Abstract
The number of neurotransmitter-filled vesicles released into the synaptic cleft with each action potential dictates the reliability of synaptic transmission. Variability of this fundamental property provides diversity of synaptic function across brain regions, but the source of this variability is unclear. The prevailing view is that release of a single (univesicular release, UVR) or multiple vesicles (multivesicular release, MVR) reflects variability in vesicle release probability, a notion that is well-supported by the calcium-dependence of release mode. However, using mouse brain slices, we now demonstrate that the number of vesicles released is regulated by the size of the readily-releasable pool, upstream of vesicle release probability. Our results point to a model wherein protein kinase A and its vesicle-associated target, synapsin, dynamically control release site occupancy to dictate the number of vesicles released without altering release probability. Together these findings define molecular mechanisms that control MVR and functional diversity of synaptic signaling.
Highlights
Excitatory glutamatergic synapses mediate the majority of fast communication between neurons in the brain
We studied regulation of neurotransmitter release at the climbing fiber (CF) to Purkinje cell (PC) synapse using 0.5 mM extracellular Ca2+ that constrains transmission to the release of zero or one vesicle with each action potential (UVR)
Our results show that the number of glutamate-filled vesicles released at individual CF terminals with each action potential is subject to bidirectional modification of the readily-releasable pool (RRP)
Summary
Excitatory glutamatergic synapses mediate the majority of fast communication between neurons in the brain. While general mechanisms underlying synaptic transmission are well-conserved, there is robust diversity in the synaptic parameters that dictate the reliability and temporal fidelity of transmission between brain regions and species (Nusser, 2018). Some synapses are limited to the release of a single vesicle per active zone, termed univesicular release (UVR; Korn et al, 1981; Stevens and Wang, 1995; Silver, 2003; Biroet al., 2005) and other synapses switch release modes in an activity-dependent manner (Bender et al, 2009; Higley et al, 2009; Pulido et al, 2015). Understanding the mechanisms that determine whether an active zone supports UVR or MVR is important to understand synaptic diversity as well as to develop unifying models of presynaptic function that account for multiple presynaptic parameters
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