Presynaptic homeostasis mediated by exocytosis of a SNARE protein.

Abstract

The neural plasticity that underlies adaptation and learning requires countervailing homeostatic mechanisms to maintain the stability and responsiveness of neural circuits. Previous work has described several forms of synaptic homeostasis1, but the mechanisms that detect changes in activity and transduce these into altered neurotransmission have remained poorly understood. Here we show that high-frequency stimulation alters the subsequent properties of neurotransmitter release to confer a presynaptic form of homeostasis, independent of postsynaptic receptors. The mechanism involves vesicular SNARE protein (v-SNARE) VAMP7 (vesicle-associated membrane protein 7), which reduces neurotransmitter release by inhibiting the entry of Ca2+ specifically through P/Q-type presynaptic Ca2+ channels. Previous work has implicated target SNARE proteins (t-SNAREs) in the inhibition of Ca2+ channels2, but without clear physiological rationale. We show that the activity-dependent regulation of release mediated by VAMP7 requires the t-SNARE syntaxin. Although VAMP7 acts at the plasma membrane to inhibit P/Q-type channels, it localizes predominantly to a subset of synaptic vesicles made by adaptor protein-3 (AP-3) that respond specifically to high-frequency stimulation3,4. The localization of VAMP7 to AP-3-derived synaptic vesicles thus provides a mechanism for the activity-dependent delivery of VAMP7 to the plasma membrane, where it associates with syntaxin to inhibit P/Q-type Ca2+ channels and transmitter release. This homeostatic form of metaplasticity operates at multiple excitatory synapses, and in its absence, the fraction of FOS+ neurons increases several fold, revealing a general property of excitatory neurotransmission that might also maintain the sparsity of neural connections.