentially affect the strength of excitatory and inhibitory transmission.
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Kintis, Efthalia. "Stochastic modelling of the neuronal membrane potential in response to synaptic input." Connect to e-thesis, 2007. http://theses.gla.ac.uk/145/.
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Thesis (MSc(R)) - University of Glasgow, 2007.MSc(R) thesis submitted to the Department of Mathematics, Faculty of Information and Mathematical Sciences, University of Glasgow, 2007. Includes bibliographical references.
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Liyanage, Yohan. "Agrin and ARIA at the human neuromuscular junction." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325947.
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Wilken, Paul Robert James. "Spiking models of local neocortical circuits." Thesis, University of Sussex, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326912.
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The 'local circuits' of the mammalian neocortex are defined within cortical columns less than 1mm across. There is mounting evidence that these fine-scale neural networks are an important organisational and functional unit. However, detailed study of the local circuitry is hampered by considerable technical difficulties; computer-based modelling therefore offers an important approach to understanding their basic properties. In this thesis, computer simulations are used to examine some of the fundamental questions associated with this class of neural network. We describe a spiking-network model which is inspired by anatomical and physiological study of local neocortical circuitry. Small, heterogeneous circuits are constructed from regular firing, rhythmic bursting and fast spiking neurons. These cells interact strongly through dynamic connections; synapses exhibit facilitation, depression, or a hybrid form of non-associative plasticity. A fast, asymmetric Hebbian process is also examined as a model of the 'Malsburg synapse', and is implemented in parallel with the non-associative fonns of plasticity. Exploration proceeds in three stages using a bottom-up methodology. First, we investigate the dynamical repertoire of the individual classes of circuit; the significance of architectural variation between circuits is addressed, and we examine the influence of fast adaptive processes in shaping network dynamics. Guided by available experimental data, circuits are connected in the second stage to create larger architectures; these are used to study interactions between the circuits. In the third stage, the inhibitory circuits implement surround and feedback inhibition, and local circuit effects of these two contrasting models are explored. Simulation results offer novel links between disparate experimental data. They also indicate how variation in the architecture of particular local circuits, and the different classes of connection between these circuits, might have functional pertinence. More generally, our findings suggest how this style of network may support a highly flexible, dynamically configurable computational architecture.
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Le, Bras Séverine. "Rôle de la protéine HIP-55/mAbp1 dans l'activation lymphocytaire et le trafic vésiculaire." Nice, 2004. http://www.theses.fr/2004NICE4007.
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Le système immunitaire est régulé à l'aide d'une balance continue entre les signaux positifs et négatifs pour maintenir l'homéostasie mais également la tolérance du soi. Il est donc important de comprendre les mécanismes moléculaires mis en jeu au cours del'activation lymphocytaire. Au cours de ce travail, nous avons étudié le rôle de la protéine adaptatrice HIP-55 dans la régulation de l'activation lymphocytaire en réponse à l'antigène. HIP-55, substrat des PTKs des famille Src et Syk, appartient à une nouvelle famille de protéines caractérisées par leur liaison aux filaments d'actine. Nous avons montré qu'elle est recrutée au sein de la synapse immunologique de façon dépendante de l'antigène. Son recrutement ainsi que sa fonction requièrent le domaine de liaison à l'actine et le domaine SH3. Nos travaux indiquent qu'elle régule négativement les signaux issus du TCR aboutissant à la transcription de gènes par l'intermédiaire de son interaction avec la ser/thr kinase HPK1. HIP-55 contribuerait également à réguler l'expression du TCR en surface, mécanisme efficace mis en place afin d'arrêter les signaux intracellulaires. Notre étude a donc permis d'identifier un nouveau composant de la synapse immunologique décrit ici pour être un régulateur négatif de l'activation lymphocytaire. HIP-55 pourrait donc jouer un rôle important dans l'arrêt du signal à l'antigène et par conséquent dans le contrôle de la réponse lymphocytaire. Enfin, du fait de son expression ubiquiste, l'étude de la fonction d'HIP-55 présente un intérêt majeur dans la compréhension des mécanismes qui régulent la réponse cellulaire vis-à-vis de son environnementImmune system is regulated to maintain homeostasis and tolerance through continuous balance between positive and negative signaling. Thus, understanding the molecular mechanism controlling the activation of T lymphocytes, is to be crucial. In this work, we are interested in the role played by the adapter protein HIP-55 on the regulation of antigen activated lymphocytes. HIP-55 belongs to a new family of proteins characterized by their interaction with actin filaments and represents a substrate for Src and Syk PTKs families. We were able to show the HIP-55 recruitment to the immunological synapse in antigen dependent manner. The actin-binding domain as well as the SH3 domain are both responsible for the recruitment and the function of HIP-55. Our work indicate that HIP-55 negatively regulate the TCR signaling pathway leading to gene transcription through its interaction with the ser/thr kinase HPK1. HIP-55 may also contribute to downregulate TCR expression on cell surface, a negative control of intracellular signaling. Our study has then permitted the identification of a novel component of the immunological synapse, HIP-55, which is described to negatively regulate the T cell activation. HIP-55 may play an important role to stop TCR signaling pathway and thus, to control lymphocyte responses. Finally, since HIP-55 is expressed ubiquitously, the study of its function represents a major interest in order to understand the mechanisms regulating cellular responses to the environment components
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Pizzarelli, Rocco. "Trans-synaptic signaling at GABAergic connections: possible dysfunction in some forms of Autism Spectrum Disorders." Doctoral thesis, SISSA, 2012. http://hdl.handle.net/20.500.11767/4721.
