Selective, genetically induced increase in synaptic vesicle priming.

Abstract

Synaptic vesicle (SV) release probability (<i>Pv</i>) is determined by two probabilistic factors: the probability of release sites being occupied by fusion-competent, well-primed SVs and their fusion probability (<i>P</i>_fusion). While recent studies emphasize SV priming as a key mechanism underlying functional synaptic diversity, disentangling priming from fusion is notoriously challenging. Here we developed a mouse genetic approach for inducible and selective increase of SV priming. A histidine-to-lysine mutation at position 567 of Munc13-1 increases its function. Combining this mutation with a Cre-dependent removal of the wild-type Munc13-1 allele enables cell type-selective enhancement of Munc13-1 function. This manipulation increased excitatory postsynaptic current amplitude at hippocampal synapses exclusively through elevating <i>Pv</i> without affecting release site number or quantal size. A sequential, two-step priming model predicts that the enhanced <i>Pv</i> results from an elevated proportion of well-primed SVs, without altering <i>P</i>_fusion. Last, we provide unequivocal evidence that the postsynaptic target cell type-dependent variability in presynaptic glutamate release is mainly the consequence of variability in SV priming.