Elevated synaptic vesicle fusion with impaired activity-dependent neurotransmission in a genomic ferlinopathy model

Ferlins are a family of Ca 2+ /phospholipid-binding C2 domain transmembrane proteins (e.g. Myoferlin, Dysferlin, Otoferlin) mutated in multiple heritable human disease conditions. The unifying function of all Ferlins is Ca 2+ -dependent vesicle fusion, with roles in muscle formation, membrane repair, and neurotransmission. Drosophila has one well-conserved Ferlin, misfire ( mfr ), which provides the opportunity to test global Ferlin function via single gene manipulation. We find misfire null mutants form and maintain normal muscles with elevated muscle function. Consistently, we find misfire expressed in motor neurons with loss-of-function elevating synaptic vesicle fusion. Basal neurotransmission is normal at the glutamatergic neuromuscular junction (NMJ) model synapse, but misfire null mutants exhibit progressive synaptic depression with accumulating failures during high-frequency stimulation. We discover that experience-dependent neurotransmission potentiation from chronic neuronal activity elevation is eliminated in the absence of misfire function. These findings suggest neuronal presynaptic vesicle regulation may be the ancestral Ferlin role, similar to Otoferlin function in humans and mouse disease models. Taken together, these results show that misfire modulates synaptic vesicle fusion during neurotransmission and mediates activity-dependent changes in both signaling fidelity and synaptic strength.