Stochastic RNA editing of the Complexin C-terminus within single neurons regulates neurotransmitter release

Neurotransmitter release requires assembly of the SNARE complex fusion machinery, with multiple SNARE-binding proteins regulating when and where synaptic vesicle fusion occurs. The presynaptic protein Complexin (Cpx) controls spontaneous and evoked neurotransmitter release by modulating SNARE complex zippering. Although the central SNARE-binding helix is essential, post-translational modifications to Cpx’s C-terminal membrane-binding amphipathic helix regulate its ability to control synaptic vesicle fusion. Here, we demonstrate that RNA editing of the Cpx C-terminus modifies its ability to clamp SNARE-mediated fusion and alters presynaptic output. RNA editing of Cpx across single neurons is stochastic, generating up to eight edit variants that fine tune neurotransmitter release by altering the subcellular localization and clamping properties of the protein. Similar stochastic editing rules for other synaptic genes were observed, indicating editing variability at single adenosines and across multiple mRNAs generates unique synaptic proteomes within the same population of neurons to fine tune presynaptic output.