Glycogen synthase kinase 3 regulates NMDA receptor channel trafficking and function in cortical neurons
Chen, Paul J.
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Emerging evidence has suggested that glycogen synthase kinase 3 (GSK-3) is a key regulatory kinase involved in a plethora of processes in the nervous system including neuronal development, mood stabilization and neurodegeneration. However, the cellular mechanisms underlying the actions of GSK-3 remain to be identified. In this study, we examined the impact of GSK-3 on the NMDA receptor (NMDAR) channel, a central player involved in cognitive and emotional processes. We found that application of various structurally different GSK-3 inhibitors caused a long-lasting reduction of NMDAR-mediated ionic and synaptic current in cortical pyramidal neurons. Cellular knockdown of GSK-3β in neuronal cultures using siRNA led to smaller NMDAR current and loss of its regulation by GSK-3 inhibitors. Combined evidence suggested that GSK-3 inhibitors induced the down-regulation of NMDAR current through a decrease of functional surface NMDARs. This down-regulation was achieved by suppressing the binding of NMDARs to the scaffolding protein PSD-95, therefore increasing the clathrin/dynamin-dependent NMDAR internalization. Furthermore, the GSK-3 regulation of NMDAR is diminished in β-Amyloid treated neurons and amyloid precursor protein (APP) transgenic mice, a common animal model for Alzheimer's disease (AD). Thus, our study provides a potential mechanism for the role of GSK-3 in normal cognition and neurodegenerative disease.