Astrocytes control synaptic strength by two distinct v-SNARE-dependent release pathways

The mechanisms of gliotransmitter release and their impact on neuronal signaling have remained largely elusive. The authors describe two functionally non-overlapping v-SNARE-dependent astrocytic release pathways that oppositely control synaptic strength at presynaptic sites. Thus, astrocytes are able to fine-tune fast glutamatergic neurotransmission and control fundamental processes of synaptic communication. Communication between glia cells and neurons is crucial for brain functions, but the molecular mechanisms and functional consequences of gliotransmission remain enigmatic. Here we report that astrocytes express synaptobrevin II and cellubrevin as functionally non-overlapping vesicular SNARE proteins on glutamatergic vesicles and neuropeptide Y-containing large dense-core vesicles, respectively. Using individual null-mutants for Vamp2 (synaptobrevin II) and Vamp3 (cellubrevin), as well as the corresponding compound null-mutant for genes encoding both v-SNARE proteins, we delineate previously unrecognized individual v-SNARE dependencies of astrocytic release processes and their functional impact on neuronal signaling. Specifically, we show that astroglial cellubrevin-dependent neuropeptide Y secretion diminishes synaptic signaling, while synaptobrevin II–dependent glutamate release from astrocytes enhances synaptic signaling. Our experiments thereby uncover the molecular mechanisms of two distinct v-SNARE-dependent astrocytic release pathways that oppositely control synaptic strength at presynaptic sites, elucidating new avenues of communication between astrocytes and neurons.