Ca2+- and Phospholipid-Dependent Mechanisms for the Coupling of Synaptic Vesicle Consumption and Re-Supply Rates

Abstract

The efficacy and reliability of synaptic transmission depend on the ability of the transmitter release machinery to replenish the releasable pool of synaptic vesicles (SV) during and following activity. To sustain transmitter release during periods of high-frequency activity, a mechanism must exist that increases the recovery rate of the releasable SV pool. We sought to identify Ca2+-dependent SV replenishment mechanisms that operate in vivo, study how they dynamically interact during periods of synaptic activity, and illustrate how they affects transmitter release dynamics and short-term synaptic plasticity. Munc13s are a family of presynaptic proteins with three domains that are directly or indirectly regulated by Ca2+. Munc13s are functionally absolutely essential for the priming of SVs, and have a central role in the organization of SVs prior to and during transmitter release. Here, we present novel genetically modified mouse lines in which Ca2+- and phospholipid sensing by the regulatory domains of Munc13-1 is altered. Our analyses demonstrate that the SV replenishment rates can be controlled bi-directionally by Munc13-1, with consequent effects on short-term synaptic plasticity and information processing.