Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome.
Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome.
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DOI：
10.1126/scitranslmed.aam8572
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发表时间：
2020-05-20
影响因子：
17.1
通讯作者：
Bear MF
中科院分区：
文献类型：
--
作者：
McCamphill PK;Stoppel LJ;Senter RK;Lewis MC;Heynen AJ;Stoppel DC;Sridhar V;Collins KA;Shi X;Pan JQ;Madison J;Cottrell JR;Huber KM;Scolnick EM;Holson EB;Wagner FF;Bear MF
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.
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影响因子：
3
作者：
Choi CH;Schoenfeld BP;Bell AJ;Hinchey J;Rosenfelt C;Gertner MJ;Campbell SR;Emerson D;Hinchey P;Kollaros M;Ferrick NJ;Chambers DB;Langer S;Sust S;Malik A;Terlizzi AM;Liebelt DA;Ferreiro D;Sharma A;Koenigsberg E;Choi RJ;Louneva N;Arnold SE;Featherstone RE;Siegel SJ;Zukin RS;McDonald TV;Bolduc FV;Jongens TA;McBride SM
通讯作者：
McBride SM
影响因子：
7.3
作者：
Cosford, NDP;Tehrani, L;Varney, MA
通讯作者：
Varney, MA
影响因子：
4.8
作者：
Bradley CA;Peineau S;Taghibiglou C;Nicolas CS;Whitcomb DJ;Bortolotto ZA;Kaang BK;Cho K;Wang YT;Collingridge GL
通讯作者：
Collingridge GL
影响因子：
17.1
作者：
Berry-Kravis, Elizabeth;Portes, Vincent Des;von Raison, Florian
通讯作者：
von Raison, Florian
影响因子：
11.8
作者：
Doble, Bradley W.;Patel, Satish;Woodgett, James R.
通讯作者：
Woodgett, James R.