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1
Feng, Bo, Andiara E. Freitas, Lilach Gorodetski, Jingyi Wang, Runyi Tian, Yeo Rang Lee, Akumbir S. Grewal, and Yimin Zou. "Planar cell polarity signaling components are a direct target of β-amyloid–associated degeneration of glutamatergic synapses." Science Advances 7, no. 34 (August 2021): eabh2307. http://dx.doi.org/10.1126/sciadv.abh2307.
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The signaling pathway directly controlling the maintenance of adult glutamatergic synapses has not been well understood. Planar cell polarity (PCP) signaling components were recently shown to play essential roles in the formation of glutamatergic synapses. Here, we show that they are localized in the adult synapses and are essential for their maintenance. Synapse loss at early stages of Alzheimer’s disease is thought to be induced by β-amyloid (Aβ) pathology. We found that oligomeric Aβ binds to Celsr3 and assists Vangl2 in disassembling synapses. Moreover, a Wnt receptor and regulator of PCP signaling, Ryk, is also required for Aβ-induced synapse loss. In the 5XFAD mouse model of Alzheimer’s disease, Ryk conditional knockout or a function-blocking monoclonal Ryk antibody protected synapses and preserved cognitive function. We propose that tipping of the fine balance of Wnt/PCP signaling components in glutamatergic synapses may cause synapse degeneration in neurodegenerative disorders with Aβ pathology.
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Dejanovic, Borislav, Tiffany Wu, Ming-Chi Tsai, David Graykowski, Vineela D. Gandham, Christopher M. Rose, Corey E. Bakalarski, et al. "Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models." Nature Aging 2, no. 9 (September 20, 2022): 837–50. http://dx.doi.org/10.1038/s43587-022-00281-1.
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AbstractMicroglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in TauP301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in TauP301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte–synapse association and decreased astrocytic and microglial synapses engulfment in TauP301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.
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Amano, Ryota, Mitsuyuki Nakao, Kazumichi Matsumiya, and Fumikazu Miwakeichi. "A computational model to explore how temporal stimulation patterns affect synapse plasticity." PLOS ONE 17, no. 9 (September 23, 2022): e0275059. http://dx.doi.org/10.1371/journal.pone.0275059.
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Plasticity-related proteins (PRPs), which are synthesized in a synapse activation-dependent manner, are shared by multiple synapses to a limited spatial extent for a specific period. In addition, stimulated synapses can utilize shared PRPs through synaptic tagging and capture (STC). In particular, the phenomenon by which short-lived early long-term potentiation is transformed into long-lived late long-term potentiation using shared PRPs is called “late-associativity,” which is the underlying principle of “cluster plasticity.” We hypothesized that the competitive capture of PRPs by multiple synapses modulates late-associativity and affects the fate of each synapse in terms of whether it is integrated into a synapse cluster. We tested our hypothesis by developing a computational model to simulate STC, late-associativity, and the competitive capture of PRPs. The experimental results obtained using the model revealed that the number of competing synapses, timing of stimulation to each synapse, and basal PRP level in the dendritic compartment altered the effective temporal window of STC and influenced the conditions under which late-associativity occurs. Furthermore, it is suggested that the competitive capture of PRPs results in the selection of synapses to be integrated into a synapse cluster via late-associativity.
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Grant, Seth G. N. "Synapse diversity and synaptome architecture in human genetic disorders." Human Molecular Genetics 28, R2 (July 26, 2019): R219—R225. http://dx.doi.org/10.1093/hmg/ddz178.
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Abstract Over 130 brain diseases are caused by mutations that disrupt genes encoding the proteome of excitatory synapses. These include neurological and psychiatric disorders with early and late onset such as autism, schizophrenia and depression and many other rarer conditions. The proteome of synapses is highly complex with over 1000 conserved proteins which are differentially expressed generating a vast, potentially unlimited, number of synapse types. The diversity of synapses and their location in the brain are described by the synaptome. A recent study has mapped the synaptome across the mouse brain, revealing that synapse diversity is distributed into an anatomical architecture observed at scales from individual dendrites to the whole systems level. The synaptome architecture is built from the hierarchical expression and assembly of proteins into complexes and supercomplexes which are distributed into different synapses. Mutations in synapse proteins change the synaptome architecture leading to behavioral phenotypes. Mutations in the mechanisms regulating the hierarchical assembly of the synaptome, including transcription and proteostasis, may also change synapse diversity and synaptome architecture. The logic of synaptome hierarchical assembly provides a mechanistic framework that explains how diverse genetic disorders can converge on synapses in different brain circuits to produce behavioral phenotypes.
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Wang, Yizhi, Congchao Wang, Petter Ranefall, Gerard Joey Broussard, Yinxue Wang, Guilai Shi, Boyu Lyu, et al. "SynQuant: an automatic tool to quantify synapses from microscopy images." Bioinformatics 36, no. 5 (October 9, 2019): 1599–606. http://dx.doi.org/10.1093/bioinformatics/btz760.
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Abstract Motivation Synapses are essential to neural signal transmission. Therefore, quantification of synapses and related neurites from images is vital to gain insights into the underlying pathways of brain functionality and diseases. Despite the wide availability of synaptic punctum imaging data, several issues are impeding satisfactory quantification of these structures by current tools. First, the antibodies used for labeling synapses are not perfectly specific to synapses. These antibodies may exist in neurites or other cell compartments. Second, the brightness of different neurites and synaptic puncta is heterogeneous due to the variation of antibody concentration and synapse-intrinsic differences. Third, images often have low signal to noise ratio due to constraints of experiment facilities and availability of sensitive antibodies. These issues make the detection of synapses challenging and necessitates developing a new tool to easily and accurately quantify synapses. Results We present an automatic probability-principled synapse detection algorithm and integrate it into our synapse quantification tool SynQuant. Derived from the theory of order statistics, our method controls the false discovery rate and improves the power of detecting synapses. SynQuant is unsupervised, works for both 2D and 3D data, and can handle multiple staining channels. Through extensive experiments on one synthetic and three real datasets with ground truth annotation or manually labeling, SynQuant was demonstrated to outperform peer specialized unsupervised synapse detection tools as well as generic spot detection methods. Availability and implementation Java source code, Fiji plug-in, and test data are available at https://github.com/yu-lab-vt/SynQuant. Supplementary information Supplementary data are available at Bioinformatics online.
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Mamiya, Akira, and Farzan Nadim. "Target-Specific Short-Term Dynamics Are Important for the Function of Synapses in an Oscillatory Neural Network." Journal of Neurophysiology 94, no. 4 (October 2005): 2590–602. http://dx.doi.org/10.1152/jn.00110.2005.
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Short-term dynamics such as facilitation and depression are present in most synapses and are often target-specific even for synapses from the same type of neuron. We examine the dynamics and possible functions of two synapses from the same presynaptic neuron in the rhythmically active pyloric network of the spiny lobster. Using simultaneous recordings, we show that the synapses from the lateral pyloric (LP) neuron to the pyloric dilator (PD; a member of the pyloric pacemaker ensemble) and the pyloric constrictor (PY) neurons both show short-term depression. However, the postsynaptic potentials produced by the LP-to-PD synapse are larger in amplitude, depress less, and recover faster than those produced by the LP-to-PY synapse. The main function of the LP-to-PD synapse is to slow down the pyloric rhythm. However, in some cases, it slows down the rhythm only when it is fast and has no effect or to speeds up when it is slow. In contrast, the LP-to-PY synapse functions to delay the activity of the PY neuron; this delay increases as the cycle period becomes longer. Using a computational model, we show that the short-term dynamics of synaptic depression observed for each of these synapses are tailored to their individual functions and that replacing the dynamics of either synapse with the other would disrupt these functions. Together, the experimental and modeling results suggest that the target-specific features of short-term synaptic depression are functionally important for synapses efferent from the same presynaptic neuron.
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Bloom, Ona, Emma Evergren, Nikolay Tomilin, Ole Kjaerulff, Peter Löw, Lennart Brodin, Vincent A. Pieribone, Paul Greengard, and Oleg Shupliakov. "Colocalization of synapsin and actin during synaptic vesicle recycling." Journal of Cell Biology 161, no. 4 (May 19, 2003): 737–47. http://dx.doi.org/10.1083/jcb.200212140.
