During an action potential, Ca2+ entering a presynaptic terminal triggers synaptic vesicle exocytosis and neurotransmitter release in less than a millisecond. How does Ca2+ stimulate release so ...rapidly and precisely? Work over the last decades revealed that Ca2+ binding to synaptotagmin triggers release by stimulating synaptotagmin binding to a core fusion machinery composed of SNARE and SM proteins that mediates membrane fusion during exocytosis. Complexin adaptor proteins assist synaptotagmin by activating and clamping this core fusion machinery. Synaptic vesicles containing synaptotagmin are positioned at the active zone, the site of vesicle fusion, by a protein complex containing RIM proteins. RIM proteins activate docking and priming of synaptic vesicles and simultaneously recruit Ca2+ channels to active zones, thereby connecting in a single complex primed synaptic vesicles to Ca2+ channels. This architecture allows direct flow of Ca2+ ions from Ca2+ channels to synaptotagmin, which then triggers fusion, thus mediating tight millisecond coupling of an action potential to neurotransmitter release.
Tom Südhof reviews the molecular and biochemical mechanisms that lead from the action potential-triggered calcium signal at the presynaptic terminal to synaptic vesicle fusion and neurotransmitter release and discusses how our current picture of how the synapse works continues to be refined with new methodologies and tools.
Neurotransmitters are released by synaptic vesicle exocytosis at the active zone of a presynaptic nerve terminal. In this review, I discuss the molecular composition and function of the active zone. ...Active zones are composed of an evolutionarily conserved protein complex containing as core constituents RIM, Munc13, RIM-BP, α-liprin, and ELKS proteins. This complex docks and primes synaptic vesicles for exocytosis, recruits Ca2+ channels to the site of exocytosis, and positions the active zone exactly opposite to postsynaptic specializations via transsynaptic cell-adhesion molecules. Moreover, this complex mediates short- and long-term plasticity in response to bursts of action potentials, thus critically contributing to the computational power of a synapse.
Neurotransmitters are released by synaptic vesicle exocytosis at the active zone of a presynaptic nerve terminal. In this review, Südhof discusses the molecular composition of the active zone and the roles that it plays on synaptic function and plasticity.
Unified Theory of Concrete Structuresdevelops an integrated theory that encompasses the various stress states experienced by both RC PC structures under the various loading conditions of bending, ...axial load, shear and torsion. Upon synthesis, the new rational theories replace the many empirical formulas currently in use for shear, torsion and membrane stress.The unified theory is divided into six model components: a) the struts-and-ties model, b) the equilibrium (plasticity) truss model, c) the Bernoulli compatibility truss model, d) the Mohr compatibility truss model, e) the softened truss model, and f) the softened membrane model. Hsu presents the six models as rational tools for the solution of the four basic types of stress, focusing on the significance of their intrinsic consistencies and their inter-relationships. Because of its inherent rationality, this unified theory of reinforced concrete can serve as the basis for the formulation of a universal and international design code.Includes an appendix and accompanying website hosting the authors’ finite element program SCS along with instructions and examples Offers comprehensive coverage of content ranging from fundamentals of flexure, shear and torsion all the way to non-linear finite element analysis and design of wall-type structures under earthquake loading. Authored by world-leading experts on torsion and shear
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.
Südhof’s review proposes that multifarious trans-synaptic cell-adhesion molecules organize synapses by signaling bidirectionally to orchestrate synapse formation, thereby enabling synapses to function as the fundamental computational elements of the brain and to mediate information processing by neural circuits.
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.
Throughout life, millions of neural circuits containing trillions of synapses are assembled and restructured to efficiently compute and transmit information. Underlying such complexity is a molecular code governed by a mosaic of synaptic proteins. In this Review, the properties and functions of neurexins and their ligands serve as a paradigm for how the molecular logic of neural circuits is constructed.
In a neural circuit, synapses transfer information rapidly between neurons and transform this information during transfer. The diverse computational properties of synapses are shaped by the ...interactions between pre- and postsynaptic neurons. How synapses are assembled to form a neural circuit, and how the specificity of synaptic connections is achieved, is largely unknown. Here, I posit that synaptic adhesion molecules (SAMs) organize synapse formation. Diverse SAMs collaborate to achieve the astounding specificity and plasticity of synapses, with each SAM contributing different facets. In orchestrating synapse assembly, SAMs likely act as signal transduction devices. Although many candidate SAMs are known, only a few SAMs appear to have a major impact on synapse formation. Thus, a limited set of collaborating SAMs likely suffices to account for synapse formation. Strikingly, several SAMs are genetically linked to neuropsychiatric disorders, suggesting that impairments in synapse assembly are instrumental in the pathogenesis of neuropsychiatric disorders.
The brain processes information by transmitting signals at synapses, which connect neurons into vast networks of communicating cells. In these networks, synapses not only transmit signals but also ...transform and refine them. Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions. In humans, alterations in genes encoding neurexins or neuroligins have recently been implicated in autism and other cognitive diseases, linking synaptic cell adhesion to cognition and its disorders.
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