Ca ²⁺ -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 remain poorly understood. We show here that Munc13-1-mediated priming of synaptic vesicles (SVs) at active zones controls hMF STF and PTP in response to Ca ²⁺ -phospholipid and Ca ²⁺ -calmodulin (CaM) signaling. Knock-in mice expressing Munc13-1 variants that are insensitive to Ca ²⁺ -phospholipid and Ca ²⁺ -CaM signaling exhibit severely impaired STF and PTP at hMF synapses. Moreover, the PTP-induction threshold is strongly increased upon the loss 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 Ca ²⁺ -dependent regulation of Munc13-1-mediated SV priming co-determines hMF short-term plasticity and working memory formation.