Spontaneous neurotransmitter release is regulated by Unc-5
The spontaneous quantal release of single vesicles of neurotransmitter in the absence of an action potential is a universal feature of all neuronal chemical synapses. These miniature events have long been thought to be stochastic and unregulated, leading to measurement of their frequency as a widely employed estimate of the number of synaptic connections within neuronal networks. Here we show using high resolution live imaging of Drosophila adult glutamatergic synapses that the spontaneous release of neurotransmitter occurs from only a subset of synaptic release sites. We discover that the proportion of release sites participating in spontaneous neurotransmitter release is regulated by a novel synaptic function of the transmembrane signalling receptor Unc-5 which is heparan sulfate proteoglycan dependent, but Netrin independent. We show that synaptic Unc-5 forms a complex with the SNARE protein Syntaxin to regulate neurotransmitter release. The depletion of Unc-5 in adult synapses diminishes miniature events, inducing terminal degeneration and behavioural decline. Our results reveal that spontaneous neurotransmitter release is a singular, essential and independently regulated property of synapses that is critical for the structural integrity and behavioural contribution of synaptic connections.