Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome
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Updated: Jun 19, 2026
Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
Christopher J Yuskaitis1, Marjelo A Mines, Margaret K King
1Department of Psychiatry and Behavioral Neurobiology, 1720 7th Ave South, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA. cjy@uab.edu
Abstract:
Fragile X syndrome (FXS), the most common form of inherited mental retardation and a genetic cause of autism, results from mutated fragile X mental retardation-1 (Fmr1). This study examined the effects on glycogen synthase kinase-3 (GSK3) of treatment with a metabotropic glutamate receptor (mGluR) antagonist, MPEP, and the GSK3 inhibitor, lithium, in C57Bl/6 Fmr1 knockout mice. Increased mGluR signaling may contribute to the pathology of FXS, and the mGluR5 antagonist MPEP increased inhibitory serine-phosphorylation of brain GSK3 selectively in Fmr1 knockout mice but not in wild-type mice. Inhibitory serine-phosphorylation of GSK3 was lower in Fmr1 knockout, than wild-type, mouse brain regions and was increased by acute or chronic lithium treatment, which also increased hippocampal brain-derived neurotrophic factor levels. Fmr1 knockout mice displayed alterations in open-field activity, elevated plus-maze, and passive avoidance, and these differences were ameliorated by chronic lithium treatment. These findings support the hypothesis that impaired inhibition of GSK3 contributes to the pathogenesis of FXS and support GSK3 as a potential therapeutic target.
Insights
Fragile X syndrome (FXS) involves impaired inhibition of glycogen synthase kinase-3 (GSK3). Lithium treatment improved behavioral deficits and increased GSK3 inhibition in Fmr1 knockout mice, suggesting GSK3 as a therapeutic target for FXS.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and a genetic factor in autism.
- FXS results from mutations in the fragile X mental retardation-1 (Fmr1) gene.
- Aberrant metabotropic glutamate receptor (mGluR) signaling is implicated in FXS pathology.
Purpose of the Study:
- To investigate the impact of mGluR antagonism and GSK3 inhibition on GSK3 signaling in a mouse model of FXS.
- To explore the therapeutic potential of targeting GSK3 in FXS.
Main Methods:
- Utilized C57Bl/6 Fmr1 knockout mice and wild-type littermates.
- Administered MPEP (mGluR5 antagonist) and lithium (GSK3 inhibitor).
- Assessed GSK3 inhibitory serine-phosphorylation, brain-derived neurotrophic factor (BDNF) levels, and behavioral outcomes (open-field, elevated plus-maze, passive avoidance).
Main Results:
- MPEP selectively increased inhibitory GSK3 phosphorylation in Fmr1 knockout mice.
- Basal inhibitory GSK3 phosphorylation was lower in Fmr1 knockout mice compared to wild-type.
- Lithium treatment increased inhibitory GSK3 phosphorylation and BDNF levels, and ameliorated behavioral alterations in Fmr1 knockout mice.
Conclusions:
- Impaired inhibition of GSK3 is a key factor in the pathogenesis of FXS.
- Targeting GSK3, potentially through lithium treatment, shows promise as a therapeutic strategy for FXS.
- These findings highlight GSK3 as a viable therapeutic target for FXS.