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Synapses are recognized as being highly plastic in structure and function, strongly influenced by their own histories of impulse traffic and by signals from nearby cells. Synaptic contacts are fundamental for the development, homeostasis and remodeling of complex neural circuits. Synapses are highly varied in their molecular composition. Understand this diversity is important because it sheds light on the way they function. In particular, this may be useful for understanding the mechanisms at the basis of synaptic dysfunctions associated with neurodevelopmental disorders, such as Autism Spectrum Disorders (ASD) in order to develop properly targeted therapeutic tools. During the first part of my Phd course I characterized the functional role of gephyrin at inhibitory synapses (paper N. 1). Gephyrin is a scaffold protein essential for stabilizing glycine and GABAA receptors at inhibitory synapses. Using recombinant intrabodies against gephyrin (scFv-gephyrin) I tested the hypothesis that this protein exerts a trans-synaptic action on GABA and glutamate release. Pair recordings from interconnected hippocampal cells in culture revealed a reduced probability of GABA release in scFv-gephyrintransfected neurons compared with controls. This effect was associated with a significant decrease in VGAT, the vesicular GABA transporter, and in neuroligin 2 (NL2), a protein that, interacting with the neurexins, ensures the cross-talk between the post- and presynaptic sites. I also found that, hampering gephyrin function produced a significant reduction in VGLUT, the vesicular glutamate transporter, an effect accompanied by a significant decrease in frequency of miniature excitatory postsynaptic currents. Over-expressing NLG2 in gephyrindeprived neurons rescued GABAergic but not glutamatergic innervation, suggesting that the observed changes in the latter were not due to a homeostatic compensatory mechanism. These results suggest a key role of gephyrin in regulating trans-synaptic signaling at both inhibitory and excitatory synapses. Several lines of evidence suggest that proteins involved in synaptic function are altered in ASDs. In particular, in a small percentage of cases, ASDs have been found to be associated with single mutations in genes encoding for cell adhesion molecules of the neuroligin-neurexin families. One of these involves the postsynaptic cell adhesion molecule neuroligin (NL) 3. In the second part of my PhD, I used transgenic mice carrying the human R451C mutation of Nlgn3, to study GABAergic and glutamatergic signaling in the hippocampus early in postnatal life (paper N. 2). I performed whole cell recordings from CA3 pyramidal neurons in hippocampal slices from NL3 R451C knock-in mice and I found an enhanced frequency of Giant Depolarizing Potentials, as compared to controls. This effect was probably dependent on an increased GABAergic drive to principal cells as demonstrated by the enhanced frequency of miniature GABAAmediated (GPSCs) postsynaptic currents, but not AMPA-mediated postsynaptic currents (EPSCs). The increase in frequency of mGPSCs suggest a presynaptic 9 type of action. This was further supported by the experiments with the fast-off GABAA receptor antagonist TPMPA that, as expected for an enhanced GABA transient in the cleft, showed a reduced blocking effect on miniature events. Although an increased number of available postsynaptic GABAA receptors, if these are not saturated by the content of a single GABA containing vesicle may account for these results, this was not the case since a similar number of receptor channels was revealed with peak-scaled non-stationary fluctuation analysis in both WT and NL3R451C knock-in mice, indicating that the observed effects were not postsynaptic in origin. Presynaptic changes in GABA release can be attributed to modifications in the probability of GABA release, in the number of release sites or in the content of GABA in single synaptic vesicles. Changes in probability of GABA release seem unlikely considering that we examined miniature events generated by the release of a single quantum. Our data do not allow distinguishing between the other two possibilities (changes in the number of release sites or in vesicle GABA content). However, in agreement with previous data from Südhof group showing an enhancement of the presynaptic
GABAergic marker VGAT (but not VGlut1) in the hippocampus of NL3R451C KI mice (Tabuchi et al., 2007), it is likely that an increased GABAergic innervation may contribute to the enhancement of GABA release. In additional experiments I found that changes in frequency of miniature GABAergic events were associated with an acceleration of mGPSCs decay possibly of postsynaptic origin. The increased frequency of mEPSCs detected in adult, but not young NL3 R451C mice may represent a late form of compensatory homeostatic correction to counter the excessive GABAA-mediated inhibition. Therefore, it is reasonable to assume that alterations in the excitatory/inhibitory balance, crucial for the refinement of neuronal circuits early in postnatal development, accounts for the behavioral deficits observed in ASDs patients. Although also in the present case, a modification of gephyrin expression in R451C NL 3 knock-in mice was associated with changes in GABAergic innervations suggesting the involvement of a trans-synaptic signal, the role of NL3 mutation in this effect remains to be elucidated. Finally, I contribute in writing a review article (paper N. 3) that gives an up dated picture of alterations of GABAergic signaling present in different forms of Autism Spectrum Disorders.
