Short-term plasticity persists in the absence of PKC phosphorylation of Munc18-1

Post tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knockin mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1 SA mice). Expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3 to CA1 synapse, and the granule cell parallel fiber to Purkinje cell (PF to PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1 SA mice. In Munc18-1 SA mice, 70% of PTP remained at CA3 to CA1 synapses, and the amplitude of PTP was not reduced at PF to PC synapses. These findings indicate that at both CA3 to CA1 and PF to PC synapses, phorbol esters and PTP enhance synaptic transmission primarily by mechanisms that are independent of PKC phosphorylation of Munc18-1. Significance Statement A leading mechanism for a prevalent form of short-term plasticity, post-tetanic potentiation (PTP), involves protein kinase C phosphorylation of Munc18-1. This study tests this mechanism by creating a knock in mouse in which Munc18-1 is replaced by a mutated form of Munc18-1 that cannot be phosphorylated. The main finding is that most PTP at hippocampal CA3 to CA1 synapses, or at cerebellar granule cell to Purkinje cell synapses does not rely on PKC phosphorylation of Munc18-1. Thus, mechanisms independent of PKC phosphorylation of Munc18-1 are important mediators of PTP.