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

Abstract

Summary 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 Ca++ 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.

Input-Specific Plasticity and Homeostasis at the Drosophila Larval Neuromuscular Junction

“…These are consistent with spontaneous quantal “miniature” events detected at the dissected larva in macropatch recordings (Karunanithi et al, 2002; Nguyen and Stewart, 2016) or imaging (Cho et al, 2015; Melom et al, 2013; Muhammad et al, 2015; Peled and Isacoff, 2011; Peled et al, 2014) as well as imaging in cultured neurons (Reese and Kavalali, 2015, 2016). These spontaneous events had larger amplitudes at Is synapses (Figure S2C–H), but were more frequent at Ib synapses (Figure 2L, S2C, F).…”

“…Quantal resolution measurement of excitatory transmission through Ca 2+ -permeant glutamate receptors (GluRs) has been achieved by imaging chemical or genetically-encoded Ca 2+ indicators (GECIs) in the postsynaptic cell (Cho et al, 2015; Guerrero et al, 2005; Lin and Schnitzer, 2016; Melom et al, 2013; Muhammad et al, 2015; Peled and Isacoff, 2011; Peled et al, 2014; Reese and Kavalali, 2015, 2016; Siegel and Lohmann, 2013). We generated a vastly improved postsynaptically targeted GECI based on GCaMP6f.…”

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

“…Manipulation of the diverse vesicular proteins can selectively alter different forms of neurotransmitter release. Recent studies demonstrate that nonsynchronous forms of neurotransmitter release are important to the regulation of synaptic plasticity, memory processing, and antidepressant action (Autry et al, 2011;Xu et al, 2012;Nosyreva et al, 2013;Cho et al, 2015). The precision of the synaptic message is maintained at the postsynaptic level as variations in presynaptic release differentially affect receptors and downstream targets (Atasoy et al, 2008;Autry et al, 2011;Sara et al, 2011;Stepanyuk et al, 2014).…”

“…In vitro phosphorylation of complexin I and II by protein kinase CK2 has been shown to enhance complexin binding to SNARE complexes (Shata et al, 2007). Activity-dependent phosphorylation of complexin by protein kinase A (PKA) enhances spontaneous neurotransmitter release and affects synaptic structural plasticity in Drosophila (Cho et al, 2015).…”

Possible target-related proteins of stress-resistant rats suggested by label-free proteomic analysis

“…33 Phosphorylation of complexin by PKA regulates spontaneous neurotransmitter release and structural synaptic plasticity. 34 Moreover, Jorquera believes that complexin 2 regulates both spontaneous and evoked neurotransmitter release by modulating the timing and properties of synaptotagmin activity. 35 In addition, there is a growing body of evidence to support the idea that disturbed synaptic transmission contributes to the pathophysiology of mood disorders.…”