Synaptic proteins as multi-sensor devices of neurotransmission

Neuronal communication is tightly regulated in time and space. Following neuronal activation, an electrical signal triggers neurotransmitter (NT) release at the active zone. The process starts by the signal reaching the synapse followed by a fusion of the synaptic vesicle (SV) and diffusion of the released NT in the synaptic cleft. The NT then binds to the appropriate receptor and induces a membrane potential change at the target cell membrane. The entire process is controlled by a fairly small set of synaptic proteins, collectively called SYCONs. The biochemical features of SYCONs underlie the properties of NT release. SYCONs are characterized by their ability to detect and respond to changes in environmental signals. For example, consider synaptotagmin I (Syt1), a prototype of a protein family with over 20 gene and variants in mammals. Syt1 is a specific example of a multi-sensor device with a large repertoire of discrete states. Several of these states are stimulated by a local concentration of signaling molecules such as Ca2+. The ability of this protein to sense signaling molecules and to adopt multiple biochemical states is shared by other SYCONs such as the synapsins (Syns). Specific biochemical states of Syns determine the accessibility of SV for NT release. Each of these states is defined by a specific alternative spliced variant with a unique profile of phosphorylation modified sites. The plasticity of the synapse is a direct reflection of SYCON's multiple biochemical states. State transitions occurs in a wide range of time scales, and therefore these molecules need to cope with events that last milliseconds (i.e., exocytosis in fast responding synapses) and with events that can carry on for many minutes (i.e., organization of SV pools). We suggest that SYCONs are optimized throughout evolution as multi-sensor devices. A full repertoire of the switches leading to alternation of protein states and a detailed characterization of protein-protein network within the synapse is critical for the development of a dynamic model of synaptic transmission

A Population Genetic Approach to Mapping Neurological Disorder Genes Using Deep Resequencing

Deep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders. Here, we present the results from a large-sample resequencing (n = 285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and Schizophrenia. Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts. In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone. Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls. This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies. Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders

Synaptic proteins as multi-sensor devices of neurotransmission

Abstract Neuronal communication is tightly regulated in time and space. Following neuronal activation, an electrical signal triggers neurotransmitter (NT) release at the active zone. The process starts by the signal reaching the synapse followed by a fusion of the synaptic vesicle (SV) and diffusion of the released NT in the synaptic cleft. The NT then binds to the appropriate receptor and induces a membrane potential change at the target cell membrane. The entire process is controlled by a fairly small set of synaptic proteins, collectively called SYCONs. The biochemical features of SYCONs underlie the properties of NT release. SYCONs are characterized by their ability to detect and respond to changes in environmental signals. For example, consider synaptotagmin I (Syt1), a prototype of a protein family with over 20 gene and variants in mammals. Syt1 is a specific example of a multi-sensor device with a large repertoire of discrete states. Several of these states are stimulated by a local concentration of signaling molecules such as Ca2+. The ability of this protein to sense signaling molecules and to adopt multiple biochemical states is shared by other SYCONs such as the synapsins (Syns). Specific biochemical states of Syns determine the accessibility of SV for NT release. Each of these states is defined by a specific alternative spliced variant with a unique profile of phosphorylation modified sites. The plasticity of the synapse is a direct reflection of SYCON's multiple biochemical states. State transitions occurs in a wide range of time scales, and therefore these molecules need to cope with events that last milliseconds (i.e., exocytosis in fast responding synapses) and with events that can carry on for many minutes (i.e., organization of SV pools). We suggest that SYCONs are optimized throughout evolution as multi-sensor devices. A full repertoire of the switches leading to alternation of protein states and a detailed characterization of protein-protein network within the synapse is critical for the development of a dynamic model of synaptic transmission.</p