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Ca2+-phospholipid–dependent regulation of Munc13-1 is essential for post-tetanic potentiation at mossy fiber synapses and supports working memory.
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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 (SVs) at active zones controls hMF STF and PTP in response to Ca2+-phospholipid and Ca2+-calmodulin (CaM) signaling. Knock-in 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 block of Ca2+-phospholipid-Munc13-1 signaling. Since these synaptic defects are accompanied by working memory deficits, especially in mice expressing the Ca2+-phospholipid-insensitive Munc13-1 variant, we conclude that the Ca2+-dependent regulation of Munc13-1-mediated SV priming co-determines hMF short-term plasticity and working memory formation.
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LÓPEZ MURCIA, Francisco José, et al. Ca2+-phospholipid–dependent regulation of Munc13-1 is essential for post-tetanic potentiation at mossy fiber synapses and supports working memory. Cell Reports. 2026. Vol. 45, num. 3, pags. 117029. ISSN 2211-1247. [consulted: 6 of June of 2026]. Available at: https://hdl.handle.net/2445/228717