The Experts below are selected from a list of 70725 Experts worldwide ranked by ideXlab platform
Thomas C Sudhof - One of the best experts on this subject based on the ideXlab platform.
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latrophilin gpcrs direct Synapse specificity by coincident binding of flrts and teneurins
Science, 2019Co-Authors: Richard Sando, Xian Jiang, Thomas C SudhofAbstract:Bidirectional signaling by cell adhesion molecules is thought to mediate Synapse formation, but the mechanisms involved remain elusive. We found that the adhesion G protein-coupled receptors latrophilin-2 and latrophilin-3 selectively direct formation of perforant-path and Schaffer-collateral Synapses, respectively, to hippocampal CA1-region neurons. Latrophilin-3 binds to two transcellular ligands: fibronectin leucine-rich repeat transmembrane proteins (FLRTs) and teneurins. In transgenic mice in vivo, both binding activities were required for input-specific Synapse formation, which suggests that coincident binding of both ligands is necessary for Synapse formation. In cultured neurons in vitro, teneurin or FLRT alone did not induce excitatory Synapse formation, whereas together they potently did so. Thus, postsynaptic latrophilins promote excitatory Synapse formation by simultaneous binding of two unrelated presynaptic ligands, which is required for formation of synaptic inputs at specific dendritic localizations.
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towards an understanding of Synapse formation
Neuron, 2018Co-Authors: Thomas C SudhofAbstract:Synapses are intercellular junctions specialized for fast, point-to-point information transfer from a presynaptic neuron to a postsynaptic cell. At a Synapse, a presynaptic terminal secretes neurotransmitters via a canonical release machinery, while a postsynaptic specialization senses neurotransmitters via diverse receptors. Synaptic junctions are likely organized by trans-synaptic cell-adhesion molecules (CAMs) that bidirectionally orchestrate Synapse formation, restructuring, and elimination. Many candidate synaptic CAMs were described, but which CAMs are central actors and which are bystanders remains unclear. Moreover, multiple genes encoding synaptic CAMs were linked to neuropsychiatric disorders, but the mechanisms involved are unresolved. Here, I propose that engagement of multifarious synaptic CAMs produces parallel trans-synaptic signals that mediate the establishment, organization, and plasticity of Synapses, thereby controlling information processing by neural circuits. Among others, this hypothesis implies that Synapse formation can be understood in terms of inter- and intracellular signaling, and that neuropsychiatric disorders involve an impairment in such signaling.
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synaptic neurexin complexes a molecular code for the logic of neural circuits
Cell, 2017Co-Authors: Thomas C SudhofAbstract:Summary Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here, we posit that the establishment, properties, and dynamics of Synapses are governed by a molecular logic that is controlled by diverse trans -synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate Synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, especially schizophrenia, autism, and Tourette syndrome. Thus, neurexins nucleate an overall trans -synaptic signaling network that controls Synapse properties, which thereby determines the precise responses of Synapses to spike patterns in a neuron and circuit and which is vulnerable to impairments in neuropsychiatric disorders.
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neuroligin 1 performs neurexin dependent and neurexin independent functions in Synapse validation
The EMBO Journal, 2009Co-Authors: Jaewon Ko, Antony A Boucard, Demet Arac, Axel T Brunger, Chen Zhang, Thomas C SudhofAbstract:Postsynaptic neuroligins are thought to perform essential functions in Synapse validation and synaptic transmission by binding to, and dimerizing, presynaptic α- and β-neurexins. To test this hypothesis, we examined the functional effects of neuroligin-1 mutations that impair only α-neurexin binding, block both α- and β-neurexin binding, or abolish neuroligin-1 dimerization. Abolishing α-neurexin binding abrogated neuroligin-induced generation of neuronal Synapses onto transfected non-neuronal cells in the so-called artificial Synapse-formation assay, even though β-neurexin binding was retained. Thus, in this assay, neuroligin-1 induces apparent Synapse formation by binding to presynaptic α-neurexins. In transfected neurons, however, neither α- nor β-neurexin binding was essential for the ability of postsynaptic neuroligin-1 to dramatically increase Synapse density, suggesting a neurexin-independent mechanism of Synapse formation. Moreover, neuroligin-1 dimerization was not required for either the non-neuronal or the neuronal Synapse-formation assay. Nevertheless, both α-neurexin binding and neuroligin-1 dimerization were essential for the increase in apparent Synapse size that is induced by neuroligin-1 in transfected neurons. Thus, neuroligin-1 performs diverse synaptic functions by mechanisms that include as essential components of α-neurexin binding and neuroligin dimerization, but extend beyond these activities.
