Binding of Filamentous Actin to CaMKII as Potential Regulation Mechanism of Bidirectional Synaptic Plasticity by \u03b2 CaMKII in Cerebellar Purkinje Cells

Thiago M Pinto,Volker Steuber,Maria J Schilstra,Antonio C Roque

doi:10.1038/s41598-020-65870-9

Abstract

Calcium-calmodulin dependent protein kinase II (CaMKII) regulates many forms of synaptic plasticity, but little is known about its functional role during plasticity induction in the cerebellum. Experiments have indicated that the β isoform of CaMKII controls the bidirectional inversion of plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in cerebellar cortex. Because the cellular events that underlie these experimental findings are still poorly understood, we developed a simple computational model to investigate how β CaMKII regulates the direction of plasticity in cerebellar PCs. We present the first model of AMPA receptor phosphorylation that simulates the induction of long-term depression (LTD) and potentiation (LTP) at the PF-PC synapse. Our simulation results suggest that the balance of CaMKII-mediated phosphorylation and protein phosphatase 2B (PP2B)-mediated dephosphorylation of AMPA receptors can determine whether LTD or LTP occurs in cerebellar PCs. The model replicates experimental observations that indicate that β CaMKII controls the direction of plasticity at PF-PC synapses, and demonstrates that the binding of filamentous actin to CaMKII can enable the β isoform of the kinase to regulate bidirectional plasticity at these synapses.

Highlights

Synaptic plasticity is an activity-dependent change in the strength of synaptic connections between pre and postsynaptic neurons
To understand the role of β calmodulin dependent protein kinase II (CaMKII) in cerebellar long-term depression (LTD) and long-term potentiation (LTP) at parallel fibre (PF)-Purkinje cell (PC) synapses, we developed a mathematical model of the phosphorylation and dephosphorylation of AMPA receptors by CaMKII and protein phosphatase 2B (PP2B)
Postsynaptic LTD at PF-PC synapses is balanced by postsynaptic LTP, but the exact conditions and cellular mechanisms that determine the direction of synaptic plasticity induction in vivo are not fully understood

Summary

Introduction

Synaptic plasticity is an activity-dependent change in the strength of synaptic connections between pre and postsynaptic neurons. PF LTD (often called cerebellar LTD) is a process in which the strength of the PF-PC synapse is depressed by large increases in the postsynaptic calcium concentration in response to the coincident activation of PF and climbing fibre (CF) input onto the PC8–13. The strengthening of excitatory synapses between PFs and PCs by PF LTP is mediated by smaller calcium concentration increases that can result from the activation of PFs without any coincident CF input to the PC. CaMKII is a critical mediator of the calcium signalling systems that underlie the induction of synaptic plasticity. Two CaMKII isoforms, α CaMKII and β CaMKII, have been shown to mediate synaptic plasticity in the cerebellum, and to be essential for cerebellar learning and memory formation[29,31,32,33]. Β CaMKII is the predominant isoform of CaMKII in the cerebellum, the exact role of β CaMKII in cerebellar learning has yet to be established

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Conclusion