GSK-3 as a Therapeutic Target for FASD

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Research Component 3 will investigate glycogen synthase kinase-3 (GSK-3) as a potential therapeutic target in FASD. Studies outlined in this proposal will test the hypothesis that inhibition of GSK-3 activity reverses deficits in adult hippocampal neurogenesis and associated learning behaviors in a mouse model of moderate fetal alcohol spectrum disorder (FASD). Although originally discovered as a key metabolic regulator, GSK-3 has experienced resurgence in research interest due to its ability to regulate multiple signaling processes in the developing and adult CNS. Furthermore, GSK-3 inhibition has been shown to have therapeutic effects in a wide array of neurological and neurodevelopmental disorders, including developmental alcohol toxicity. GSK-3 inhibition has been shown to exert therapeutic benefits in preclinical rodent models of stroke, Alzheimer's disease, bipolar disorder, and schizophrenia. The current proposal is based, in part, on published studies performed in collaboration with Dr. Allan's laboratory demonstrating that GSK-3 inhibition restores adult hippocampal neurogenesis and associated learning behaviors in a genetic mouse model of fragile x syndrome. Based on these findings, we hypothesize that GSK-3 inhibition also restores learning and neurogenic defects in our mouse model of moderate FASD. We will test this hypothesis using a combination of pharmacological and genetic approaches. Specifically, we propose to determine whether GSK-3P expression patterns are altered in adult hippocampus of FASD mice (Specific Aim 1), whether pharmacological inhibition of GSK-3 activity restores neurogenesis and improves functional plasticity of newborn granule neurons (Specific Aim 2) and whether inducible and selective gene deletion of GSK-3P in adult hippocampal progenitors improves neurogenesis and learning (Specific Aim 3). If successful, these studies will broaden our understanding of both FASD and GSK-3 mechanisms in adult neurogenesis, and could lead to identification of a novel therapeutic target for improving hippocampal function and reversing behavioral deficits in clinical FASD.