McCamphill Patrick K, Stoppel Laura J, Senter Rebecca K, Lewis Michael C, Heynen Arnold J, Stoppel David C, Sridhar Vinay, Collins Katie A, Shi Xi, Pan Jen Q, Madison Jon, Cottrell Jeffrey R, Huber Kimberly M, Scolnick Edward M, Holson Edward B, Wagner Florence F, Bear Mark F
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Sci Transl Med. 2020 May 20;12(544). doi: 10.1126/scitranslmed.aam8572.
Fragile X syndrome is caused by gene silencing and loss of the encoded fragile X mental retardation protein (FMRP), which binds to mRNA and regulates translation. Studies in the mouse model of fragile X syndrome indicate that aberrant cerebral protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5) signaling contributes to disease pathogenesis, but clinical trials using mGluR5 inhibitors were not successful. Animal studies suggested that treatment with lithium might be an alternative approach. Targets of lithium include paralogs of glycogen synthase kinase 3 (GSK3), and nonselective small-molecule inhibitors of these enzymes improved disease phenotypes in a fragile X syndrome mouse model. However, the potential therapeutic use of GSK3 inhibitors has been hampered by toxicity arising from inhibition of both α and β paralogs. Recently, we developed GSK3 inhibitors with sufficient paralog selectivity to avoid a known toxic consequence of dual inhibition, that is, increased β-catenin stabilization. We show here that inhibition of GSK3α, but not GSK3β, corrected aberrant protein synthesis, audiogenic seizures, and sensory cortex hyperexcitability in mice. Although inhibiting either paralog prevented induction of NMDA receptor-dependent long-term depression (LTD) in the hippocampus, only inhibition of GSK3α impaired mGluR5-dependent and protein synthesis-dependent LTD. Inhibition of GSK3α additionally corrected deficits in learning and memory in mice; unlike mGluR5 inhibitors, there was no evidence of tachyphylaxis or enhanced psychotomimetic-induced hyperlocomotion. GSK3α selective inhibitors may have potential as a therapeutic approach for treating fragile X syndrome.
脆性X综合征是由基因沉默和编码的脆性X智力低下蛋白（FMRP）缺失引起的，该蛋白与mRNA结合并调节翻译。脆性X综合征小鼠模型的研究表明，代谢型谷氨酸受体5（mGluR5）信号下游的异常脑蛋白合成促成了疾病的发病机制，但使用mGluR5抑制剂的临床试验未获成功。动物研究表明，锂治疗可能是一种替代方法。锂的作用靶点包括糖原合酶激酶3（GSK3）的旁系同源物，这些酶的非选择性小分子抑制剂改善了脆性X综合征小鼠模型的疾病表型。然而，GSK3抑制剂的潜在治疗用途因抑制α和β旁系同源物而产生的毒性而受到阻碍。最近，我们开发了具有足够旁系同源物选择性的GSK3抑制剂，以避免双重抑制的已知毒性后果，即β-连环蛋白稳定性增加。我们在此表明，抑制GSK3α而非GSK3β可纠正小鼠异常的蛋白合成听源性癫痫发作和感觉皮层过度兴奋。虽然抑制任何一种旁系同源物都可阻止海马体中NMDA受体依赖性长时程抑制（LTD）的诱导，但只有抑制GSK3α会损害mGluR5依赖性和蛋白合成依赖性LTD。抑制GSK3α还可纠正小鼠学习和记忆方面的缺陷；与mGluR5抑制剂不同，没有证据表明会出现快速耐受性或精神模拟物诱导的运动亢进增强。GSK3α选择性抑制剂可能有潜力作为治疗脆性X综合征的一种治疗方法。
