Septins Regulate Developmental Switching from Microdomain to Nanodomain Coupling of Ca2+ Influx to Neurotransmitter Release at a Central Synapse

Neurotransmitter release depends critically on close spatial coupling of Ca2+ entry to synaptic vesicles at the nerve terminal; however, the molecular substrates determining their physical proximity are unknown. Using the calyx of Held synapse, where microdomain coupling predominates at immature stages and developmentally switches to nanodomain coupling, we demonstrate that deletion of the filamentous protein Septin 5 imparts immature synapses with striking morphological and functional features reminiscent of mature synapses. This includes synaptic vesicles tightly localized to active zones, resistance to the slow Ca2+ buffer EGTA and a reduced number of Ca2+ channels required to trigger single fusion events. Disrupting Septin 5 organization acutely transforms microdomain to nanodomain coupling and potentiates quantal output in immature wild-type terminals. These observations suggest that Septin 5 is a core molecular substrate that differentiates distinct release modalities at the central synapse.