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Developmental Selective GSK3α Inhibition Rescues Working Memory Deficits in a Mouse Model of Schizophrenia
Johannes Passecker1,2,3, Chloe M Aloimonos1, Aleksandra Dagunts1
1Integrative Neuroscience Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Complex Psychiatry
|December 1, 2025
Summary
Early postnatal treatment with a selective GSK3α inhibitor improved working memory and exploratory behavior in a mouse model of 22q11.2 deletion syndrome, offering a potential therapeutic strategy for cognitive deficits.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- 22q11.2 deletion syndrome causes cognitive deficits and increases schizophrenia risk.
- Current treatments lack efficacy and have side effects.
- GSK3 inhibitors show promise but nonselective ones have toxicity concerns.
Purpose of the Study:
- To evaluate a novel GSK3α-selective inhibitor for treating cognitive deficits in a 22q11.2 deletion syndrome mouse model.
- To assess the inhibitor's effects on spatial working memory and behavior.
Main Methods:
- Utilized the Df(16)A+/- mouse model.
- Administered a GSK3α-selective inhibitor during early postnatal development (P7-P28).
- Assessed spatial working memory and approach-avoidance behavior in adult mice.
Main Results:
- Early GSK3α inhibition restored spatial working memory in Df(16)A+/- mice.
- Heightened exploratory behavior in Df(16)A+/- mice was normalized by GSK3α inhibition.
- Effects were observed in a genotype-independent manner.
Conclusions:
- Paralog-selective GSK3α inhibition is a feasible and effective strategy.
- This approach shows potential for rescuing cognitive function in neurodevelopmental disorders.
- Further research into GSK3α inhibitors for 22q11.2 deletion syndrome is warranted.
