The neurodevelopmental effects of ethanol toxicity on axonal growth cones and the cell adhesion molecule L1

Ethanol toxicity in utero is a common cause of mental retardation. Although extensive neuronal death has been previously noted, surprisingly little is known about the surviving neurons and their contributions to fetal alcohol syndrome (FAS). The neuropathology of FAS is remarkably similar to that caused by mutations of the cell adhesion molecule, L1, which is critical for axonal outgrowth, fasciculation, migration and growth cone guidance. Axonal growth cones respond to guidance cues in order to initiate and maintain targeted growth and synapse formation. Here it is shown that at physiological concentrations, ethanol arrests cell motility and inhibits axonal growth cones' responses to semaphorin3A (sema3A), an L1-dependent guidance cue, as well as to lysophosphatidic acid (LPA) and netrin, L1-independent cues. It is proposed, therefore, that ethanol impairs L1 functions not by specifically binding L1, but by disrupting plasma membrane organization required for the normal function of L1 and guidance cues.