Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Madrid, Spain.
Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
EMBO J. 2021 Jan 15;40(2):e105513. doi: 10.15252/embj.2020105513. Epub 2020 Nov 16.
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, GSK3β, 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 GSK3α, but not GSK3β, is required for LTD. The specific engagement of GSK3α 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 GSK3α and mediates GSK3α-induced LTD. These results link GSK3α and tau in a common mechanism for synaptic depression and rule out a major role for GSK3β in this process.
糖原合酶激酶-3（GSK3）是大脑中一种重要的信号蛋白，调节着不同形式的突触可塑性。GSK3 的神经元功能通常归因于其两种同工酶之一的 GSK3β，仅仅是因为它在大脑中广泛表达。因此，GSK3 同工酶在突触可塑性中的特异性功能尚未得到充分探索。我们现在直接针对海马体中的 NMDA 受体依赖性长时程抑制（LTD）来解决这个问题。在这里，我们使用 shRNA 敲低在小鼠海马体中的特定靶向 GSK3 同工酶，以及新型同工酶选择性药物来剖析它们在 LTD 中的作用。通过电生理和活体成像方法，我们发现 GSK3α，而不是 GSK3β，是 LTD 所必需的。GSK3α 的特异性结合是通过 LTD 诱导期间其在树突棘中的瞬时锚定来实现的。我们发现，微管结合蛋白 tau 是 GSK3α 这种树突棘锚定所必需的，并且介导 GSK3α 诱导的 LTD。这些结果将 GSK3α 和 tau 联系在一个共同的突触抑制机制中，并排除了 GSK3β 在这个过程中的主要作用。
