GSK-3β regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIα

Abstract

Understanding the normal functions of GSK-3{beta} in the central nervous system is of major interest because deregulation of this kinase is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. GSK-3{beta} plays a role in the induction of NMDA receptor-dependent long-term depression (LTD) and several substrates for GSK-3{beta} have been identified in this form of synaptic plasticity, including KLC-2, PSD-95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK-3{beta}, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type II (PI4KII) as a neuronal GSK-3{beta} substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KII in organotypic rat hippocampal slices. We found that knockdown of PI4KII had no effect on synaptic AMPA receptors but substantially inhibited synaptic NMDA receptors. Furthermore, the ability of the selective GSK-3 inhibitor, CT99021, to inhibit synaptic NMDA receptors was occluded in shRNA-PI4KII transfected neurons. The effects of knocking down PI4KII knockdown were fully rescued by a shRNA-resistant wild type construct but could not be rescued by a mutant construct that was unable to be phosphorylated by GSK-3{beta}. The data suggest that GSK-3{beta} phosphorylates PI4KII to stabilize the expression of synaptic NMDA receptors.