Neuronal Cell Migration in Fetal Alcohol Syndrome

Abstract

Maternal alcohol consumption during pregnancy can cause serious birth defects, of which fetal alcohol syndrome (FAS) is the most devastating. Recognized by characteristic craniofacial abnormalities and growth deficiency, this condition produces severe alcohol-induced damage in the developing brain. FAS children experience ataxia, deficits in intellectual functioning, difficulties in learning, memory, problem-solving, and attention. Multiple aspects of central nervous system development can be affected by alcohol exposure, but the most striking abnormalities are in neuronal cell migration. Although the cellular mechanisms by which alcohol affects the migration of immature neurons are not fully understood, recent studies reveal that Ca2+ signaling and cyclic nucleotide signaling are the central targets of alcohol action in neuronal cell migration. An acute administration of ethanol reduces the frequency of transient Ca2+ elevations in migrating neurons and cGMP levels, and increases cAMP levels. Experimental manipulations of these second messenger pathways, through stimulating Ca2+ and cGMP signaling or inhibiting cAMP signaling, completely reverses the action of ethanol on neuronal cell migration in vitro as well as in vivo. Each second-messenger has multiple but distinct downstream targets, including CaMKII, calcineurin, PP1, Rho GTPase, MAPK, and PI3K. Therefore, the aberrant migration of immature neurons in the fetal brain caused by maternal alcohol consumption may be corrected by controlling the activity of these second-messenger pathways. In this chapter, using cerebellar granule cell migration as a model system, we first describe how alcohol exposure impairs the migration of immature neurons, and then discuss the signaling mechanisms involved.