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.

Public Health Relevance

Fetal alcohol spectrum disorder is associated with deficits in learning and memory. This project will investigate the potential utility of manipulating the activity of an enzyme (glycogen synthase kinase-3) as a novel therapeutic intervention against these deficits.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZAA1-GG (50))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of New Mexico Health Sciences Center
United States
Zip Code
Kenton, Johnny A; Castillo, Rebecca; Holmes, Andrew et al. (2018) Cortico-hippocampal GluN2B is essential for efficient visual-spatial discrimination learning in a touchscreen paradigm. Neurobiol Learn Mem 156:60-67
Thompson, Shannon M; Berkowitz, Laura E; Clark, Benjamin J (2018) Behavioral and Neural Subsystems of Rodent Exploration. Learn Motiv 61:3-15
Clark, Benjamin J; Simmons, Christine M; Berkowitz, Laura E et al. (2018) The retrosplenial-parietal network and reference frame coordination for spatial navigation. Behav Neurosci 132:416-429
van Erp, Theo G M; Walton, Esther; Hibar, Derrek P et al. (2018) Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium. Biol Psychiatry 84:644-654
Bird, C W; Baculis, B C; Mayfield, J J et al. (2018) The brain-derived neurotrophic factor VAL68MET polymorphism modulates how developmental ethanol exposure impacts the hippocampus. Genes Brain Behav :e12484
Gustus, Kymberly C; Li, Lu; Chander, Praveen et al. (2018) Genetic inactivation of synaptosomal-associated protein 25 (SNAP-25) in adult hippocampal neural progenitors impairs pattern discrimination learning but not survival or structural maturation of newborn dentate granule cells. Hippocampus 28:735-744
Bird, Clark W; Taylor, Devin H; Pinkowski, Natalie J et al. (2018) Long-term Reductions in the Population of GABAergic Interneurons in the Mouse Hippocampus following Developmental Ethanol Exposure. Neuroscience 383:60-73
Hamidovic, Ajna; Candelaria, Lionel; Rodriguez, Ihsan et al. (2018) Learning and memory performance following acute intranasal insulin administration in abstinent smokers. Hum Psychopharmacol 33:e2649
Harvey, Ryan E; Rutan, Stephanie A; Willey, Gabrielle R et al. (2018) Linear Self-Motion Cues Support the Spatial Distribution and Stability of Hippocampal Place Cells. Curr Biol 28:1803-1810.e5
Varaschin, Rafael K; Allen, Nyika A; Rosenberg, Martina J et al. (2018) Prenatal Alcohol Exposure Increases Histamine H3 Receptor-Mediated Inhibition of Glutamatergic Neurotransmission in Rat Dentate Gyrus. Alcohol Clin Exp Res 42:295-305

Showing the most recent 10 out of 46 publications