The long-term goals of our laboratory are to understand the molecular mechanisms for the neurotoxic effects of ethanol on the developing brain. Alcohol consumption by pregnant women can result in intrauterine fetal neurotoxicity, i.e. fetal alcohol syndrome (FAS), with sequelae in affected children including hyperactivity, learning disorders, mental retardation, depression, and psychosis. Previous pharmacological evidence has implicated N-methyl-D-aspartate (NMDA) receptor inhibition as an important direct effect of ethanol, and increased sensitivity to the sedative effect of ethanol occurs with mutations in the cAMP second messenger pathway in drosophila. We will utilize mice genetically deficient in the calcium-stimulated adenylyl cyclases type I (AC1) and VIII (AC8), important mediators of N-methyl-D-aspartate (NMDA) receptor signaling, to determine if alteration in mammalian AC function modulates ethanol sensitivity in vivo.
The specific aims of this proposal will test the hypotheses that AC1 and/or AC8 deficiency results in 1) increased sensitivity to the apoptotic actions of ethanol during the synaptogenesis period of brain development; increase in sensitivity to the NMDA receptor antagonist component of ethanol action; and 3) greater long-term behavioral deficits for similar degrees of ethanol-mediated neuronal death in the perinatal period.] The results of these genetic, pharmacological, and molecular biological studies will further elucidate the molecular mechanisms by which ethanol alters neuronal physiology and survival and provide the basis for considering isoform-specific modulation of AC function as a therapeutic target for fetal alcohol syndrome.