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It has been hypothesized that in the mature nerve terminal, interactions between synapsin and actin regulate the clustering of synaptic vesicles and the availability of vesicles for release during synaptic activity. Here, we have used immunogold electron microscopy to examine the subcellular localization of actin and synapsin in the giant synapse in lamprey at different states of synaptic activity. In agreement with earlier observations, in synapses at rest, synapsin immunoreactivity was preferentially localized to a portion of the vesicle cluster distal to the active zone. During synaptic activity, however, synapsin was detected in the pool of vesicles proximal to the active zone. In addition, actin and synapsin were found colocalized in a dynamic filamentous cytomatrix at the sites of synaptic vesicle recycling, endocytic zones. Synapsin immunolabeling was not associated with clathrin-coated intermediates but was found on vesicles that appeared to be recycling back to the cluster. Disruption of synapsin function by microinjection of antisynapsin antibodies resulted in a prominent reduction of the cytomatrix at endocytic zones of active synapses. Our data suggest that in addition to its known function in clustering of vesicles in the reserve pool, synapsin migrates from the synaptic vesicle cluster and participates in the organization of the actin-rich cytomatrix in the endocytic zone during synaptic activity.
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Stevens-Sostre, Whitney A., and Mrinalini Hoon. "Cellular and Molecular Mechanisms Regulating Retinal Synapse Development." Annual Review of Vision Science 10, no. 1 (September 15, 2024): 377–402. http://dx.doi.org/10.1146/annurev-vision-102122-105721.
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Synapse formation within the retinal circuit ensures that distinct neuronal types can communicate efficiently to process visual signals. Synapses thus form the core of the visual computations performed by the retinal circuit. Retinal synapses are diverse but can be broadly categorized into multipartner ribbon synapses and 1:1 conventional synapses. In this article, we review our current understanding of the cellular and molecular mechanisms that regulate the functional establishment of mammalian retinal synapses, including the role of adhesion proteins, synaptic proteins, extracellular matrix and cytoskeletal-associated proteins, and activity-dependent cues. We outline future directions and areas of research that will expand our knowledge of these mechanisms. Understanding the regulators moderating synapse formation and function not only reveals the integrated developmental processes that establish retinal circuits, but also divulges the identity of mechanisms that could be engaged during disease and degeneration.
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Uchigashima, Motokazu, Toshihisa Ohtsuka, Kazuto Kobayashi, and Masahiko Watanabe. "Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures." Proceedings of the National Academy of Sciences 113, no. 15 (March 25, 2016): 4206–11. http://dx.doi.org/10.1073/pnas.1514074113.
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Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets.
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Staple, Julie K., Florence Morgenthaler, and Stefan Catsicas. "Presynaptic Heterogeneity: Vive la difference." Physiology 15, no. 1 (February 2000): 45–49. http://dx.doi.org/10.1152/physiologyonline.2000.15.1.45.
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Since individual synapses of the same neuron may have different molecular composition, an important question in neurobiology is how the properties of individual synapses are established and maintained. Recent technical advances allow assay of activity at individual synapses and investigation of the relationship between function and molecular composition at the synapse.
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Aramideh, Jason Abbas, Andres Vidal-Itriago, Marco Morsch, and Manuel B. Graeber. "Cytokine Signalling at the Microglial Penta-Partite Synapse." International Journal of Molecular Sciences 22, no. 24 (December 7, 2021): 13186. http://dx.doi.org/10.3390/ijms222413186.
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Microglial cell processes form part of a subset of synaptic contacts that have been dubbed microglial tetra-partite or quad-partite synapses. Since tetrapartite may also refer to the presence of extracellular matrix components, we propose the more precise term microglial penta-partite synapse for synapses that show a microglial cell process in close physical proximity to neuronal and astrocytic synaptic constituents. Microglial cells are now recognised as key players in central nervous system (CNS) synaptic changes. When synaptic plasticity involving microglial penta-partite synapses occurs, microglia may utilise their cytokine arsenal to facilitate the generation of new synapses, eliminate those that are not needed anymore, or modify the molecular and structural properties of the remaining synaptic contacts. In addition, microglia–synapse contacts may develop de novo under pathological conditions. Microglial penta-partite synapses have received comparatively little attention as unique sites in the CNS where microglial cells, cytokines and other factors they release have a direct influence on the connections between neurons and their function. It concerns our understanding of the penta-partite synapse where the confusion created by the term “neuroinflammation” is most counterproductive. The mere presence of activated microglia or the release of their cytokines may occur independent of inflammation, and penta-partite synapses are not usually active in a neuroimmunological sense. Clarification of these details is the main purpose of this review, specifically highlighting the relationship between microglia, synapses, and the cytokines that can be released by microglial cells in health and disease.
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Kano, Masanobu, and Takaki Watanabe. "Developmental synapse remodeling in the cerebellum and visual thalamus." F1000Research 8 (July 25, 2019): 1191. http://dx.doi.org/10.12688/f1000research.18903.1.
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Functional neural circuits of mature animals are shaped during postnatal development by eliminating early-formed redundant synapses and strengthening of necessary connections. In the nervous system of newborn animals, redundant synapses are only transient features of the circuit. During subsequent postnatal development, some synapses are strengthened whereas other redundant connections are weakened and eventually eliminated. In this review, we introduce recent studies on the mechanisms of developmental remodeling of climbing fiber–to–Purkinje cell synapses in the cerebellum and synapses from the retina to neurons in the dorsal lateral geniculate nucleus of the visual thalamus (retinogeniculate synapses). These are the two representative models of developmental synapse remodeling in the brain and they share basic principles, including dependency on neural activity. However, recent studies have disclosed that, in several respects, the two models use different molecules and strategies to establish mature synaptic connectivity. We describe similarities and differences between the two models and discuss remaining issues to be tackled in the future in order to understand the general schemes of developmental synapse remodeling.
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NICHOLLS, J. G., Y. LIU, B. W. PAYTON, and D. P. KUFFLER. "The Specificity of Synapse Formation by identified Leech Neurones in culture." Journal of Experimental Biology 153, no. 1 (October 1, 1990): 141–53. http://dx.doi.org/10.1242/jeb.153.1.141.
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The physiological and fine structural events accompanying synapse formation have been followed while identified neurones of known function make contact in tissue culture. Particular pairs of identified neurones isolated from the central nervous system (CNS) of the leech form chemical synapses; other pairs of cells form nonrectifying electrical junctions, rectifying electrical junctions, mixed chemical and electrical synapses or no synapses at all, depending upon the partners that have been paired. Moreover, certain specific regions on the cell surface (such as the soma, initial cell segment or axon tips) preferentially develop chemical or electrical synapses. Of particular interest are the large, serotonergic Retzius cells that form mixed chemical and electrical synapses in culture, as in the animal. When these cells are juxtaposed at their initial segments, it has been shown that chemical synapses can develop reliably within 6h of contact in culture. Shortly after transmission can be detected physiologically, the principal features of synaptic structure are evident. The physiological and morphological characteristics resemble those of mature synapses studied within the central nervous system. Only at later times, after the chemical synapses have been formed, do electrical connections appear. By contrast, when other specialized regions of the Retzius cells are apposed (the tips of their axons), electrical synapses appear earlier. By comparing the connections that different types of serotonergic neurones make in culture we have been able to assess the role played by the transmitter in determining specificity: the results show that the transmitter does not determine what type of synapse is made on a particular partner. For example, Retzius cells make purely chemical synapses upon the sensory P neurone in culture; other serotonergic neurones (known as DL and VL) make purely electrical connections on this same pressure sensory neurone. Together, these results demonstrate that highly specific cell-cell recognition is a necessary feature of synapse formation after neurones have grown to their appropriate destinations.
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Wei, Mei, Wei Wang, Yao Liu, Xiang Mao, Tai Sheng Chen, and Peng Lin. "Protection of Cochlear Ribbon Synapses and Prevention of Hidden Hearing Loss." Neural Plasticity 2020 (November 1, 2020): 1–11. http://dx.doi.org/10.1155/2020/8815990.
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In the auditory system, ribbon synapses are vesicle-associated structures located between inner hair cells (IHCs) and spiral ganglion neurons that are implicated in the modulation of trafficking and fusion of synaptic vesicles at the presynaptic terminals. Synapse loss may result in hearing loss and difficulties with understanding speech in a noisy environment. This phenomenon happens without permanent hearing loss; that is, the cochlear synaptopathy is “hidden.” Recent studies have reported that synapse loss might be critical in the pathogenesis of hidden hearing loss. A better understanding of the molecular mechanisms of the formation, structure, regeneration, and protection of ribbon synapses will assist in the design of potential therapeutic strategies. In this review, we describe and summarize the following aspects of ribbon synapses: (1) functional and structural features, (2) potential mechanisms of damage, (3) therapeutic research on protecting the synapses, and (4) the role of synaptic regeneration in auditory neuropathy and the current options for synapse rehabilitation.
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Guo, Amin, Qi Wu, Xin Yan, Kanghua Chen, Yuxiang Liu, Dingfa Liang, Yuxiao Yang, et al. "Differential roles of lysosomal cholesterol transporters in the development ofC. elegansNMJs." Life Science Alliance 7, no. 10 (July 31, 2024): e202402584. http://dx.doi.org/10.26508/lsa.202402584.