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activity dependent validation of excitatory versus inhibitory Synapses by neuroligin 1 versus neuroligin 2
Neuron, 2007Co-Authors: Alexander A Chubykin, Nils Brose, Mark R. Etherton, Deniz Atasoy, Jay R Gibson, Ege T. Kavalali, Thomas C SudhofAbstract:Summary Neuroligins enhance Synapse formation in vitro, but surprisingly are not required for the generation of Synapses in vivo. We now show that in cultured neurons, neuroligin-1 overexpression increases excitatory, but not inhibitory, synaptic responses, and potentiates synaptic NMDAR/AMPAR ratios. In contrast, neuroligin-2 overexpression increases inhibitory, but not excitatory, synaptic responses. Accordingly, deletion of neuroligin-1 in knockout mice selectively decreases the NMDAR/AMPAR ratio, whereas deletion of neuroligin-2 selectively decreases inhibitory synaptic responses. Strikingly, chronic inhibition of NMDARs or CaM-Kinase II, which signals downstream of NMDARs, suppresses the Synapse-boosting activity of neuroligin-1, whereas chronic inhibition of general synaptic activity suppresses the Synapse-boosting activity of neuroligin-2. Taken together, these data indicate that neuroligins do not establish, but specify and validate, Synapses via an activity-dependent mechanism, with different neuroligins acting on distinct types of Synapses. This hypothesis reconciles the overexpression and knockout phenotypes and suggests that neuroligins contribute to the use-dependent formation of neural circuits.
Bernardo L Sabatini - One of the best experts on this subject based on the ideXlab platform.
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natural oligomers of the alzheimer amyloid β protein induce reversible Synapse loss by modulating an nmda type glutamate receptor dependent signaling pathway
The Journal of Neuroscience, 2007Co-Authors: Ganesh M Shankar, Brenda L Bloodgood, Matthew Townsend, Dominic M Walsh, Dennis J Selkoe, Bernardo L SabatiniAbstract:Alzheimer9s disease (AD) is characterized by decreased Synapse density in hippocampus and neocortex, and Synapse loss is the strongest anatomical correlate of the degree of clinical impairment. Although considerable evidence supports a causal role for the amyloid-β protein (Aβ) in AD, a direct link between a specific form of Aβ and Synapse loss has not been established. We demonstrate that physiological concentrations of naturally secreted Aβ dimers and trimers, but not monomers, induce progressive loss of hippocampal Synapses. Pyramidal neurons in rat organotypic slices had markedly decreased density of dendritic spines and numbers of electrophysiologically active Synapses after exposure to picomolar levels of soluble oligomers. Spine loss was reversible and was prevented by Aβ-specific antibodies or a small-molecule modulator of Aβ aggregation. Mechanistically, Aβ-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDAR-mediated calcium influx into active spines was reduced by Aβ oligomers. Partial blockade of NMDARs by pharmacological antagonists was sufficient to trigger spine loss. We conclude that soluble, low- n oligomers of human Aβ trigger Synapse loss that can be reversed by therapeutic agents. Our approach provides a quantitative cellular model for elucidating the molecular basis of Aβ-induced neuronal dysfunction.
