Selective, genetically induced increase in synaptic vesicle priming

Aldahabi, Mohammad and Bálint, Flóra and Lőrincz, Andrea and Lipstein, Noa and Brose, Nils and Nusser, Zoltán (2026) Selective, genetically induced increase in synaptic vesicle priming. SCIENCE ADVANCES, 12 (15). No. -eaee6848. ISSN 2375-2548

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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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