Postsynaptic Syntaxin 4 negatively regulates the efficiency of neurotransmitter release

Signaling from the postsynaptic compartment regulates multiple aspects of synaptic development and function. Syntaxin 4 (Syx4) is a plasma membrane t-SNARE that promotes the growth and plasticity of <i>Drosophila</i> neuromuscular junctions (NMJs) by regulating the localization of key synaptic proteins in the postsynaptic compartment. Here, we describe electrophysiological analyses and report that loss of <i>Syx4</i> leads to enhanced neurotransmitter release, despite a decrease in the number of active zones. We describe a requirement for postsynaptic <i>Syx4</i> in regulating several presynaptic parameters, including Ca²⁺ cooperativity and the abundance of the presynaptic calcium channel Cacophony (Cac) at active zones. These findings indicate Syx4 negatively regulates presynaptic neurotransmitter release through a retrograde signaling mechanism from the postsynaptic compartment.