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Cholesterol homeostasis in neurons is critical for synapse formation and maintenance. Neurons with impaired cholesterol uptake undergo progressive synapse loss and eventual degeneration. To investigate the molecular mechanisms of neuronal cholesterol homeostasis and its role during synapse development, we studied motor neurons ofCaenorhabditis elegansbecause these neurons rely on dietary cholesterol. Combining lipidomic analysis, we discovered that NCR-1, a lysosomal cholesterol transporter, promotes cholesterol absorption and synapse development. Loss ofncr-1causes smaller synapses, and low cholesterol exacerbates the deficits. Moreover, NCR-1 deficiency hinders the increase in synapses under high cholesterol. Unexpectedly, NCR-2, the NCR-1 homolog, increases the use of cholesterol and sphingomyelins and impedes synapse formation. NCR-2 deficiency causes an increase in synapses regardless of cholesterol concentration. Inhibiting the degradation or synthesis of sphingomyelins can induce or suppress the synaptic phenotypes inncr-2mutants. Our findings indicate that neuronal cholesterol homeostasis is differentially controlled by two lysosomal cholesterol transporters and highlight the importance of neuronal cholesterol homeostasis in synapse development.
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Liu, Kang K. L., Michael F. Hagan, and John E. Lisman. "Gradation (approx. 10 size states) of synaptic strength by quantal addition of structural modules." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1715 (March 5, 2017): 20160328. http://dx.doi.org/10.1098/rstb.2016.0328.
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Memory storage involves activity-dependent strengthening of synaptic transmission, a process termed long-term potentiation (LTP). The late phase of LTP is thought to encode long-term memory and involves structural processes that enlarge the synapse. Hence, understanding how synapse size is graded provides fundamental information about the information storage capability of synapses. Recent work using electron microscopy (EM) to quantify synapse dimensions has suggested that synapses may structurally encode as many as 26 functionally distinct states, which correspond to a series of proportionally spaced synapse sizes. Other recent evidence using super-resolution microscopy has revealed that synapses are composed of stereotyped nanoclusters of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and scaffolding proteins; furthermore, synapse size varies linearly with the number of nanoclusters. Here we have sought to develop a model of synapse structure and growth that is consistent with both the EM and super-resolution data. We argue that synapses are composed of modules consisting of matrix material and potentially one nanocluster. LTP induction can add a trans-synaptic nanocluster to a module, thereby converting a silent module to an AMPA functional module. LTP can also add modules by a linear process, thereby producing an approximately 10-fold gradation in synapse size and strength. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’.
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Schafer, Dorothy P., and Beth Stevens. "Synapse elimination during development and disease: immune molecules take centre stage." Biochemical Society Transactions 38, no. 2 (March 22, 2010): 476–81. http://dx.doi.org/10.1042/bst0380476.
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Synapse elimination is a normal developmental process occurring throughout the central and peripheral nervous systems. Meanwhile, gradual and early loss of synapses is a characteristic that is common to several neurodegenerative disease states. Recent evidence has emerged implicating molecules canonically involved in the immune system and inflammation accompanying neurodegeneration (e.g. classical complement cascade) as important players in the normal elimination of synapses in the developing nervous system. As a result, a question has emerged as to whether mechanisms underlying elimination of synapses during normal development are recapitulated and contribute to early synapse loss and nervous system dysfunction during neurodegenerative disease. The present review explores this possibility and provides a description of many neuroimmune proteins that may participate in the elimination of synapses and synaptic dysfunction in the developing and diseased brain.
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Sajedinia, Zahra, and Sébastien Hélie. "A New Computational Model for Astrocytes and Their Role in Biologically Realistic Neural Networks." Computational Intelligence and Neuroscience 2018 (July 5, 2018): 1–10. http://dx.doi.org/10.1155/2018/3689487.
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Recent studies in neuroscience show that astrocytes alongside neurons participate in modulating synapses. It led to the new concept of “tripartite synapse”, which means that a synapse consists of three parts: presynaptic neuron, postsynaptic neuron, and neighboring astrocytes. However, it is still unclear what role is played by the astrocytes in the tripartite synapse. Detailed biocomputational modeling may help generate testable hypotheses. In this article, we aim to study the role of astrocytes in synaptic plasticity by exploring whether tripartite synapses are capable of improving the performance of a neural network. To achieve this goal, we developed a computational model of astrocytes based on the Izhikevich simple model of neurons. Next, two neural networks were implemented. The first network was only composed of neurons and had standard bipartite synapses. The second network included both neurons and astrocytes and had tripartite synapses. We used reinforcement learning and tested the networks on categorizing random stimuli. The results show that tripartite synapses are able to improve the performance of a neural network and lead to higher accuracy in a classification task. However, the bipartite network was more robust to noise. This research provides computational evidence to begin elucidating the possible beneficial role of astrocytes in synaptic plasticity and performance of a neural network.
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HEIDELBERGER, RUTH, MENG M. WANG, and DAVID M. SHERRY. "Differential distribution of synaptotagmin immunoreactivity among synapses in the goldfish, salamander, and mouse retina." Visual Neuroscience 20, no. 1 (January 2003): 37–49. http://dx.doi.org/10.1017/s095252380320105x.
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Synaptotagmin I is the leading candidate for the calcium sensor that triggers exocytosis at conventional synapses. However, physiological characterization of the calcium sensor for phasic release at the ribbon-style synapses of the goldfish Mb1 bipolar cell demonstrates a lower than predicted affinity for calcium, suggesting that a modified or different sensor triggers exocytosis at this synapse. We examined synaptotagmin immunolabeling in goldfish retina using two different antibodies directed against synaptotagmin epitopes that specifically labeled the expected 65-kDa protein on western blots of goldfish and mouse retinal membranes. The first antiserum strongly labeled conventional synapses in the inner plexiform layer (IPL), but did not label the ribbon-style synapse-containing synaptic terminals of goldfish Mb1 bipolar cells or photoreceptors. The second antibody also specifically labeled the expected 65-kDa protein on western blots but did not label any synapses in the goldfish retina. A third synaptotagmin antibody that performed poorly on western blots selectively labeled goldfish photoreceptor terminals. These results suggest that synaptotagmin may exist in at least three distinct “forms” in goldfish retinal synapses. These forms, which are differentially localized to conventional synapses, bipolar cell, and photoreceptor terminals, may represent differences in isoform, posttranslational modifications, epitope availability, and protein-binding partners. Labeling with these antibodies in the salamander and mouse retina revealed species-specific differences, indicating that synaptotagmin epitopes can vary across species as well as among synapses.
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Bate, Clive, William Nolan, Harriet McHale-Owen, and Alun Williams. "Sialic Acid within the Glycosylphosphatidylinositol Anchor Targets the Cellular Prion Protein to Synapses." Journal of Biological Chemistry 291, no. 33 (June 20, 2016): 17093–101. http://dx.doi.org/10.1074/jbc.m116.731117.
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Although the cellular prion protein (PrPC) is concentrated at synapses, the factors that target PrPC to synapses are not understood. Here we demonstrate that exogenous PrPC was rapidly targeted to synapses in recipient neurons derived from Prnp knock-out(0/0) mice. The targeting of PrPC to synapses was dependent upon both neuronal cholesterol concentrations and the lipid and glycan composition of its glycosylphosphatidylinositol (GPI) anchor. Thus, the removal of either an acyl chain or sialic acid from the GPI anchor reduced the targeting of PrPC to synapses. Isolated GPIs (derived from PrPC) were also targeted to synapses, as was IgG conjugated to these GPIs. The removal of sialic acid from GPIs prevented the targeting of either the isolated GPIs or the IgG-GPI conjugate to synapses. Competition studies showed that pretreatment with sialylated GPIs prevented the targeting of PrPC to synapses. These results are consistent with the hypothesis that the sialylated GPI anchor attached to PrPC acts as a synapse homing signal.
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Hu, Xiaoge, Jian-hong Luo, and Junyu Xu. "The Interplay between Synaptic Activity and Neuroligin Function in the CNS." BioMed Research International 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/498957.
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Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previousin vitroandin vivostudies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum disorders or mental retardations, and mice harboring the reported NL deletions or mutations exhibit autism-related behaviors and synapse dysfunction. Conversely, synaptic activity can regulate the phosphorylation, expression, and cleavage of NLs, which, in turn, can influence synaptic activity. Thus, in clinical research, identifying the relationship between NLs and synapse function is critical. In this review, we primarily discuss how NLs and synaptic activity influence each other.
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Cabezas, Carolina, and Washington Buño. "Distinct Transmitter Release Properties Determine Differences in Short-Term Plasticity at Functional and Silent Synapses." Journal of Neurophysiology 95, no. 5 (May 2006): 3024–34. http://dx.doi.org/10.1152/jn.00739.2005.
