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Updated: Jan 9, 2026
Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
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.
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 Df(16)A +/- 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 GSK3α paralog-selective inhibitor with less potential for toxicological challenges.
Methods:
Using the Df(16)A +/- mouse model, we evaluated the effects of GSK3α inhibition on spatial working memory and approach-avoidance behavior.
Results:
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.
Conclusion:
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.
