Selective, genetically induced increase in synaptic vesicle priming

Authors:

Mohammad Aldahabi, Flora Balint, Andrea Lorincz, Noa Lipstein, Nils Brose, Zoltan Nusser

Keywords:

synaptic vesicle; vesicle priming; fusion probability

Abstract:

Synaptic vesicle (SV) release probability (Pv) is determined by two probabilistic factors: the probability of release sites being occupied by fusion-competent, well-primed SVs and their fusion probability (P_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 Pv without affecting release site number or quantal size. A sequential, two-step priming model predicts that the enhanced Pv results from an elevated proportion of well-primed SVs, without altering P_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.

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