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Updated: Dec 21, 2025
Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome
Patrick K McCamphill1, Laura J Stoppel1, Rebecca K Senter1
1Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract:
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 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 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 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.
Insights
Selective inhibition of GSK3α, but not GSK3β, corrected fragile X syndrome (FXS) phenotypes in mice. This approach offers a promising therapeutic strategy for FXS, avoiding toxic side effects associated with dual inhibition.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Fragile X syndrome (FXS) results from FMR1 gene silencing and loss of fragile X mental retardation protein (FMRP), leading to aberrant cerebral protein synthesis.
- Previous attempts targeting metabotropic glutamate receptor 5 (mGluR5) signaling were unsuccessful in clinical trials.
- Lithium and nonselective glycogen synthase kinase 3 (GSK3) inhibitors showed promise in animal models but were limited by toxicity from dual paralog inhibition.
Purpose of the Study:
- To investigate the therapeutic potential of selective GSK3 paralog inhibitors for FXS.
- To determine if selective inhibition of GSK3α or GSK3β can correct FXS-associated phenotypes in the Fmr1 mouse model.
Main Methods:
- Utilized a selective GSK3α inhibitor and a selective GSK3β inhibitor in the Fmr1 mouse model of FXS.
- Assessed correction of aberrant protein synthesis, audiogenic seizures, sensory cortex hyperexcitability, and long-term depression (LTD) in the hippocampus.
- Evaluated effects on learning and memory, and potential for tachyphylaxis or psychotomimetic-induced hyperlocomotion.
Main Results:
- Selective inhibition of GSK3α, but not GSK3β, corrected aberrant protein synthesis, audiogenic seizures, and sensory cortex hyperexcitability in Fmr1 mice.
- GSK3α inhibition, but not GSK3β inhibition, specifically impaired mGluR5-dependent and protein synthesis-dependent LTD.
- GSK3α inhibition corrected learning and memory deficits without inducing tachyphylaxis or psychotomimetic side effects observed with mGluR5 inhibitors.
Conclusions:
- Selective inhibition of GSK3α represents a potential therapeutic strategy for fragile X syndrome.
- Targeting GSK3α offers a more specific and potentially safer approach compared to nonselective GSK3 inhibitors or mGluR5 inhibitors.
