Fragile X syndrome is caused by FMR1 gene silencing and loss of the encoded fragile X mental retardation protein (FMRP), which binds to mRNA and regulates translation. Studies in the Fmr1-/y 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 Fmr1-/y 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 Fmr1-/y 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.

中文翻译：

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选择性抑制糖原合成酶激酶 3α 可纠正脆性 X 综合征小鼠模型的病理生理学。


脆性 X 综合征是由 FMR1 基因沉默和编码的脆性 X 智力迟钝蛋白 (FMRP) 丢失引起的，FMRP 与 mRNA 结合并调节翻译。对脆性 X 综合征的 Fmr1-/y 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有助于疾病发病机制，但使用 mGluR5 抑制剂的临床试验并不成功。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成酶激酶 3 (GSK3) 的旁系同源物，这些酶的非选择性小分子抑制剂可改善脆性 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受到抑制 α 和 β 旁系同源物产生的毒性的阻碍。最近，我们开发了具有足够旁系同源选择性的 GSK3 抑制剂，以避免双重抑制的已知毒性后果，即增加 β-连环蛋白稳定性。我们在此表明​​，抑制 GSK3α（而非 GSK3β）可以纠正 Fmr1-/y 小鼠的异常蛋白质合成、听源性癫痫发作和感觉皮层过度兴奋。虽然抑制任一旁系同源物可以阻止海马中 NMDA 受体依赖性长期抑制 (LTD) 的诱导，但仅抑制 GSK3α 就会损害 mGluR5 依赖性和蛋白质合成依赖性 LTD。抑制 GSK3α 还可纠正 Fmr1-/y 小鼠的学习和记忆缺陷；与 mGluR5 抑制剂不同，没有证据表明存在快速耐受或增强拟精神病药引起的过度运动。 GSK3α 选择性抑制剂可能具有作为治疗脆性 X 综合征的潜力。