Fetal alcohol syndrome and related disorders occur in approximately 1% of births in the U.S. and are the leading non-genetic cause of mental retardation. A major gap in our knowledge is lack of understanding of the effect of alcohol on the relationship between neurons and glia. To address this gap, we are investigating the role of glia in alcohol-mediated neurotoxicity, with a specific focus on communication between microglial cells and cerebellar neurons. Our pilot studies in the neonatal rat model of alcohol exposure revealed a single dose of alcohol caused approximately 40% loss of microglia. In cultures, we found that moderate levels of alcohol inhibited proliferation and produced significant microglial death. In addition, these studies identified the peroxisome proliferator activated receptor gamma (PPARgamma) signaling pathway as a specific target of alcohol in microglia and demonstrated effective prevention of alcohol-induced microglial death with a pharmacologic agonist of PPARgamma. Analyses of co-cultures of microglia and cerebellar granule cells demonstrated that microglia actively protect neurons from alcohol-induced death and also prevent alcohol-induced neurite loss. These findings suggest that microglia in the developing brain may provide protection for neurons against alcohol toxicity, and that the dramatic loss of microglia in vivo during alcohol exposure may contribute to neuronal vulnerability to alcohol. We will investigate the hypothesis that alcohol toxicity in microglia in the developing brain can be blocked by activation of PPARgamma, with preservation of microglial neuroprotective activity. The complementary in vivo (neonatal rat model of fetal alcohol exposure) and in vitro (purified cultures of microglia and cerebellar granule cells from neonatal rat) models used in the pilot studies will be employed to test this hypothesis. We will evaluate the ability of PPARgamma agonists to prevent alcohol toxicity in vivo, including loss of microglia, granule cells and Purkinje cells. The neuroprotective factors secreted by microglia will be identified. The potential effect of PPARgamma activation on microglial production of protective factors will be determined. Results of these studies will provide the first understanding of the potential neuroprotective role of microglia during prenatal alcohol exposure and the involvement of the PPARy signal transduction pathway in alcohol toxicity. Application of this knowledge may provide new therapeutic strategies for prevention or treatment of the neuropathology associated with prenatal alcohol exposure.