New manuscript – Spontaneous neurotransmitter release is regulated by Unc-5
For decades, spontaneous neurotransmitter vesicle release (also known as miniature neurotransmission or ‘minis’), which occurs at every chemical synapse in the brain, was considered little more than synaptic noise — a background hum without meaningful function. Our lab has spent years showing that’s wrong. Minis are not noise. They are an independent, essential mode of synaptic signalling, required for synapse maturation, maintenance, and long-term terminal function. Now, in a new manuscript led by Samuel Vernon, we go further. Using a novel optical electrophysiology platform, we can now image individual synaptic vesicle fusion events with single-active-zone resolution in adult Drosophila synapses. What we found challenges canonical models of quantal neurotransmission.
We show that adult active zones of synaptic vesicle release are not uniform — but are obligately heterogeneous. Approximately one quarter participate in both evoked and spontaneous release. Another quarter are exclusively evoked, while an additional quarter are exclusively spontaneous. The remaining active zones were silent during the imaging period. Spontaneous and evoked neurotransmission are therefore spatially segregated in adult synapses, occurring at distinct release sites, as had previously been described for developing synapses.
What regulates this segregation? Unc-5: a transmembrane receptor best known for its role in axon guidance. We find Unc-5 is enriched at active zones engaged in spontaneous release, and that bidirectionally manipulating its levels shifts the balance between release modalities. This function is independent of its canonical ligand Netrin, and instead requires synaptic heparan sulfate proteoglycan activity. Mechanistically, we show Unc-5 interacts directly with the SNARE protein Syntaxin, providing a molecular explanation of how this signalling receptor can alter synaptic vesicle fusion release probability. Disrupting this regulation, and the heterogeneity it maintains, leads to synaptic terminal structural degeneration and behavioral decline.
Together, these findings reframe how we think about synaptic vesicle release in neuronal synaptic connections: not as a uniform probabilistic process, but as spatially organized, independently regulated components, with each element having a critical role for brain function in vivo.
Read the preprint here – https://doi.org/10.64898/2026.06.02.729526
