Phosphorylation of Complexin by PKA Regulates Activity-Dependent Spontaneous Neurotransmitter Release and Structural Synaptic Plasticity

Synaptic plasticity is a fundamental feature of the nervous system that allows adaptation to changing behavioral environments. Most studies of synaptic plasticity have examined the regulated trafficking of postsynaptic glutamate receptors that generates alterations in synaptic transmission. Whether and how changes in the presynaptic release machinery contribute to neuronal plasticity is less clear. The SNARE complex mediates neurotransmitter release in response to presynaptic Ca2+ entry. Here we show that the SNARE fusion clamp Complexin undergoes activity-dependent phosphorylation that alters the basic properties of neurotransmission in Drosophila. Retrograde signaling following stimulation activates PKA-dependent phosphorylation of the Complexin C terminus that selectively and transiently enhances spontaneous release. Enhanced spontaneous release is required for activity-dependent synaptic growth. These data indicate that SNARE-dependent fusion mechanisms can be regulated in an activity-dependent manner and highlight the key role of spontaneous neurotransmitter release as a mediator of functional and structural plasticity. •Complexin dynamically regulates spontaneous release (minis)•PKA phosphorylation of Complexin mediates presynaptic plasticity•Retrograde signaling triggers PKA regulation of Complexin’s clamping properties•Enhanced minis mediated through Complexin modulates synaptic growth Cho et al. demonstrate that spontaneous neurotransmission is regulated and drives structural synaptic plasticity via a retrograde signaling pathway. Complexin phosphorylation by PKA modulates its clamping function, impinging directly on the vesicle fusion machinery to acutely alter synaptic neurotransmission.