Article

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

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nature Neuroscience (Impact Factor: 14.98). 03/2012; 15(5):738-45. DOI: 10.1038/nn.3067
Source: PubMed

ABSTRACT Synaptic vesicles in the brain harbor several soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins. With the exception of synaptobrevin2, or VAMP2 (syb2), which is directly involved in vesicle fusion, the role of these SNAREs in neurotransmission is unclear. Here we show that in mice syb2 drives rapid Ca(2+)-dependent synchronous neurotransmission, whereas the structurally homologous SNARE protein VAMP4 selectively maintains bulk Ca(2+)-dependent asynchronous release. At inhibitory nerve terminals, up- or downregulation 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 trafficking of VAMP4 and syb2 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.

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    • "This task is inherently more complex as SVs are homogenous in size and display a defined protein and lipid composition that can only be maintained by high fidelity adaptor-mediated sorting processes that serve to ''proofread'' SV composition. This task may be further complicated by the existence of functionally distinct pools of vesicles that may display compositional heterogeneity (Hua et al., 2011b; Raingo et al., 2012; Ramirez et al., 2012). However, CME as well as endosomal pathways of vesicle budding employed to reform functional SVs operate on a timescale of tens of seconds and, thus, provide a potential kinetic bottleneck when used for compensatory membrane retrieval at synapses undergoing high rates of firing. "
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    • "Although asynchronous release is generally present after a train of action potentials as a delayed return of the post-synaptic current level to the baseline, it occurs also after a single action potential (Iremonger and Bains 2007). Thus, to compare the degree of asynchronicity of neurotransmitter release among different synapses or conditions one can measure (i) the cumulative integration of total charge transferred in post-synaptic currents recorded during a train of stimulation, (ii) the increase in the variance of consecutive post-synaptic current episodes evoked during a high frequency train of stimulation and also, (iii) the integrative current that remains after the cessation of stimulation (Raingo et al. 2012) (see Fig. 1). Interestingly, some synapses seem to solely rely on this mode of delayed transmission. "
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