Ca2+-phospholipid-dependent regulation of Munc13-1 is essential for post-tetanic potentiation at mossy fiber synapses and supports working memory

Hippocampal mossy fiber (hMF) to CA3 pyramidal cell synapses are thought to support the formation of working memory through presynaptic short-term facilitation (STF) and post-tetanic potentiation (PTP). However, the molecular mechanisms underlying these transient forms of synaptic enhancement are unclear. We show here that Munc13-1-mediated priming of synaptic vesicles at active zones controls hMF STF and PTP in response to Ca 2+ -phospholipid and Ca 2+ -calmodulin signaling. Knockin mice expressing Munc13-1 variants insensitive to either signaling pathway exhibit pronounced deficits in STF and PTP, and the PTP induction threshold is markedly increased upon blockade of Ca 2+ -phospholipid-Munc13-1 signaling. Since these synaptic defects are accompanied by working memory deficits, especially in mice expressing the Ca 2+ -phospholipid-insensitive Munc13-1 variant, we conclude that the Ca 2+ -dependent regulation of Munc13-1-mediated SV priming co-determines hMF short-term plasticity and working memory formation.