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INTRODUCTION: The 22q11.2 deletion syndrome is a genetic disorder characterized by pronounced age-dependent emergence of learning and cognitive deficits, including working memory and anxiety-related symptoms. The deletion confers a 20-fold increased risk of a schizophrenia diagnosis, but there are currently no approved pharmacological therapies for this condition. We have previously shown that treatment with a glycogen synthase kinase 3 (GSK3) paralog-nonselective inhibitor during early postnatal development rescues working memory task acquisition in the mouse model of the 22q11.2 deletion. However, GSK3 paralog-nonselective inhibitors are associated with significant toxicological side effects, limiting their therapeutic potential. Here, we build upon this work by testing a newly developed ³Ò³§°­3α paralog-selective inhibitor with less potential for toxicological challenges.METHODS: Using the mouse model, we evaluated the effects of ³Ò³§°­3α inhibition on spatial working memory and approach-avoidance behavior.RESULTS: We found that early postnatal ³Ò³§°­3α inhibition from postnatal day 7 (P7) to P28 restored spatial working memory performance in adult mice under conditions of increased working memory demand. Additionally, we observed heightened exploratory behavior in mice that was reverted to baseline levels by ³Ò³§°­3α inhibition in a genotype-independent manner.CONCLUSION: Overall, we provide evidence supporting the feasibility and effectiveness of paralog-selective ³Ò³§°­3α inhibition-mediated rescue of cognitive function in a model of altered neurodevelopment.