1. Presynaptic Short-Term Plasticity Persists in the Absence of PKC Phosphorylation of Munc18-1.
- Author
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Wang, Chih-Chieh, Weyrer, Christopher, Fioravante, Diasynou, Kaeser, Pascal S, and Regehr, Wade G
- Subjects
Neurosciences ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Underpinning research ,Aetiology ,Amino Acid Substitution ,Animals ,Female ,Gene Knock-In Techniques ,Hippocampus ,Male ,Mice ,Mice ,Knockout ,Miniature Postsynaptic Potentials ,Munc18 Proteins ,Mutation ,Missense ,Neuronal Plasticity ,Phorbol Esters ,Phosphorylation ,Point Mutation ,Protein Kinase C ,Protein Processing ,Post-Translational ,Purkinje Cells ,Recombinant Proteins ,Synaptic Transmission ,Munc18-1 ,PKC ,plasticity ,post-tetanic potentiation ,synapse ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
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 knock-in mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1SA mice), and we studied mice of either sex. The 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 (PF)-to-Purkinje cell (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 the activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1SA mice. In Munc18-1SA 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 (PKC) 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.
- Published
- 2021