Alterations in P-CREB activity: A pathway for FAS related neurotoxiticity

Abstract

NEUROTOXITICITY ROBIN ROBERSON, IRENE CAMERONI, LAURA TOSO, DANIEL ABEBE, STEPHANIE BISSELL, CATHERINE SPONG, National Institutes of Health (NIH), Unit on Perinatal and Develomental Neurobiology, NICHD&NIAAA, Bethesda, Maryland, University of Milano-Bicocca, Obstetrics and Gynecology, Monza, Milan, Italy OBJECTIVE: Fetal alcohol syndrome (FAS) is the leading cause of a spectrum of preventable non-genetic learning disorders. In the adult, neurogenesis occurs in the hippocampal dentate gyrus, which is thought to be important for learning and memory. Previously we have shown alterations in the NMDA receptor underlie some of the learning abnormalities in FAS. NMDA exerts it action through CREB. CREB is a transcription factor that controls gene expression via phosphorylation promoting neuronal survival. Using a model for FAS, we measured P-CREB levels in hippocampal subregions to evaluate if alterations in P-CREB underlie the FAS learning abnormalities after in utero alcohol exposure. STUDY DESIGN: Pregnant C57Bl6/J mice were treated on gestational day 8 with alcohol, n = 10 or control (saline) n = 5. Adult males were assessed in the Morris water maze for learning on days 50-56. On day 57, 5 males/ treatment were perfused for immunohistochemistry, and stained with SER 144 P-CREB antibody with relative densities of staining assessed using NIH Image software. Statistical analysis ANOVA, P!.05 significant. RESULTS: The hippocampal areas CA1, dentate and CA3 were quantitated. In the control, P-CREB staining was greatest in dentate granule cells and lowest in CA1. In all of the hippocampal subregions, alcohol exposure in utero resulted in significant downregulation of P-CREB (P!.001).