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Recent evidence suggests that functional and silent synapses are not only postsynaptically different but also presynaptically distinct. The presynaptic differences may be of functional importance in memory formation because a proposed mechanism for long-term potentiation is the conversion of silent synapses into functional ones. However, there is little direct experimentally evidence of these differences. We have investigated the transmitter release properties of functional and silent Schaffer collateral synapses and show that on the average functional synapses displayed a lower percentage of failures and higher excitatory postsynaptic current (EPSC) amplitudes than silent synapses at +60 mV. Moreover, functional but not silent synapses show paired-pulse facilitation (PPF) at +60 mV and thus presynaptic short-term plasticity will be distinct in the two types of synapse. We examined whether intraterminal endoplasmic reticulum Ca2+ stores influenced the release properties of these synapses. Ryanodine (100 μM) and thapsigargin (1 μM) increased the percentage of failures and decreased both the EPSC amplitude and PPF in functional synapses. Caffeine (10 mM) had the opposite effects. In contrast, silent synapses were insensitive to both ryanodine and caffeine. Hence we have identified differences in the release properties of functional and silent synapses, suggesting that synaptic terminals of functional synapses express regulatory molecular mechanisms that are absent in silent synapses.
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Schöpf, Clemens L., Cornelia Ablinger, Stefanie M. Geisler, Ruslan I. Stanika, Marta Campiglio, Walter A. Kaufmann, Benedikt Nimmervoll, et al. "Presynaptic α2δ subunits are key organizers of glutamatergic synapses." Proceedings of the National Academy of Sciences 118, no. 14 (March 29, 2021): e1920827118. http://dx.doi.org/10.1073/pnas.1920827118.
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In nerve cells the genes encoding for α2δ subunits of voltage-gated calcium channels have been linked to synaptic functions and neurological disease. Here we show that α2δ subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular α2δ subunit triple-knockout/knockdown model, we demonstrate a failure in presynaptic differentiation evidenced by defective presynaptic calcium channel clustering and calcium influx, smaller presynaptic active zones, and a strongly reduced accumulation of presynaptic vesicle-associated proteins (synapsin and vGLUT). The presynaptic defect is associated with the downscaling of postsynaptic AMPA receptors and the postsynaptic density. The role of α2δ isoforms as synaptic organizers is highly redundant, as each individual α2δ isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Moreover, α2δ-2 and α2δ-3 with mutated metal ion-dependent adhesion sites can fully rescue presynaptic synapsin expression but only partially calcium channel trafficking, suggesting that the regulatory role of α2δ subunits is independent from its role as a calcium channel subunit. Our findings influence the current view on excitatory synapse formation. First, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Second, the dependence of presynaptic differentiation on α2δ implicates α2δ subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that α2δ subunits act as transsynaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.
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Terada, Sumio, Tetsuhiro Tsujimoto, Yosuke Takei, Tomoyuki Takahashi, and Nobutaka Hirokawa. "Impairment of Inhibitory Synaptic Transmission in Mice Lacking Synapsin I." Journal of Cell Biology 145, no. 5 (May 31, 1999): 1039–48. http://dx.doi.org/10.1083/jcb.145.5.1039.
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Deletion of the synapsin I genes, encoding one of the major groups of proteins on synaptic vesicles, in mice causes late onset epileptic seizures and enhanced experimental temporal lobe epilepsy. However, mice lacking synapsin I maintain normal excitatory synaptic transmission and modulation but for an enhancement of paired-pulse facilitation. To elucidate the cellular basis for epilepsy in mutants, we examined whether the inhibitory synapses in the hippocampus from mutant mice are intact by electrophysiological and morphological means. In the cultured hippocampal synapses from mutant mice, repeated application of a hypertonic solution significantly suppressed the subsequent transmitter release, associated with an accelerated vesicle replenishing time at the inhibitory synapses, compared with the excitatory synapses. In the mutants, morphologically identifiable synaptic vesicles failed to accumulate after application of a hypertonic solution at the inhibitory preterminals but not at the excitatory preterminals. In the CA3 pyramidal cells in hippocampal slices from mutant mice, inhibitory postsynaptic currents evoked by direct electrical stimulation of the interneuron in the striatum oriens were characterized by reduced quantal content compared with those in wild type. We conclude that synapsin I contributes to the anchoring of synaptic vesicles, thereby minimizing transmitter depletion at the inhibitory synapses. This may explain, at least in part, the epileptic seizures occurring in the synapsin I mutant mice.
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Su, Jianmin, Jiang Chen, Kumiko Lippold, Aboozar Monavarfeshani, Gabriela Lizana Carrillo, Rachel Jenkins, and Michael A. Fox. "Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex." Journal of Cell Biology 212, no. 6 (March 14, 2016): 721–36. http://dx.doi.org/10.1083/jcb.201509085.
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Inhibitory synapses comprise only ∼20% of the total synapses in the mammalian brain but play essential roles in controlling neuronal activity. In fact, perturbing inhibitory synapses is associated with complex brain disorders, such as schizophrenia and epilepsy. Although many types of inhibitory synapses exist, these disorders have been strongly linked to defects in inhibitory synapses formed by Parvalbumin-expressing interneurons. Here, we discovered a novel role for an unconventional collagen—collagen XIX—in the formation of Parvalbumin+ inhibitory synapses. Loss of this collagen results not only in decreased inhibitory synapse number, but also in the acquisition of schizophrenia-related behaviors. Mechanistically, these studies reveal that a proteolytically released fragment of this collagen, termed a matricryptin, promotes the assembly of inhibitory nerve terminals through integrin receptors. Collectively, these studies not only identify roles for collagen-derived matricryptins in cortical circuit formation, but they also reveal a novel paracrine mechanism that regulates the assembly of these synapses.
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Jiang, Danye, and Melanie Samuel. "MICROGLIA MAY INSTRUCT SYNAPTIC FATE VIA SIRPα IN MOUSE RETINA." Innovation in Aging 3, Supplement_1 (November 2019): S967. http://dx.doi.org/10.1093/geroni/igz038.3507.
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Abstract As we age, our nervous system undergoes many deleterious alterations: cognitive and sensory functions decrease while the risk of disease increases. Synapses are responsible for neural information processing, and the decline of these structures via microglia-mediated remodeling is thought to underline many age-related neural changes. However, the molecular pathways responsible for microglia-mediated synapses removal in development and old age remain unknown. To begin to elucidate these pathways, we leveraged the precisely organized murine retina where neurons form synapses in distinct lamina. Using this system, we screened 102 lacZ reporter lines available through the Knockout Mouse Project (KOMP) and uncovered a unique synapse regulatory candidate, SIRPα. We show that SIRPα is present in microglia prior to synapse formation but becomes selectively enriched in neural synapse terminals as these connections mature. Further, the levels of SIRPα decrease in the context of age-related neural decline. In ongoing studies, we are testing the hypothesis that neuronal SIRPα regulates its receptor CD47 to modulate refinement by microglial SIRPα. Together, these studies will resolve the molecular cues through which microglia prune synapses in development and dissect how these programs may go awry in the context of aging and disease.
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Fu, Zhanyan, Philip Washbourne, Pavel Ortinski, and Stefano Vicini. "Functional Excitatory Synapses in HEK293 Cells Expressing Neuroligin and Glutamate Receptors." Journal of Neurophysiology 90, no. 6 (December 2003): 3950–57. http://dx.doi.org/10.1152/jn.00647.2003.
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The discovery that neuroligin is a key protein involved in synapse formation offers the unprecedented opportunity to induce functional synapses between neurons and heterologous cells. We took this opportunity recording for the first-time synaptic currents in human embryonic kidney 293 (HEK293) cells transfected with neuroligin and the N-methyl-d-aspartate or AMPA receptor subunits in a co-culture with rat cerebellar granule cells. These currents were similar to synaptic currents recorded in neurons, and their decay kinetics was determined by the postsynaptic subunit combination. Although neuroligin expression was sufficient to detect functional synapses, cotransfection of HEK293 cells with Postsynaptic density-95/synapse-associated protein-90 (PSD-95) significantly increased current frequency. Our results support the central role of neuroligin in the formation of CNS synapses, validate the proposal that PSD-95 allows synaptic maturation, and provide a unique experimental model to study how molecular components determine functional properties of excitatory synapses.
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Johnson, B. R., J. H. Peck, and R. M. Harris-Warrick. "Distributed amine modulation of graded chemical transmission in the pyloric network of the lobster stomatogastric ganglion." Journal of Neurophysiology 74, no. 1 (July 1, 1995): 437–52. http://dx.doi.org/10.1152/jn.1995.74.1.437.
