Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome

• Main Authors: McCamphill, Patrick K. (Author), Stoppel, Laura J. (Author), Senter, Rebecca K. (Author), Lewis, Michael C. (Author), Heynen, Arnold J. (Author), Stoppel, David C. (Author), Sridhar, Vinay (Author), Collins, Katie A. (Author), Shi, Xi (Author), Pan, Jen Q. (Author), Madison, Jon (Author), Cottrell, Jeffrey R. (Author), Huber, Kimberly M. (Author), Scolnick, Edward M. (Author), Holson, Edward B. (Author), Wagner, Florence F. (Author), Bear, Mark F. (Author)
• Format: Article
• Language: English
• Published: American Association for the Advancement of Science (AAAS), 2022-03-14T18:03:06Z.
• Subjects: Article
• Online Access: Get fulltext

 Copyright © 2020 The Authors, some rights reserved. 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.