Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synapsins regulate synaptic transmission by controlling the reserve pool of synaptic vesicles. Each of the three mammalian synapsin genes is subject to alternative splicing, yielding several isoforms whose roles are unknown. To investigate the function of these isoforms, we examined the synaptic effects of introducing each isoform into glutamatergic cultured hippocampal neurons from synapsin triple knock-out mice. Remarkably, we found that synapsin IIa was the only isoform that could rescue the synaptic depression phenotype of the triple knock-out mice; other isoforms examined, including the well-studied synapsin Ia isoform, had no significant effect on the kinetics of synaptic depression. The slowing of synaptic depression by synapsin IIa was quantitatively paralleled by an increase in the density of reserve pool synaptic vesicles, as measured either by fluorescent tagging of the vesicle protein synaptobrevin-2 or by staining with the styryl dye FM4-64 [N-(3-triethylammoniumpropyl)-4-(6-(4-diethylamino)phenyl)-hexatrienyl)pyridinium dibromide]. Our results provide further support for the hypothesis that synapsins define the kinetics of synaptic depression at glutamatergic synapses by controlling the size of the vesicular reserve pool and identify synapsin IIa as the isoform primarily responsible for this task.
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PMID:Synapsin IIa controls the reserve pool of glutamatergic synaptic vesicles. 1894 91

Presynaptic terminals are specialized sites for information transmission where vesicles fuse with the plasma membrane and are locally recycled. Recent work has extended this classical view, with the observation that a subset of functional vesicles is dynamically shared between adjacent terminals by lateral axonal transport. Conceptually, such transport would be expected to disrupt vesicle retention around the active zone, yet terminals are characterized by a high-density vesicle cluster, suggesting that counteracting stabilizing mechanisms must operate against this tendency. The synapsins are a family of proteins that associate with synaptic vesicles and determine vesicle numbers at the terminal, but their specific function remains controversial. Here, using multiple quantitative fluorescence-based approaches and electron microscopy, we show that synapsin is instrumental for resisting vesicle dispersion and serves as a regulatory element for controlling lateral vesicle sharing between synapses. Deleting synapsin disrupts the organization of presynaptic vesicle clusters, making their boundaries hard to define. Concurrently, the fraction of vesicles amenable to transport is increased, and more vesicles are translocated to the axon. Importantly, in neurons from synapsin knock-out mice the resting and recycling pools are equally mobile. Synapsin, when present, specifically restricts the mobility of resting pool vesicles without affecting the division of vesicles between these pools. Specific expression of synapsin IIa, the sole isoform affecting synaptic depression, rescues the knock-out phenotype. Together, our results show that synapsin is pivotal for maintaining synaptic vesicle cluster integrity and that it contributes to the regulated sharing of vesicles between terminals.
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PMID:Synapsin selectively controls the mobility of resting pool vesicles at hippocampal terminals. 2244 64

Synaptic transmission is expensive in terms of its energy demands and was recently shown to decrease the ATP concentration within presynaptic terminals transiently, an observation that we confirm. We hypothesized that, in addition to being an energy source, ATP may modulate the synapsins directly. Synapsins are abundant neuronal proteins that associate with the surface of synaptic vesicles and possess a well defined ATP-binding site of undetermined function. To examine our hypothesis, we produced a mutation (K270Q) in synapsin IIa that prevents ATP binding and reintroduced the mutant into cultured mouse hippocampal neurons devoid of all synapsins. Remarkably, staining for synaptic vesicle markers was enhanced in these neurons compared with neurons expressing wild-type synapsin IIa, suggesting overly efficient clustering of vesicles. In contrast, the mutation completely disrupted the capability of synapsin IIa to slow synaptic depression during sustained 10 Hz stimulation, indicating that it interfered with synapsin-dependent vesicle recruitment. Finally, we found that the K270Q mutation attenuated the phosphorylation of synapsin IIa on a distant PKA/CaMKI consensus site known to be essential for vesicle recruitment. We conclude that ATP binding to synapsin IIa plays a key role in modulating its function and in defining its contribution to hippocampal short-term synaptic plasticity.
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PMID:ATP binding to synaspsin IIa regulates usage and clustering of vesicles in terminals of hippocampal neurons. 2560 16