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1. In the pyloric network of the lobster stomatogastric ganglion, graded synapses organize the network output. The amines dopamine (DA), serotonin, and octopamine each elicit a distinctive motor pattern from a quiescent pyloric network. We have examined the effects of these amines on the graded synaptic strengths between the six major types of neurons of this network to understand how amine modulation of synaptic strength contributes to the amine-induced motor patterns. Here we tested amine affects at 10 different graded chemical synapses of the pyloric network. We show that each amine has a statistically different spectrum of distributed effects across the network synapses. 2. Under our control conditions (isolated pairs of neurons, removal of modulatory input), most of the graded chemical synapses were weak and some synapses were nonfunctional. The output synapses of the ventricular dilator (VD) neuron were significantly stronger than the other synapses. 3. DA altered the synaptic strength of every graded chemical synapse. This amine strengthened the weak chemical output synapses of the anterior burster (AB), lateral pyloric (LP), and pyloric constrictor (PY) neurons and weakened (and in some cases abolished) the strong chemical output synapses of the VD neuron. The AB-->inferior cardiac neuron (IC) and PY-->IC graded chemical synapses were nonfunctional under our control conditions; DA activated these silent synapses. 4. Serotonin enhanced the AB's output chemical synapses but weakened all the other graded chemical synapses examined. Octopamine's effects were much weaker than those of the other two amines. It enhanced the AB-->LP synapse and the LP's output synapses and weakly strengthened the AB-->PY, VD-->LP, and VD-->PY synapses. 5. The amines alter the input resistance of many of the pyloric neurons, and this could contribute to the observed changes in synaptic strength by altering passive current flow between input and output sites in the cells. However, the input resistance changes were relatively small compared with the changes in synaptic strength and cannot alone account for the synaptic modulation. In some cases the sign of the input resistance change was inconsistent with the change in synaptic strength. Thus the amines appear to modify synaptic transmission directly in this system. 6. This study completes our description of amine effects on all the graded synapses of the pyloric network. We summarize our present and earlier work to show that modulators can reconfigure the entire synaptic organization of a neural network by acting at many distributed synaptic sites.(ABSTRACT TRUNCATED AT 400 WORDS)
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Brunskine, Cindy, Stefan Passlick, and Christian Henneberger. "Structural Heterogeneity of the GABAergic Tripartite Synapse." Cells 11, no. 19 (October 7, 2022): 3150. http://dx.doi.org/10.3390/cells11193150.
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The concept of the tripartite synapse describes the close interaction of pre- and postsynaptic elements and the surrounding astrocyte processes. For glutamatergic synapses, it is established that the presence of astrocytic processes and their structural arrangements varies considerably between and within brain regions and between synapses of the same neuron. In contrast, less is known about the organization of astrocytic processes at GABAergic synapses although bi-directional signaling is known to exist at these synapses too. Therefore, we established super-resolution expansion microscopy of GABAergic synapses and nearby astrocytic processes in the stratum radiatum of the mouse hippocampal CA1 region. By visualizing the presynaptic vesicular GABA transporter and the postsynaptic clustering protein gephyrin, we documented the subsynaptic heterogeneity of GABAergic synaptic contacts. We then compared the volume distribution of astrocytic processes near GABAergic synapses between individual synapses and with glutamatergic synapses. We made two novel observations. First, astrocytic processes were more abundant at the GABAergic synapses with large postsynaptic gephyrin clusters. Second, astrocytic processes were less abundant in the vicinity of GABAergic synapses compared to glutamatergic, suggesting that the latter may be selectively approached by astrocytes. Because of the GABA transporter distribution, we also speculate that this specific arrangement enables more efficient re-uptake of GABA into presynaptic terminals.
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Rothwell, Cailin M., Eric de Hoog, and Gaynor E. Spencer. "The role of retinoic acid in the formation and modulation of invertebrate central synapses." Journal of Neurophysiology 117, no. 2 (February 1, 2017): 692–704. http://dx.doi.org/10.1152/jn.00737.2016.
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Trophic factors can influence many aspects of nervous system function, such as neurite outgrowth, synapse formation, and synapse modulation. The vitamin A metabolite, retinoic acid, can exert trophic effects to promote neuronal survival and outgrowth in many species and is also known to modulate vertebrate hippocampal synapses. However, its role in synaptogenesis has not been well studied, and whether it can modulate existing invertebrate synapses is also not known. In this study, we first examined a potential trophic effect of retinoic acid on the formation of excitatory synapses, independently of its role in neurite outgrowth, using cultured neurons of the mollusc Lymnaea stagnalis. We also investigated its role in modulating both chemical and electrical synapses between various Lymnaea neurons in cell culture. Although we found no evidence to suggest retinoic acid affected short-term synaptic plasticity in the form of post-tetanic potentiation, we did find a significant cell type-specific modulation of electrical synapses. Given the prevalence of electrical synapses in invertebrate nervous systems, these findings highlight the potential for retinoic acid to modulate network function in the central nervous system of at least some invertebrates. NEW & NOTEWORTHY This study performed the first electrophysiological analysis of the ability of the vitamin A metabolite, retinoic acid, to exert trophic influences during synaptogenesis independently of its effects in supporting neurite outgrowth. It was also the first study to examine the ability of retinoic acid to modify both chemical and electrical synapses in any invertebrate, nonchordate species. We provide evidence that all-trans retinoic acid can modify invertebrate electrical synapses of central neurons in a cell-specific manner.
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Jaworski, Alexander, Cynthia L. Smith, and Steven J. Burden. "GA-Binding Protein Is Dispensable for Neuromuscular Synapse Formation and Synapse-Specific Gene Expression." Molecular and Cellular Biology 27, no. 13 (May 7, 2007): 5040–46. http://dx.doi.org/10.1128/mcb.02228-06.
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ABSTRACT The mRNAs encoding postsynaptic components at the neuromuscular junction are concentrated in the synaptic region of muscle fibers. Accumulation of these RNAs in the synaptic region is mediated, at least in part, by selective transcription of the corresponding genes in synaptic myofiber nuclei. The transcriptional mechanisms that are responsible for synapse-specific gene expression are largely unknown, but an Ets site in the promoter regions of acetylcholine receptor (AChR) subunit genes and other “synaptic” genes is required for synapse-specific transcription. The Ets domain transcription factor GA-binding protein (GABP) has been implicated to mediate synapse-specific gene expression. Inactivation of GABPα, the DNA-binding subunit of GABP, leads to early embryonic lethality, preventing analysis of synapse formation in gabpα mutant mice. To study the role of GABP at neuromuscular synapses, we conditionally inactivated gabpα in skeletal muscle and studied synaptic differentiation and muscle gene expression. Although expression of rb, a target of GABP, is elevated in muscle tissue deficient in GABPα, clustering of synaptic AChRs at synapses and synapse-specific gene expression are normal in these mice. These data indicate that GABP is dispensable for synapse-specific transcription and maintenance of normal AChR expression at synapses.
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Thakar, Sonal, Liqing Wang, Ting Yu, Mao Ye, Keisuke Onishi, John Scott, Jiaxuan Qi, et al. "Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation." Proceedings of the National Academy of Sciences 114, no. 4 (January 5, 2017): E610—E618. http://dx.doi.org/10.1073/pnas.1612062114.
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The signaling mechanisms that choreograph the assembly of the highly asymmetric pre- and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of ∼50% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of ∼50% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.
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Sueoka, Brandon, Kuan Yew Cheong, and Feng Zhao. "Natural biomaterial honey-based resistive switching device for artificial synapse in neuromorphic systems." Applied Physics Letters 120, no. 8 (February 21, 2022): 083301. http://dx.doi.org/10.1063/5.0081704.
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Resistive switching is a promising technology for artificial synapses, the most critical component and building block of a neural network for brain-inspired neuromorphic computing. The artificial synapse is capable of emulating a signal process and memory functions of biological synapses. The artificial synapse fabricated by natural bioorganic materials is essential for developing soft, flexible, and biocompatible electronics and sustainable, biodegradable, and environmentally friendly neuromorphic systems. In this work, a natural biomaterial—honey based resistive switching device—was demonstrated to emulate some important functionalities of biological synapses, including synaptic potentiation and depression, short-term and long-term memory, spatial summation, and shunting inhibition. The results indicate the potential of honey based resistive switching for artificial synaptic devices in renewable neuromorphic systems and bioelectronics.
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Verron, Quentin, Elin Forslund, Ludwig Brandt, Mattias Leino, Thomas W. Frisk, Per E. Olofsson, and Björn Önfelt. "NK cells integrate signals over large areas when building immune synapses but require local stimuli for degranulation." Science Signaling 14, no. 684 (May 25, 2021): eabe2740. http://dx.doi.org/10.1126/scisignal.abe2740.
