VAMP4 directs synaptic vesicles to a pool that selectively maintains asynchronous neurotransmission

Abstract

Synaptic vesicles in the brain harbor several SNARE proteins. With the exception of synaptobrevin2/VAMP2 (syb2) that is directly involved in vesicle fusion, the role of these SNAREs in neurotransmission is unclear. Here, we show that in mice while syb2 drives rapid Ca2+-dependent synchronous neurotransmission, the structurally homologous SNARE protein VAMP4 selectively maintains bulk Ca2+-dependent asynchronous release. At inhibitory nerve terminals, up- or down-regulation of VAMP4 causes a correlated change in asynchronous release. Biochemically, VAMP4 forms a stable complex with SNAREs syntaxin-1 and SNAP-25 that does not interact with complexins or synaptotagmin-1, proteins essential for synchronous neurotransmission. Optical imaging of individual synapses indicates that VAMP4 and syb2 trafficking show minimal overlap. Taken together, these findings suggest that VAMP4 and syb2 diverge functionally, traffic independently and support distinct forms of neurotransmission. These results provide molecular insight into how synapses diversify their release properties by taking advantage of distinct synaptic vesicle-associated SNAREs.

GABA B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

“…S7), indicating an increase in Pr (23). Thus, the difference between spike-evoked and spontaneous vesicle release regulation observed under our experimental conditions reflects differential regulation of exocytosis during spontaneous and evoked synaptic activity (24). Although GABA B R blockade did not affect regulation of mEPSC frequency, it impaired inactivityinduced increase in mEPSC amplitude, suggesting the postsynaptic GABA B Rs are involved in this regulation.…”

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

“…Recent work has identified potential molecular determinants involved in asynchronous release, which has allowed a better definition of this process beyond a simple kinetic distinction. Although vesicle-SNARE (v-SNARE) syb2 is involved in rapid Ca 2+ -dependent synchronous neurotransmission, vesicle-associated membrane protein 4 (VAMP4) seems to selectively maintain bulk Ca 2+ -dependent asynchronous release (Raingo et al, 2012). VAMP4 did not show robust trafficking under resting conditions, although it was shown that VAMP4-enriched vesicles can respond to elevated presynaptic Ca 2+ signals and promote release (Raingo et al, 2012;Bal et al, 2013).…”

“…Although vesicle-SNARE (v-SNARE) syb2 is involved in rapid Ca 2+ -dependent synchronous neurotransmission, vesicle-associated membrane protein 4 (VAMP4) seems to selectively maintain bulk Ca 2+ -dependent asynchronous release (Raingo et al, 2012). VAMP4 did not show robust trafficking under resting conditions, although it was shown that VAMP4-enriched vesicles can respond to elevated presynaptic Ca 2+ signals and promote release (Raingo et al, 2012;Bal et al, 2013). In addition, syt7 has recently emerged as a key Ca 2+ -sensing synaptic protein that maintains asynchronous neurotransmitter release independently of syt1 (Wen et al, 2010;Bacaj et al, 2013;Jackman et al, 2016).…”

Examination of Synaptic Vesicle Recycling Using FM Dyes During Evoked, Spontaneous, and Miniature Synaptic Activities

“…Complementary methods to consider will include uptake into synaptic vesicles of antibodies whose epitopes are intra-lumenal domains of vesicle proteins 22,48 . They also include expressing pH-sensitive GFP variants targeted to vesicle lumen [49][50][51] , and uptake of pH-sensitive antibody conjugates [52][53][54] both of which detect the intra-vesicular pH changes accompanying exo-endocytosis.…”