Spontaneous Vesicle Fusion Is Differentially Regulated at Cholinergic and GABAergic Synapses

The locomotion of C. elegans is balanced by excitatory and inhibitory neurotransmitter release at neuromuscular junctions. However, the molecular mechanisms that maintain the balance of synaptic transmission remain enigmatic. Here, we investigated the function of voltage-gated Ca2+ channels in triggering spontaneous release at cholinergic and GABAergic synapses. Recordings of the miniature excitatory/inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively) showed that UNC-2/CaV2 and EGL-19/CaV1 channels are the two major triggers for spontaneous release. Notably, however, Ca2+-independent spontaneous release was observed at GABAergic but not cholinergic synapses. Functional screening led to the identification of hypomorphic unc-64/Syntaxin-1A and snb-1/VAMP2 mutants in which mEPSCs are severely impaired, whereas mIPSCs remain unaltered, indicating differential regulation of these currents at cholinergic and GABAergic synapses. Moreover, Ca2+-independent spontaneous GABA release was nearly abolished in the hypomorphic unc-64 and snb-1 mutants, suggesting distinct mechanisms for Ca2+-dependent and Ca2+-independent spontaneous release. [Display omitted] •VGCCs trigger vesicle fusion differently at cholinergic and GABAergic synapses•UNC-2/CaV2 and EGL-19/CaV1 account for Ca2+-dependent spontaneous release•Ca2+-independent spontaneous release is observed at GABAergic synapses•Mutation in unc-64/syntaxin-1A or snb-1/VAMP2 leads to synaptic imbalance Liu et al. show that spontaneous release is differentially regulated between cholinergic and GABAergic synapses at the C. elegans NMJ. Ca2+-independent spontaneous release is observed in GABAergic synapses and regulated by synaptic proteins such as syntaxin-1A and VAMP2.