SAD-B Phosphorylation of CAST Controls Active Zone Vesicle Recycling for Synaptic Depression

Short-term synaptic depression (STD) is a common form of activity-dependent plasticity observed widely in the nervous system. Few molecular pathways that control STD have been described, but the active zone (AZ) release apparatus provides a possible link between neuronal activity and plasticity. Here, we show that an AZ cytomatrix protein CAST and an AZ-associated protein kinase SAD-B coordinately regulate STD by controlling reloading of the AZ with release-ready synaptic vesicles. SAD-B phosphorylates the N-terminal serine (S45) of CAST, and S45 phosphorylation increases with higher firing rate. A phosphomimetic CAST (S45D) mimics CAST deletion, which enhances STD by delaying reloading of the readily releasable pool (RRP), resulting in a pool size decrease. A phosphonegative CAST (S45A) inhibits STD and accelerates RRP reloading. Our results suggest that the CAST/SAD-B reaction serves as a brake on synaptic transmission by temporal calibration of activity and synaptic depression via RRP size regulation. [Display omitted] •CAST S45 is phosphorylated by SAD-B or after presynaptic activity•S45D CAST delays RRP reloading and enhances synaptic depression•CAST deletion delays RRP reloading and enhances synaptic depression•CAST phosphorylation provides temporal control of synaptic efficacy Mochida et al. examine the molecular mechanisms underlying depression, an important form of synaptic plasticity. Their work shows that CAST, in concert with a protein kinase, SAD-B, regulates depression by controlling synaptic vesicle trafficking within presynaptic terminals. This pathway serves as a dynamic brake on synaptic transmission.