Neuroscience
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Review
The Control of Neuronal Calcium Homeostasis by SNAP-25 and its Impact on Neurotransmitter Release.
The process of neurotransmitter release is central to the control of cell-to-cell communication in brain. SNAP-25 is a component of the SNARE complex, which, together with syntaxin-1 and synaptobrevin, mediates synaptic vesicle fusion with the plasma membrane. ⋯ Consistently, reduced levels of the protein affect presynaptic calcium homeostasis and result in pathologically enhanced glutamate exocytosis. The SNAP-25-dependent alterations of synaptic calcium dynamics may have direct impact on the development of neuropsychiatric disorders where the Snap-25 gene has been found to be involved.
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Trafficking or delivery of neurotransmitter receptors on postsynaptic membranes is critical for basal neurotransmission and synaptic plasticity. Importantly, dysfunction of such postsynaptic receptor trafficking can lead to severe brain diseases such as Alzheimer's Disease, autism spectrum disorder, and intellectual disability, yet underlying mechanisms remain elusive. One attractive hypothesis is that postsynaptic SNARE proteins play key roles in the delivery of receptors by mediating membrane fusion at postsynaptic neurons. ⋯ In this review, we propose to employ a pyramidal-neuron specific conditional knockout (cKO) model to study the roles of candidate SNARE proteins in postsynaptic receptor trafficking. We highlight our recent results which we obtained from such approaches to syntaxin-4 protein. These results provide clear evidence on the critical role of syntaxin-4 in trafficking of ionotropic glutamate receptors which are essential for basal neurotransmission, synaptic plasticity and spatial memory.
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Neurons have the remarkable ability to release a batch of neurotransmitters into the synapse immediately after an action potential. This signature event is made possible by the simultaneous fusion of a number of synaptic vesicles to the plasma membrane upon Ca2+ entry into the active zone. ⋯ Syt1 is the major Ca2+-sensor and orchestrates the synchronous start of individual vesicle fusion events while SNAREs are the membrane fusion machinery that dictates the kinetics of each single fusion event. The data also suggest that Ca2+-bound Syt1 is involved in the upstream docking step which leads to an increase in the number of fusion events or the size of the release, leaving the SNARE complex alone to carry out membrane fusion by themselves.
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Recent studies associated schizophrenia with enhanced functionality of the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Altered degradation pathways of the three core SNARE proteins: synaptosomal-associated protein 25 (SNAP25), syntaxin-1 and vesicle-associated membrane protein (VAMP) could contribute to enhanced complex function. To investigate these pathways, we first identified a 15-kDa SNAP25 fragment (f-S25) in human and rat brains, highly enriched in synaptosomal extractions, and mainly attached to cytosolic membranes with low hydrophobicity. ⋯ Statistical mediation analyses supported the hypothesis that reduced f-S25 density could upregulate SNARE fusion events in schizophrenia. Cortical calpain activity in schizophrenia did not differ from controls. f-S25 levels did not correlate with total calpain activity, indicating that if present, schizophrenia-related calpain dysfunction might occur locally at the presynaptic terminals. Overall, the present findings suggest the existence of an endogenous SNARE complex inhibitor related to SNAP25 proteolysis, associated with enhanced SNARE activity in schizophrenia.