Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming

Abstract

Synapses contain a limited number of synaptic vesicles (SVs) that can be released in response to action potentials (APs). Therefore, sustaining synaptic transmission over a wide range of AP firing rates and timescales depends on SV release and replenishment. Although actin dynamics impact synaptic transmission, how presynaptic regulators of actin signaling cascades control SV release and replenishment remain unresolved. Rac1, a Rho GTPase, is a regulator of actin signaling cascades that control synaptogenesis, neuronal development, and postsynaptic function. However, the presynaptic role of Rac1 in regulating synaptic transmission is unclear. To unravel the roles of presynaptic Rac1 in controlling synaptic transmission, we performed selective presynaptic ablation of Rac1 at the mature mouse calyx of Held. We show that presynaptic Rac1 deletion leads to increased synaptic strength due to increased SV release probability which results in faster SV replenishment and increased spontaneous SV release rates with no change in presynaptic morphology or active zone ultrastructure. Based on our data, we conclude that presynaptic Rac1 controls synaptic strength by regulating the intrinsic SV release probability through SV priming. Therefore, we propose that presynaptic Rac1 is a key regulator of synaptic transmission and plasticity.