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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
1P50AA022534-01
Application #
8600487
Study Section
Special Emphasis Panel (ZAA1-GG (50))
Project Start
2014-08-05
Project End
2019-06-30
Budget Start
2014-08-05
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$212,502
Indirect Cost
$71,772
Name
University of New Mexico Health Sciences Center
Department
Type
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Sanchez, Joshua J; Noor, Shahani; Davies, Suzy et al. (2017) Prenatal alcohol exposure is a risk factor for adult neuropathic pain via aberrant neuroimmune function. J Neuroinflammation 14:254
Cunningham, Lee Anna; Newville, Jessie; Li, Lu et al. (2017) Prenatal Alcohol Exposure Leads to Enhanced Serine 9 Phosphorylation of Glycogen Synthase Kinase-3? (GSK-3?) in the Hippocampal Dentate Gyrus of Adult Mouse. Alcohol Clin Exp Res 41:1907-1916
Izquierdo, A; Brigman, J L; Radke, A K et al. (2017) The neural basis of reversal learning: An updated perspective. Neuroscience 345:12-26
BolaƱos, Alfredo D; Coffman, Brian A; Candelaria-Cook, Felicha T et al. (2017) Altered Neural Oscillations During Multisensory Integration in Adolescents with Fetal Alcohol Spectrum Disorder. Alcohol Clin Exp Res 41:2173-2184
Varaschin, Rafael K; Allen, Nyika A; Rosenberg, Martina J et al. (2017) Prenatal Alcohol Exposure Increases Histamine H3 Receptor-Mediated Inhibition of Glutamatergic Neurotransmission in Rat Dentate Gyrus. Alcohol Clin Exp Res :
Hamidovic, Ajna (2017) Targeting Mediators of Smoking Persistence with Intranasal Insulin. Front Pharmacol 8:706
Newville, Jessie; Valenzuela, Carlos Fernando; Li, Lu et al. (2017) Acute oligodendrocyte loss with persistent white matter injury in a third trimester equivalent mouse model of fetal alcohol spectrum disorder. Glia 65:1317-1332
Noor, Shahani; Sanchez, Joshua J; Vanderwall, Arden G et al. (2017) Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels. Brain Behav Immun 61:80-95
Marquardt, Kristin; Sigdel, Rahul; Brigman, Jonathan L (2017) Touch-screen visual reversal learning is mediated by value encoding and signal propagation in the orbitofrontal cortex. Neurobiol Learn Mem 139:179-188
Morton, Russell A; Valenzuela, C Fernando (2016) Further characterization of the effect of ethanol on voltage-gated Ca(2+) channel function in developing CA3 hippocampal pyramidal neurons. Brain Res 1633:19-26

Showing the most recent 10 out of 29 publications