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

Deregulation of GSK-3 beta is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. To understand how GSK-3 beta becomes dysregulated in these conditions, it is important to understand its physiological functions in the central nervous system. In this context, 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 alpha (PI4KII alpha) 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 alpha in organotypic rat hippocampal slices. We found that knockdown of PI4KII alpha has no effect on synaptic AMPA receptor-mediated synaptic transmission but substantially reduces NMDA receptor-mediated synaptic transmission. Furthermore, the ability of the selective GSK-3 inhibitor, CT99021, to reduce the amplitude of NMDA receptor-mediated currents was occluded in shRNA-PI4KII alpha transfected neurons. The effects of knocking down PI4KII alpha were fully rescued by a shRNA-resistant wild-type construct, but not by a mutant construct that cannot be phosphorylated by GSK-3 beta. These data suggest that GSK-3 beta phosphorylates PI4KII alpha to stabilize NMDA receptors at the synapse.

Automated summary

Deregulation of GSK-3 beta is closely related to various serious brain conditions, and understanding its physiological functions in the central nervous system is crucial for disease research. Studies have shown that GSK-3 beta stabilizes synaptic NMDA receptors by phosphorylating PI4KII alpha, thereby controlling synaptic transmission.