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Immune synapses are large-scale, transient molecular assemblies that serve as platforms for antigen presentation to B and T cells and for target recognition by cytotoxic T cells and natural killer (NK) cells. The formation of an immune synapse is a tightly regulated, stepwise process in which the cytoskeleton, cell surface receptors, and intracellular signaling proteins rearrange into supramolecular activation clusters (SMACs). We generated artificial immune synapses (AIS) consisting of synthetic and natural ligands for the NK cell–activating receptors LFA-1 and CD16 by microcontact printing the ligands into circular-shaped SMAC structures. Live-cell imaging and analysis of fixed human NK cells in this reductionist system showed that the spatial distribution of activating ligands influenced the formation, stability, and outcome of NK cell synapses. Whereas engagement of LFA-1 alone promoted synapse initiation, combined engagement of LFA-1 and CD16 was required for the formation of mature synapses and degranulation. Organizing LFA-1 and CD16 ligands into donut-shaped AIS resulted in fewer long-lasting, symmetrical synapses compared to dot-shaped AIS. NK cells spreading evenly over either AIS shape exhibited similar arrangements of the lytic machinery. However, degranulation only occurred in regions containing ligands that therefore induced local signaling, suggesting the existence of a late checkpoint for degranulation. Our results demonstrate that the spatial organization of ligands in the synapse can affect its outcome, which could be exploited by target cells as an escape mechanism.
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Zhao, Qing-Tai, Fengben Xi, Yi Han, Andreas Grenmyr, Jin Hee Bae, and Detlev Gruetzmacher. "Ferroelectric Devices for Neuromorphic Computing." ECS Meeting Abstracts MA2022-02, no. 32 (October 9, 2022): 1183. http://dx.doi.org/10.1149/ma2022-02321183mtgabs.
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Neuromorphic computing inspired by the neural network systems of the human brain enables energy efficient computing for big-data processing. A neural network is formed by thousands or even millions of neurons which are connected by even a higher number of synapses. Neurons communicate with each other through the connected synapses. The main responsibility of synapses is to transfer information from the pre-synaptic to the postsynaptic neurons. Synapses can memorize and process the information simultaneously. The plasticity of a synapse to strengthen or weaken their activity over time make it capable of learning and computing. Thus, artificial synapses which can emulate functionalities and the plasticity of bio-synapses form the backbones of neuromorphic computing. Alternative artificial synapses have been successfully demonstrated. The classical two-terminal memristor devices, like resistive random access memory (ReRAM), phase change memory (PCM) and ferroelectric tunnel junctions (FTJs) with one terminal connected to the pre-synaptic neuron and another connected with the post-synaptic neuron, own advantages of simple structure, easy processing with high density, and capability of integration with CMOS. However, signal processing and learning cannot be performed simultaneously in 2-terminal devices, thus limiting their synaptic functionalities. Ferroelectric field effect transistors (FeFET) which uses ferroelectric as the gate oxide are the most interesting three-terminal artificial synapse devices, in which the gate or the source is connected to the pre-synaptic neuron while the drain is used for the terminal of the post-synaptic neuron , thus can perform signal transmission and learning simultaneously. However, traps at the channel interface can degrade the device performance causing low endurance. Focuses of those abovementioned devices have been mainly put on the homosynaptic plasticity, which is input specific, meaning that the plasticity occurs only at the synapse with a pre-synaptic activation . The homosynaptic plasticity has a drawback of positive feedback loop: when a synapse is potentiated, the probability of the synapse to be further potentiated is increased. Similarly, when a synapse is depressed the probability of the synapse of being further depressed is higher. Therefore, synaptic weights tend to be either strengthened to the maximum value or weakened to zero, causing the system to be unstable. In contrast, heterosynaptic plasticity can be induced at any synapse at the same time after episodes of strong postsynaptic activity, avoiding the positive feedback problem and stabilize the activity of the post-synaptic neuron. To address the above challenges we proposed a very simple 4-terminal synapse structure based on gated Schottky diodes on silicon (FEMOD) with a ferroelectric layer. The conductance of the Schottky diode is modulated by the polarization of the ferroelectric layer. With this simple synapse structure we can achieve multiple hetero-synaptic functions, including excitatory/ inhibitory post-synaptic current (EPSC/IPSC), paired-pulse facilitation/depression (PPF/PPD), long-term potentiation/depression (LTP/LTD), as well as biological neuron-like spike-timing-dependent plasticity (STDP) characteristics. The modulatory synapse can modify the weight of another synapse with a very low voltage. Furthermore, logic gates, like AND and NAND which are highly desired for in-memory computing can be realized with such simple structure. Figure 1
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Goldman, Mark S. "Enhancement of Information Transmission Efficiency by Synaptic Failures." Neural Computation 16, no. 6 (June 1, 2004): 1137–62. http://dx.doi.org/10.1162/089976604773717568.
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Many synapses have a high percentage of synaptic transmission failures. I consider the hypothesis that synaptic failures can increase the efficiency of information transmission across the synapse. I use the information transmitted per vesicle release about the presynaptic spike train as a measure of synaptic transmission efficiency and show that this measure can increase with the synaptic failure probability. I analytically calculate the Shannon mutual information transmitted across two model synapses with probabilistic transmission: one with a constant probability of vesicle release and one with vesicle release probabilities governed by the dynamics of synaptic depression. For inputs generated by a non-Poisson process with positive autocorrelations, both synapses can transmit more information per vesicle release than a synapse with perfect transmission, although the information increases are greater for the depressing synapse than for a constant-probability synapse with the same average transmission probability. The enhanced performance of the depressing synapse over the constant-release-probability synapse primarily reflects a decrease in noise entropy rather than an increase in the total transmission entropy. This indicates alimitation of analysis methods, such as decorrelation, that consider only the total response entropy. My results suggest that synaptic transmission failures governed by appropriately tuned synaptic dynamics can increase the information-carrying efficiency of a synapse.
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Kikuchi, Toko, Juncal Gonzalez-Soriano, Asta Kastanauskaite, Ruth Benavides-Piccione, Angel Merchan-Perez, Javier DeFelipe, and Lidia Blazquez-Llorca. "Volume Electron Microscopy Study of the Relationship Between Synapses and Astrocytes in the Developing Rat Somatosensory Cortex." Cerebral Cortex 30, no. 6 (January 27, 2020): 3800–3819. http://dx.doi.org/10.1093/cercor/bhz343.
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Abstract In recent years, numerous studies have shown that astrocytes play an important role in neuronal processing of information. One of the most interesting findings is the existence of bidirectional interactions between neurons and astrocytes at synapses, which has given rise to the concept of “tripartite synapses” from a functional point of view. We used focused ion beam milling and scanning electron microscopy (FIB/SEM) to examine in 3D the relationship of synapses with astrocytes that were previously labeled by intracellular injections in the rat somatosensory cortex. We observed that a large number of synapses (32%) had no contact with astrocytic processes. The remaining synapses (68%) were in contact with astrocytic processes, either at the level of the synaptic cleft (44%) or with the pre- and/or post-synaptic elements (24%). Regarding synaptic morphology, larger synapses with more complex shapes were most frequently found within the population that had the synaptic cleft in contact with astrocytic processes. Furthermore, we observed that although synapses were randomly distributed in space, synapses that were free of astrocytic processes tended to form clusters. Overall, at least in the developing rat neocortex, the concept of tripartite synapse only seems to be applicable to a subset of synapses.
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Robinson, Cristina M., Mikin R. Patel, and Donna J. Webb. "Super resolution microscopy is poised to reveal new insights into the formation and maturation of dendritic spines." F1000Research 5 (June 22, 2016): 1468. http://dx.doi.org/10.12688/f1000research.8649.1.
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Dendritic spines and synapses are critical for neuronal communication, and they are perturbed in many neurological disorders; however, the study of these structures in living cells has been hindered by their small size. Super resolution microscopy, unlike conventional light microscopy, is diffraction unlimited and thus is well suited for imaging small structures, such as dendritic spines and synapses. Super resolution microscopy has already revealed important new information about spine and synapse morphology, actin remodeling, and nanodomain composition in both healthy cells and diseased states. In this review, we highlight the advancements in probes that make super resolution more amenable to live-cell imaging of spines and synapses. We also discuss recent data obtained by super resolution microscopy that has advanced our knowledge of dendritic spine and synapse structure, organization, and dynamics in both healthy and diseased contexts. Finally, we propose a series of critical questions for understanding spine and synapse formation and maturation that super resolution microscopy is poised to answer.
