Distinct synaptic vesicle recycling in inhibitory nerve terminals is coordinated by SV2A

Proper brain function requires a balance between excitatory and inhibitory neuronal activity. This balance, which is disrupted in various neural disorders, ultimately depends on the functional properties of both excitatory and inhibitory neurons; however, how the physiological properties of presynaptic terminals are controlled in these neurons is largely unknown. In this study, we generated pHluorin-conjugated, synaptic vesicle-specific tracers that are preferentially expressed in excitatory or inhibitory nerve terminals. We found that synaptic vesicle recycling is ∼1.8-fold slower in inhibitory nerve terminals than excitatory nerve terminals, resulting in reduced efficacy of synaptic transmission in inhibitory presynaptic terminals during repetitive activities. Interestingly, this relative difference in trafficking efficiency is mediated by synaptic vesicle protein 2A (SV2A), which is more highly expressed in inhibitory synapses and differentially controls sorting of synaptic protein, synaptotagmin I. These findings indicate that SV2A coordinates distinct properties of synaptic vesicle recycling between excitatory and inhibitory synapses.