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 both SV release and replenishment. Although actin dynamics impact synaptic transmission, how regulators of actin dynamics control SV release and replenishment remain unresolved. Rac1 is a regulator of actin signaling cascades that control synaptogenesis, neuronal development, and postsynaptic function, however, its presynaptic role in regulating synaptic transmission is unclear. To unravel the regulatory roles of presynaptic Rac1 in synaptic transmission, we ablated presynaptic Rac1 at the mature mouse calyx of Held. 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. 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 controls actin dynamics and acts as a key regulator of synaptic transmission and plasticity.

Heterozygosity for neurodevelopmental disorder-associatedTRIOvariants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice

“…We present evidence here that Trio plays key roles in regulating neurotransmitter release and synaptic vesicle cycling. Several recent studies suggest that Trio may act via Rac1 and RhoA to regulate these processes -Rac1 co-localizes with SVs in the neuronal pre-synaptic compartment, where it negatively regulates glutamate Pr and SV replenishment (118)(119)(120).…”