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Martin, Nicola, Sonja Welsch, Clare Jolly, John A. G. Briggs, David Vaux, and Quentin J. Sattentau. "Virological Synapse-Mediated Spread of Human Immunodeficiency Virus Type 1 between T Cells Is Sensitive to Entry Inhibition." Journal of Virology 84, no. 7 (January 20, 2010): 3516–27. http://dx.doi.org/10.1128/jvi.02651-09.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) can disseminate between CD4+ T cells via diffusion-limited cell-free viral spread or by directed cell-cell transfer using virally induced structures termed virological synapses. Although T-cell virological synapses have been well characterized, it is unclear whether this mode of viral spread is susceptible to inhibition by neutralizing antibodies and entry inhibitors. We show here that both cell-cell and cell-free viral spread are equivalently sensitive to entry inhibition. Fluorescence imaging analysis measuring virological synapse lifetimes and inhibitor time-of-addition studies implied that inhibitors can access preformed virological synapses and interfere with HIV-1 cell-cell infection. This concept was supported by electron tomography that revealed the T-cell virological synapse to be a relatively permeable structure. Virological synapse-mediated HIV-1 spread is thus efficient but is not an immune or entry inhibitor evasion mechanism, a result that is encouraging for vaccine and drug design.
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Rodriguez-Moreno, Javier, Astrid Rollenhagen, Jaime Arlandis, Andrea Santuy, Angel Merchan-Pérez, Javier DeFelipe, Joachim H. R. Lübke, and Francisco Clasca. "Quantitative 3D Ultrastructure of Thalamocortical Synapses from the “Lemniscal” Ventral Posteromedial Nucleus in Mouse Barrel Cortex." Cerebral Cortex 28, no. 9 (July 28, 2017): 3159–75. http://dx.doi.org/10.1093/cercor/bhx187.
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Abstract Thalamocortical synapses from “lemniscal” neurons of the dorsomedial portion of the rodent ventral posteromedial nucleus (VPMdm) are able to induce with remarkable efficacy, despite their relative low numbers, the firing of primary somatosensory cortex (S1) layer 4 (L4) neurons. To which extent this high efficacy depends on structural synaptic features remains unclear. Using both serial transmission (TEM) and focused ion beam milling scanning electron microscopy (FIB/SEM), we 3D-reconstructed and quantitatively analyzed anterogradely labeled VPMdm axons in L4 of adult mouse S1. All VPMdm synapses are asymmetric. Virtually all are established by axonal boutons, 53% of which contact multiple (2–4) elements (overall synapse/bouton ratio = 1.6). Most boutons are large (mean 0.47 μm3), and contain 1–3 mitochondria. Vesicle pools and postsynaptic density (PSD) surface areas are large compared to others in rodent cortex. Most PSDs are complex. Most synapses (83%) are established on dendritic spine heads. Furthermore, 15% of the postsynaptic spines receive a second, symmetric synapse. In addition, 13% of the spine heads have a large protrusion inserted into a membrane pouch of the VPMdm bouton. The unusual combination of structural features in VPMdm synapses is likely to contribute significantly to the high efficacy, strength, and plasticity of these thalamocortical synapses.
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Edwards, F. A. "Anatomy and electrophysiology of fast central synapses lead to a structural model for long-term potentiation." Physiological Reviews 75, no. 4 (October 1, 1995): 759–87. http://dx.doi.org/10.1152/physrev.1995.75.4.759.
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Detailed knowledge of the anatomy of central synapses is essential to the interpretation of the vast quantity of electrophysiological findings that have been published in recent years. When their function is considered, it is not surprising that, in both anatomy and electrophysiology, fast central synapses show important differences to the neuromuscular junction. This review concentrates on the detailed anatomy of the common excitatory synapses that impinge on dendritic spines, but also refers to other glutamatergic and GABAergic synapses. This information is brought together with present knowledge of the electrophysiology of fast neurotransmission in the brain. Various types of evidence are outlined, explaining why it is now widely accepted that release of transmitter from a single vesicle virtually saturates the small number of receptors available on the postsynaptic membrane of central synapses. Finally, the anatomic literature suggests that a particular type of spine synapse, which electron microscopy reveals to have a perforated active zone, may represent a synapse with high efficacy. This suggestion is shown to be completely compatible with the electrophysiological data, and a model is presented that shows that all the apparently conflicting data in the field of long-term potentiation could be compatible. This stresses the need for cooperative collaboration between laboratories that have apparently conflicting findings.
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Moss, Brenda L., Abby D. Fuller, Christie L. Sahley, and Brian D. Burrell. "Serotonin Modulates Axo-Axonal Coupling Between Neurons Critical for Learning in the Leech." Journal of Neurophysiology 94, no. 4 (October 2005): 2575–89. http://dx.doi.org/10.1152/jn.00322.2005.
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S cells form a chain of electrically coupled neurons that extends the length of the leech CNS and plays a critical role in sensitization during whole-body shortening. This process requires serotonin, which acts in part by altering the pattern of activity in the S-cell network. Serotonin-containing axons and varicosities were observed in Faivre's nerve where the S-to-S-cell electrical synapses are located. To determine whether serotonin modulates these synapses, S-cell action-potential (AP) propagation was studied in a two-ganglion chain containing one electrical synapse. Suction electrodes were placed on the cut ends of the connectives to stimulate one S cell while recording the other, coupled S cell's APs. A third electrode, placed en passant, recorded the APs near the electrical synapse before they propagated through it. Low concentrations of the gap junction inhibitor octanol increased AP latency across the two-ganglion chain, and this effect was localized to the region of axon containing the electrical synapse. At higher concentrations, APs failed to propagate across the synapse. Serotonin also increased AP latency across the electrical synapse, suggesting that serotonin reduced coupling between S cells. This effect was independent of the direction of propagation and increased with the number of electrical synapses in progressively longer chains. Furthermore, serotonin modulated instantaneous AP frequency when APs were initiated in separate S cells and in a computational model of S-cell activity after mechanosensory input. Thus serotonergic modulation of S-cell electrical synapses may contribute to changes in the pattern of activity in the S-cell network.
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Duman, Joseph G., Yen-Kuei Tu, and Kimberley F. Tolias. "Emerging Roles of BAI Adhesion-GPCRs in Synapse Development and Plasticity." Neural Plasticity 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/8301737.
Full textAbstract:
Synapses mediate communication between neurons and enable the brain to change in response to experience, which is essential for learning and memory. The sites of most excitatory synapses in the brain, dendritic spines, undergo rapid remodeling that is important for neural circuit formation and synaptic plasticity. Abnormalities in synapse and spine formation and plasticity are associated with a broad range of brain disorders, including intellectual disabilities, autism spectrum disorders (ASD), and schizophrenia. Thus, elucidating the mechanisms that regulate these neuronal processes is critical for understanding brain function and disease. The brain-specific angiogenesis inhibitor (BAI) subfamily of adhesion G-protein-coupled receptors (adhesion-GPCRs) has recently emerged as central regulators of synapse development and plasticity. In this review, we will summarize the current knowledge regarding the roles of BAIs at synapses, highlighting their regulation, downstream signaling, and physiological functions, while noting the roles of other adhesion-GPCRs at synapses. We will also discuss the relevance of BAIs in various neurological and psychiatric disorders and consider their potential importance as pharmacological targets in the treatment of these diseases.
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Woodin, Melanie A., Toshiro Hamakawa, Mayumi Takasaki, Ken Lukowiak, and Naweed I. Syed. "Trophic Factor-Induced Plasticity of Synaptic Connections Between Identified Lymnaea Neurons." Learning & Memory 6, no. 3 (May 1, 1999): 307–16. http://dx.doi.org/10.1101/lm.6.3.307.
Full textAbstract:
Neurotrophic factors participate in both developmental and adult synaptic plasticity; however, the underlying mechanisms remain unknown. Using soma–soma synapses between the identified Lymnaea neurons, we demonstrate that the brain conditioned medium (CM)-derived trophic factors are required for the formation of excitatory but not the inhibitory synapse. Specifically, identified presynaptic [right pedal dorsal 1 (RPeD1) and visceral dorsal 4 (VD4)] and postsynaptic [visceral dorsal 2/3 (VD2/3) and left pedal dorsal 1 (LPeD1)] neurons were soma–soma paired either in the absence or presence of CM. We show that in defined medium (DM—does not contain extrinsic trophic factors), appropriate excitatory synapses failed to develop between RPeD1 and VD2/3. Instead, inappropriate inhibitory synapses formed between VD2/3 and RPeD1. Similarly, mutual inhibitory synapses developed between VD4 and LPeD1 in DM. These inhibitory synapses were termed novel because they do not exist in the intact brain. To test whether DM-induced, inappropriate inhibitory synapses could be corrected by the addition of CM, cells were first paired in DM for an initial period of 12 hr. DM was then replaced with CM, and simultaneous intracellular recordings were made from paired cells after 6–12 hr of CM substitution. Not only did CM induce the formation of appropriate excitatory synapses between both cell pairs, but it also reduced the incidence of inappropriate inhibitory synapse formation. The CM-induced plasticity of synaptic connections involved new protein synthesis and transcription and was mediated via receptor tyrosine kinases. Taken together, our data provide the first direct insight into the cellular mechanism underlying trophic factor-induced specificity and plasticity of synaptic connections between soma–soma paired Lymnaea neurons.
