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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    ABSTRACT: The function of the nervous system depends on the exocytotic release of neurotransmitter from synaptic vesicles (SVs). To sustain neurotransmission, SV membranes need to be retrieved, and SVs have to be reformed locally within presynaptic nerve terminals. In spite of more than 40 years of research, the mechanisms underlying presynaptic membrane retrieval and SV recycling remain controversial. Here, we review the current state of knowledge in the field, focusing on the molecular mechanism involved in presynaptic membrane retrieval and SV reformation. We discuss the challenges associated with studying these pathways and present perspectives for future research.
    Neuron 02/2015; 85(3):484-496. DOI:10.1016/j.neuron.2014.12.016 · 15.98 Impact Factor
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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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    ABSTRACT: Central synapses operate neurotransmission in several modes: synchronous/fast neurotransmission (neurotransmitters are released quickly and release is tightly coupled to action potentials), asynchronous neurotransmission (neurotransmitter release is slower and longer lasting), and spontaneous neurotransmission (where small amounts of neurotransmitter are released without being evoked by an action potential). A substantial body of evidence from the past two decades suggests that seemingly identical synaptic vesicles possess distinct propensities to fuse, thus selectively serving different modes of neurotransmission. In efforts to better understand the mechanism(s) underlying the different modes of synaptic transmission, many research groups found that synaptic vesicles used in different modes of neurotransmission differ by a number of synaptic proteins. Synchronous transmission with higher temporal fidelity to stimulation seems to require synaptotagmin 1 and complexin for its Ca(2+) sensitivity, RIM proteins for closer location of synaptic vesicles (SV) to the voltage operated calcium channels (VGCC), and dynamin for SV retrieval. Asynchronous release does not seem to require functional synaptotagmin 1 as a calcium sensor or complexins, but the activity of dynamin is indispensible for its maintenance. On the other hand, the control of spontaneous neurotransmission remains less clear as deleting a number of essential synaptic proteins does not abolish this type of synaptic vesicle fusion. VGCC distance from the SV seems to have little control on spontaneous transmission, while there is an involvement of functional synaptic proteins including synaptotagmins and complexin. Recently, presynaptic deficits have been proposed to contribute to a number of pathological conditions including cognitive and mental disorders. In this review, we evaluate recent advances in understanding the regulatory mechanisms of synaptic vesicle dynamics and in understanding how different molecular substrates maintain selective modes of neurotransmission. We also highlight the implications of these studies in understanding pathological conditions. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12245.
    Journal of Neurochemistry 03/2013; 126. DOI:10.1111/jnc.12245 · 4.24 Impact Factor
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    ABSTRACT: An increasing number of studies suggest that distinct pools of synaptic vesicles drive specific forms of neurotransmission. Interspersed with these functional studies are analyses of the synaptic vesicle proteome which have consistently detected the presence of so-called "non-canonical" SNAREs that typically function in fusion and trafficking of other subcellular structures within the neuron. The recent identification of certain non-canonical vesicular SNAREs driving spontaneous (e.g., VAMP7 and vti1a) or evoked asynchronous (e.g., VAMP4) release integrates and corroborates existing data from functional and proteomic studies and implies that at least some complement of non-canonical SNAREs resident on synaptic vesicles function in neurotransmission. Here, we discuss the specific roles in neurotransmission of proteins homologous to each member of the classical neuronal SNARE complex consisting of synaptobrevin2, syntaxin-1, and SNAP-25.
    01/2012; 2(1):20-27. DOI:10.4161/cl.20114
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