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Ghezali, Grégory. "Control of synaptic transmission by astroglial connexin 30 : molecular basis, activity-dependence and physiological implication." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066423/document.
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Les astrocytes périsynaptiques participent activement, au côté des neurones, dans le traitement de l’information cérébrale. Une propriété essentielle des astrocytes est d’exprimer un niveau élevé de protéines appelées connexines (Cxs), et formant les sous-unités des jonctions communicantes. Étonnamment, bien qu’il ait été suggéré très tôt que la Cx30 astrocytaire soit impliquée dans des processus cognitifs, son rôle exact dans la neurophysiologie demeure cependant encore mal connu. Nous avons récemment révélé que la Cx30, via une fonction non-canal inédite, contrôle la force et la plasticité de la transmission synaptique glutamatergique de l’hippocampe en régulant les niveaux synaptiques de glutamate par le biais du transport astrocytaire du glutamate. Cependant, les mécanismes moléculaire et cellulaire impliqués dans ce contrôle, ainsi que sa régulation dynamique par l’activité neuronale et son impact in vivo dans un contexte physiologique restaient inconnus. Dans le cadre de cette problématique, j’ai démontré durant ma thèse que: 1) La Cx30 induit la maturation morphologique des astrocytes de l’hippocampe par l’intermédiaire de la modulation d’une voie de signalisation dépendante de la laminine et régulant la polarisation cellulaire ; 2) l’expression de la Cx30, sa localisation perisynaptique, ainsi que ses fonctions sont modulées par l’activité neuronale ; 3) Le contrôle de la couverture astrocytaire des synapses du noyau supraoptique de l’hypothalamus par la Cx30 fixe les niveaux plasmatiques de base de la neurohormone ocytocine et ainsi favorise la mise en place de comportements sociaux adaptés. Dans l’ensemble, ces résultats éclairent les régulations des Cxs astrocytaires par l’activité neuronale et leur rôle dans le développement postnatal des réseaux neurogliaux, ainsi que dans le contrôle des interactions structurelles astrocytes-synapses à l’origine de processus comportementauxPerisynaptic astrocytes are active partners of neurons in cerebral information processing. A key property of astrocytes is to express high levels of the gap junction forming proteins, the connexins (Cxs). Strikingly, astroglial Cx30 was suggested early on to be involved in cognitive processes; however, its specific role in neurophysiology has yet been unexplored. We recently reveal that Cx30, through an unconventional non-channel function, controls hippocampal glutamatergic synaptic strength and plasticity by directly setting synaptic glutamate levels through astroglial glutamate clearance. Yet the cellular and molecular mechanisms involved in such control, its dynamic regulation by activity and its impact in vivo in a physiological context were unknown. To answer these questions, I demonstrated during my PhD that: 1) Cx30 drives the morphological maturation of hippocampal astrocytes via the modulation of a laminin signaling pathway regulating cell polarization; 2) Cx30 expression, perisynaptic localization and functions are modulated by neuronal activity; 3) Cx30-mediated control of astrocyte synapse coverage in the supraoptic nucleus of the hypothalamus sets basal plasmatic level of the neurohormone oxytocin and hence promotes appropriate oxytocin-based social abilities. Taken together, these data shed new light on astroglial Cxs activity-dependent regulations and roles in the postnatal development of neuroglial networks, as well as in astrocyte-synapse structural interactions mediating behavioral processes