Gsk3 Alpha, Not Gsk3 Beta, Drives Hippocampal Nmdar-Dependent Ltd Via Tau-Mediated Spine Anchoring

Glycogen synthase kinase-3 (GSK3) is an important signalling protein in the brain and modulates different forms of synaptic plasticity. Neuronal functions of GSK3 are typically attributed to one of its two isoforms, GSK3 beta, simply because of its prevalent expression in the brain. Consequently, the importance of isoform-specific functions of GSK3 in synaptic plasticity has not been fully explored. We now directly address this question for NMDA receptor-dependent long-term depression (LTD) in the hippocampus. Here, we specifically target the GSK3 isoforms with shRNA knock-down in mouse hippocampus and with novel isoform-selective drugs to dissect their roles in LTD. Using electrophysiological and live imaging approaches, we find that GSK3 alpha, but not GSK3 beta, is required for LTD. The specific engagement of GSK3 alpha occurs via its transient anchoring in dendritic spines during LTD induction. We find that the major GSK3 substrate, the microtubule-binding protein tau, is required for this spine anchoring of GSK3 alpha and mediates GSK3 alpha-induced LTD. These results link GSK3 alpha and tau in a common mechanism for synaptic depression and rule out a major role for GSK3 beta in this process.