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natural oligomers of the alzheimer amyloid β protein induce reversible Synapse loss by modulating an nmda type glutamate receptor dependent signaling pathway
The Journal of Neuroscience, 2007Co-Authors: Ganesh M Shankar, Brenda L Bloodgood, Matthew Townsend, Dominic M Walsh, Dennis J Selkoe, Bernardo L SabatiniAbstract:Alzheimer's disease (AD) is characterized by decreased Synapse density in hippocampus and neocortex, and Synapse loss is the strongest anatomical correlate of the degree of clinical impairment. Although considerable evidence supports a causal role for the amyloid-beta protein (Abeta) in AD, a direct link between a specific form of Abeta and Synapse loss has not been established. We demonstrate that physiological concentrations of naturally secreted Abeta dimers and trimers, but not monomers, induce progressive loss of hippocampal Synapses. Pyramidal neurons in rat organotypic slices had markedly decreased density of dendritic spines and numbers of electrophysiologically active Synapses after exposure to picomolar levels of soluble oligomers. Spine loss was reversible and was prevented by Abeta-specific antibodies or a small-molecule modulator of Abeta aggregation. Mechanistically, Abeta-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDAR-mediated calcium influx into active spines was reduced by Abeta oligomers. Partial blockade of NMDARs by pharmacological antagonists was sufficient to trigger spine loss. We conclude that soluble, low-n oligomers of human Abeta trigger Synapse loss that can be reversed by therapeutic agents. Our approach provides a quantitative cellular model for elucidating the molecular basis of Abeta-induced neuronal dysfunction.
Wade G. Regehr - One of the best experts on this subject based on the ideXlab platform.
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the influence of multivesicular release and postsynaptic receptor saturation on transmission at granule cell to purkinje cell Synapses
The Journal of Neuroscience, 2005Co-Authors: Kelly A Foster, John J Crowley, Wade G. RegehrAbstract:The properties of a Synapse are crucially dependent on whether an action potential can trigger the release of multiple vesicles at an individual release site [multivesicular release (MVR)] and whether fusion of a single vesicle leads to receptor saturation. MVR and receptor saturation both occur at some high p Synapses, but it is not known whether they also occur at low p Synapses. Here we examine this issue at the low p Synapse between parallel fibers and Purkinje cells using the low-affinity antagonist DGG (γ-d-glutamylglycine) to relieve AMPA receptor saturation. We find that the presence of MVR and receptor saturation at this Synapse alters the calcium dependence of synaptic transmission and reduces the extent of facilitation. These findings establish that MVR and postsynaptic receptor saturation can influence transmission even at Synapses with a low initial probability of release and suggest that these properties may be common at Synapses in the mammalian brain.
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associative short term synaptic plasticity mediated by endocannabinoids
Neuron, 2005Co-Authors: Stephan D Brenowitz, Wade G. RegehrAbstract:Summary Associative learning is important on rapid timescales, but no suitable form of short-term plasticity has been identified that is both associative and Synapse specific. Here, we assess whether endocannabinoids can mediate such plasticity. In the cerebellum, bursts of parallel fiber (PF) activity evoke endocannabinoid release from Purkinje cell dendrites that results in retrograde synaptic inhibition lasting seconds. We find that the powerful climbing fiber (CF) to Purkinje cell Synapse regulates this inhibition. Compared to PF stimulation alone, coactivation of PF and CF Synapses greatly enhanced endocannabinoid-mediated inhibition of PF Synapses. Retrograde inhibition was restricted to PFs activated within several hundred milliseconds of CF activation. This associative plasticity reflects two aspects of calcium-dependent endocannabinoid release. First, PF-mediated activation of metabotropic glutamate receptors locally reduced the dendritic calcium levels required for endocannabinoid release. Second, CF and PF coactivation evoked localized supralinear dendritic calcium signals. Thus, endocannabinoids mediate transient associative synaptic plasticity.
Thomas Biederer - One of the best experts on this subject based on the ideXlab platform.
