Supplementary Material for: Developmental selective GSK3α inhibition rescues working memory deficits in a mouse model of schizophrenia predisposition

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-non-selective inhibitor during early postnatal development rescues working memory task acquisition in the Df(16)A+/− mouse model of the 22q11.2 deletion. However, GSK3 paralog-non-selective inhibitors are associated with significant toxicological side effects, limiting their therapeutic potential. Here, we build upon this work by testing a newly developed GSK3α paralog-selective inhibitor with less potential for toxicological challenges. Using the Df(16)A+/− mouse model, we evaluated the effects of GSK3α inhibition on spatial working memory and approach-avoidance behavior. We found that early postnatal GSK3α inhibition from postnatal day 7 (P7) to P28 restored spatial working memory performance in adult Df(16)A+/− mice under conditions of increased working memory demand. Additionally, we observed heightened exploratory behavior in Df(16)A+/− mice that was reverted to baseline levels by GSK3α inhibition in a genotype-independent manner. Overall, we provide evidence supporting the feasibility and effectiveness of paralog-selective GSK3α inhibition-mediated rescue of cognitive function in a model of altered neurodevelopment.