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Knoblauch, Andreas. "Efficient Associative Computation with Discrete Synapses." Neural Computation 28, no. 1 (January 2016): 118–86. http://dx.doi.org/10.1162/neco_a_00795.
Full textAbstract:
Neural associative networks are a promising computational paradigm for both modeling neural circuits of the brain and implementing associative memory and Hebbian cell assemblies in parallel VLSI or nanoscale hardware. Previous work has extensively investigated synaptic learning in linear models of the Hopfield type and simple nonlinear models of the Steinbuch/Willshaw type. Optimized Hopfield networks of size n can store a large number of about [Formula: see text] memories of size k (or associations between them) but require real-valued synapses, which are expensive to implement and can store at most [Formula: see text] bits per synapse. Willshaw networks can store a much smaller number of about [Formula: see text] memories but get along with much cheaper binary synapses. Here I present a learning model employing synapses with discrete synaptic weights. For optimal discretization parameters, this model can store, up to a factor [Formula: see text] close to one, the same number of memories as for optimized Hopfield-type learning—for example, [Formula: see text] for binary synapses, [Formula: see text] for 2 bit (four-state) synapses, [Formula: see text] for 3 bit (8-state) synapses, and [Formula: see text] for 4 bit (16-state) synapses. The model also provides the theoretical framework to determine optimal discretization parameters for computer implementations or brainlike parallel hardware including structural plasticity. In particular, as recently shown for the Willshaw network, it is possible to store [Formula: see text] bit per computer bit and up to [Formula: see text] bits per nonsilent synapse, whereas the absolute number of stored memories can be much larger than for the Willshaw model.
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Koppel, Natasha, Matthew B. Friese, Helene L. Cardasis, Thomas A. Neubert, and Steven J. Burden. "Vezatin is required for the maturation of the neuromuscular synapse." Molecular Biology of the Cell 30, no. 20 (September 15, 2019): 2571–83. http://dx.doi.org/10.1091/mbc.e19-06-0313.
Full textAbstract:
Key genes, such as Agrin, Lrp4, and MuSK, are required for the initial formation, subsequent maturation, and long-term stabilization of mammalian neuromuscular synapses. Additional molecules are thought to function selectively during the evolution and stabilization of these synapses, but these molecular players are largely unknown. Here, we used mass spectrometry to identify vezatin, a two-pass transmembrane protein, as an acetylcholine receptor (AChR)–associated protein, and we provide evidence that vezatin binds directly to AChRs. We show that vezatin is dispensable for the formation of synapses but plays a later role in the emergence of a topologically complex and branched shape of the synapse, as well as the stabilization of AChRs. In addition, neuromuscular synapses in vezatin mutant mice display premature signs of deterioration, normally found only during aging. Thus, vezatin has a selective role in the structural elaboration and postnatal maturation of murine neuromuscular synapses.
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Fouke, Kaitlyn E., M. Elizabeth Wegman, Sarah A. Weber, Emily B. Brady, Cristina Román-Vendrell, and Jennifer R. Morgan. "Synuclein Regulates Synaptic Vesicle Clustering and Docking at a Vertebrate Synapse." Frontiers in Cell and Developmental Biology 9 (November 26, 2021). http://dx.doi.org/10.3389/fcell.2021.774650.
Full textAbstract:
Neurotransmission relies critically on the exocytotic release of neurotransmitters from small synaptic vesicles (SVs) at the active zone. Therefore, it is essential for neurons to maintain an adequate pool of SVs clustered at synapses in order to sustain efficient neurotransmission. It is well established that the phosphoprotein synapsin 1 regulates SV clustering at synapses. Here, we demonstrate that synuclein, another SV-associated protein and synapsin binding partner, also modulates SV clustering at a vertebrate synapse. When acutely introduced to unstimulated lamprey reticulospinal synapses, a pan-synuclein antibody raised against the N-terminal domain of α-synuclein induced a significant loss of SVs at the synapse. Both docked SVs and the distal reserve pool of SVs were depleted, resulting in a loss of total membrane at synapses. In contrast, antibodies against two other abundant SV-associated proteins, synaptic vesicle glycoprotein 2 (SV2) and vesicle-associated membrane protein (VAMP/synaptobrevin), had no effect on the size or distribution of SV clusters. Synuclein perturbation caused a dose-dependent reduction in the number of SVs at synapses. Interestingly, the large SV clusters appeared to disperse into smaller SV clusters, as well as individual SVs. Thus, synuclein regulates clustering of SVs at resting synapses, as well as docking of SVs at the active zone. These findings reveal new roles for synuclein at the synapse and provide critical insights into diseases associated with α-synuclein dysfunction, such as Parkinson’s disease.
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Kitaoka, Otoya, Kohei Oyabu, Kaori Kubota, Takuya Watanabe, Satoru Kondo, Teppei Matsui, Shutaro Katsurabayashi, and Katsunori Iwasaki. "Location analysis of presynaptically active and silent synapses in single-cultured hippocampal neurons." Frontiers in Neural Circuits 18 (April 23, 2024). http://dx.doi.org/10.3389/fncir.2024.1358570.
Full textAbstract:
A morphologically present but non-functioning synapse is termed a silent synapse. Silent synapses are categorized into “postsynaptically silent synapses,” where AMPA receptors are either absent or non-functional, and “presynaptically silent synapses,” where neurotransmitters cannot be released from nerve terminals. The presence of presynaptically silent synapses remains enigmatic, and their physiological significance is highly intriguing. In this study, we examined the distribution and developmental changes of presynaptically active and silent synapses in individual neurons. Our findings show a gradual increase in the number of excitatory synapses, along with a corresponding decrease in the percentage of presynaptically silent synapses during neuronal development. To pinpoint the distribution of presynaptically active and silent synapses, i.e., their positional information, we employed Sholl analysis. Our results indicate that the distribution of presynaptically silent synapses within a single neuron does not exhibit a distinct pattern during synapse development in different distance from the cell body. However, irrespective of neuronal development, the proportion of presynaptically silent synapses tends to rise as the projection site moves farther from the cell body, suggesting that synapses near the cell body may exhibit higher synaptic transmission efficiency. This study represents the first observation of changes in the distribution of presynaptically active and silent synapses within a single neuron.
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Hedrick, Nathan G., William J. Wright, and Takaki Komiyama. "Local and global predictors of synapse elimination during motor learning." Science Advances 10, no. 11 (March 15, 2024). http://dx.doi.org/10.1126/sciadv.adk0540.
Full textAbstract:
During learning, synaptic connections between excitatory neurons in the brain display considerable dynamism, with new connections being added and old connections eliminated. Synapse elimination offers an opportunity to understand the features of synapses that the brain deems dispensable. However, with limited observations of synaptic activity and plasticity in vivo, the features of synapses subjected to elimination remain poorly understood. Here, we examined the functional basis of synapse elimination in the apical dendrites of L2/3 neurons in the primary motor cortex throughout motor learning. We found no evidence that synapse elimination is facilitated by a lack of activity or other local forms of plasticity. Instead, eliminated synapses display asynchronous activity with nearby synapses, suggesting that functional synaptic clustering is a critical component of synapse survival. In addition, eliminated synapses show delayed activity timing with respect to postsynaptic output. Thus, synaptic inputs that fail to be co-active with their neighboring synapses or are mistimed with neuronal output are targeted for elimination.
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Jukic, Alma, Zhengchang Lei, Elizabeth R. Cebul, Katherine Pinter, Yommi Tadesse, Amandine Jarysta, Sandeep David, Natalie Mosqueda, Basile Tarchini, and Katie Kindt. "Presynaptic Nrxn3 is essential for ribbon-synapse maturation in hair cells." Development, September 10, 2024. http://dx.doi.org/10.1242/dev.202723.
Full textAbstract:
Hair cells of the inner ear and lateral-line system rely on specialized ribbon synapses to transmit sensory information to the central nervous system. The molecules required to assemble these synapses are not fully understood. We show that Nrxn3, a presynaptic adhesion molecule, is critical for ribbon-synapse maturation in hair cells. In both mouse and zebrafish models, the loss of Nrxn3 results in significantly fewer intact ribbon synapses. We show in zebrafish that initially, nrxn3 mutants have normal pre- and post-synapse numbers, but synapses fail to pair, leading to postsynapse loss. We also demonstrate that Nrxn3 subtly influences synapse selectivity in zebrafish lateral-line hair cells that detect anterior flow. A 60% loss of synapses in zebrafish nrxn3 mutants dramatically reduces pre- and post-synaptic responses. Despite fewer synapses, auditory responses in zebrafish and mice are unaffected. This work demonstrates that Nrxn3 is a critical and conserved molecule required for the maturation of ribbon synapses. Understanding how ribbon synapses mature is essential to generating novel therapies to treat synaptopathies linked to auditory or vestibular dysfunction.