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structural organization and function of mouse photoreceptor ribbon Synapses involve the immunoglobulin protein synaptic cell adhesion molecule 1
The Journal of Comparative Neurology, 2014Co-Authors: Adema Ribic, Michael C Crair, Thomas BiedererAbstract:Adhesive interactions in the retina instruct the developmental specification of inner retinal layers. However, potential roles of adhesion in the development and function of photoreceptor Synapses remain incompletely understood. This contrasts with our understanding of Synapse development in the CNS, which can be guided by select adhesion molecules such as the Synaptic Cell Adhesion Molecule 1 (SynCAM 1/CADM1/nectin-like 2 protein). This immunoglobulin superfamily protein modulates the development and plasticity of classical excitatory Synapses. We show here by immunoelectron microscopy and immunoblotting that SynCAM 1 is expressed on mouse rod photoreceptors and their terminals in the outer nuclear and plexiform layers in a developmentally regulated manner. Expression of SynCAM 1 on rods is low in early postnatal stages (P3–P7) but increases after eye opening (P14). In support of functional roles in the photoreceptors, electroretinogram recordings demonstrate impaired responses to light stimulation in SynCAM 1 knockout (KO) mice. In addition, the structural integrity of Synapses in the OPL requires SynCAM 1. Quantitative ultrastructural analysis of SynCAM 1 KO retina measured fewer fully assembled, triadic rod ribbon Synapses. Furthermore, rod Synapse ribbons are shortened in KO mice, and protein levels of Ribeye, a major structural component of ribbons, are reduced in SynCAM 1 KO retina. Together, our results implicate SynCAM 1 in the synaptic organization of the rod visual pathway and provide evidence for novel roles of synaptic adhesion in the structural and functional integrity of ribbon Synapses. J. Comp. Neurol. 522:900–920, 2014. © 2013 Wiley Periodicals, Inc.
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selective capability of syncam and neuroligin for functional Synapse assembly
The Journal of Neuroscience, 2005Co-Authors: Yildirim Sara, Alexander A Chubykin, Deniz Atasoy, Thomas C Sudhof, Thomas Biederer, Marina Mozhayeva, Ege T. KavalaliAbstract:Synaptic cell adhesion is central for Synapse formation and function. Recently, the synaptic cell adhesion molecules neuroligin 1 (NL1) and SynCAM were shown to induce presynaptic differentiation in cocultured neurons when expressed in a non-neuronal cell. However, it is uncertain how similar the resulting artificial Synapses are to regular Synapses. Are these molecules isofunctional, or do all neuronal cell adhesion molecules nonspecifically activate Synapse formation? To address these questions, we analyzed the properties of artificial Synapses induced by NL1 and SynCAM, compared the actions of these molecules with those of other neuronal cell adhesion molecules, and examined the functional effects of NL1 and SynCAM overexpression in neurons. We found that only NL1 and SynCAM specifically induced presynaptic differentiation in cocultured neurons. The induced nerve terminals were capable of both spontaneous and evoked neurotransmitter release, suggesting that a full secretory apparatus was assembled. By all measures, SynCAM- and NL1-induced artificial Synapses were identical. Overexpression in neurons demonstrated that only SynCAM, but not NL1, increased synaptic function in immature developing excitatory neurons after 8 d in vitro. Tests of chimeric molecules revealed that the dominant-positive effect of SynCAM on synaptic function in developing neurons was mediated by its intracellular cytoplasmic tail. Interestingly, morphological analysis of neurons overexpressing SynCAM or NL1 showed the opposite of the predictions from electrophysiological results. In this case, only NL1 increased the Synapse number, suggesting a role for NL1 in morphological Synapse induction. These results suggest that both NL1 and SynCAM act similarly and specifically in artificial Synapse induction but that this process does not reflect a shared physiological function of these molecules.
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syncam a synaptic adhesion molecule that drives Synapse assembly
Science, 2002Co-Authors: Thomas Biederer, Deniz Atasoy, Ege T. Kavalali, Yildirim Sara, Marina Mozhayeva, Xinran Liu, Thomas C SudhofAbstract:Synapses, the junctions between nerve cells through which they communicate, are formed by the coordinated assembly and tight attachment of pre- and postsynaptic specializations. We now show that SynCAM is a brain-specific, immunoglobulin domain-containing protein that binds to intracellular PDZ-domain proteins and functions as a homophilic cell adhesion molecule at the Synapse. Expression of the isolated cytoplasmic tail of SynCAM in neurons inhibited Synapse assembly. Conversely, expression of full-length SynCAM in nonneuronal cells induced Synapse formation by cocultured hippocampal neurons with normal release properties. Glutamatergic synaptic transmission was reconstituted in these nonneuronal cells by coexpressing glutamate receptors with SynCAM, which suggests that a single type of adhesion molecule and glutamate receptor are sufficient for a functional postsynaptic response.
Brenda L Bloodgood - One of the best experts on this subject based on the ideXlab platform.
