Maternal intake of ethanol (EtOH) during pregnancy is detrimental to human fetal development. Principal features of the Fetal Alcohol Syndrome (FAS), which affects offspring of alcoholic mothers, include central nervous system dysfunctions (microencephaly, mental retardation), growth deficiency and particular facial characteristics. The mechanisms(s) involved in the neurotoxic effects of EtOH during development remain elusive. In this project, we propose to test the hypothesis that the brain phosphoinositide system coupled to the muscarinic cholinergic receptors represents a likely and relevant target for the developmental neurotoxicity of EtOH. Membrane phosphoinositides which are hydrolyzed upon activation of a variety of receptors leading to changes in intracellular calcium and activation of protein kinase C, exert profound influences on nervous system functions. In particular, the muscarinic receptor-stimulated phosphoinositide metabolism appears to play a primary role in the developing nervous system. Preliminary in vitro and in vivo data suggest that this system is affected by EtOH in a concentration-, time-, age-, neurotransmitter- and brain region-dependent manner. Studies included in this proposal will address the hypothesis that inhibition of muscarinic receptor-stimulated phosphoinositide metabolism is correlated with EtOH-induced microencephaly in a dose- and age-dependent manner; that regional differences exist in the effects of EtOH, and that these are related to the subtype of muscarinic receptor present and its coupling to inositol metabolism; that the effect of EtOH is due to its interaction with the coupling of muscarinic receptors with phospholipase C; and that this action will lead to a diminished ability of acetylcholine to mobilize intracellular calcium. It is expected that these studies will provide information relevant for gaining a better understanding of a potentially relevant target for the neurotoxicity of EtOH as well as the molecular features of phosphoinositide metabolism in the developing brain.
Showing the most recent 10 out of 52 publications