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activity dependent regulation of inhibitory Synapse development by npas4
Nature, 2008Co-Authors: Yingxi Lin, Taekyung Kim, Brenda L Bloodgood, Jessica L Hauser, Ariya D Lapan, Alex Chun Koon, Athar N Malik, Michael E GreenbergAbstract:Neuronal activity regulates the development and maturation of excitatory and inhibitory Synapses in the mammalian brain. Several recent studies have identified signalling networks within neurons that control excitatory Synapse development. However, less is known about the molecular mechanisms that regulate the activity-dependent development of GABA (γ-aminobutyric acid)-releasing inhibitory Synapses. Here we report the identification of a transcription factor, Npas4, that plays a role in the development of inhibitory Synapses by regulating the expression of activity-dependent genes, which in turn control the number of GABA-releasing Synapses that form on excitatory neurons. These findings demonstrate that the activity-dependent gene program regulates inhibitory Synapse development, and suggest a new role for this program in controlling the homeostatic balance between synaptic excitation and inhibition.
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natural oligomers of the alzheimer amyloid β protein induce reversible Synapse loss by modulating an nmda type glutamate receptor dependent signaling pathway
The Journal of Neuroscience, 2007Co-Authors: Ganesh M Shankar, Brenda L Bloodgood, Matthew Townsend, Dominic M Walsh, Dennis J Selkoe, Bernardo L SabatiniAbstract:Alzheimer9s disease (AD) is characterized by decreased Synapse density in hippocampus and neocortex, and Synapse loss is the strongest anatomical correlate of the degree of clinical impairment. Although considerable evidence supports a causal role for the amyloid-β protein (Aβ) in AD, a direct link between a specific form of Aβ and Synapse loss has not been established. We demonstrate that physiological concentrations of naturally secreted Aβ dimers and trimers, but not monomers, induce progressive loss of hippocampal Synapses. Pyramidal neurons in rat organotypic slices had markedly decreased density of dendritic spines and numbers of electrophysiologically active Synapses after exposure to picomolar levels of soluble oligomers. Spine loss was reversible and was prevented by Aβ-specific antibodies or a small-molecule modulator of Aβ aggregation. Mechanistically, Aβ-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDAR-mediated calcium influx into active spines was reduced by Aβ oligomers. Partial blockade of NMDARs by pharmacological antagonists was sufficient to trigger spine loss. We conclude that soluble, low- n oligomers of human Aβ trigger Synapse loss that can be reversed by therapeutic agents. Our approach provides a quantitative cellular model for elucidating the molecular basis of Aβ-induced neuronal dysfunction.
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natural oligomers of the alzheimer amyloid β protein induce reversible Synapse loss by modulating an nmda type glutamate receptor dependent signaling pathway
The Journal of Neuroscience, 2007Co-Authors: Ganesh M Shankar, Brenda L Bloodgood, Matthew Townsend, Dominic M Walsh, Dennis J Selkoe, Bernardo L SabatiniAbstract:Alzheimer's disease (AD) is characterized by decreased Synapse density in hippocampus and neocortex, and Synapse loss is the strongest anatomical correlate of the degree of clinical impairment. Although considerable evidence supports a causal role for the amyloid-beta protein (Abeta) in AD, a direct link between a specific form of Abeta and Synapse loss has not been established. We demonstrate that physiological concentrations of naturally secreted Abeta dimers and trimers, but not monomers, induce progressive loss of hippocampal Synapses. Pyramidal neurons in rat organotypic slices had markedly decreased density of dendritic spines and numbers of electrophysiologically active Synapses after exposure to picomolar levels of soluble oligomers. Spine loss was reversible and was prevented by Abeta-specific antibodies or a small-molecule modulator of Abeta aggregation. Mechanistically, Abeta-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDAR-mediated calcium influx into active spines was reduced by Abeta oligomers. Partial blockade of NMDARs by pharmacological antagonists was sufficient to trigger spine loss. We conclude that soluble, low-n oligomers of human Abeta trigger Synapse loss that can be reversed by therapeutic agents. Our approach provides a quantitative cellular model for elucidating the molecular basis of Abeta-induced neuronal dysfunction.
