Alcohol in Neocortex Development and Plasticity

描述：胎儿酒精综合征（FAS）以星座为特征

DESCRIPTION: Fetal alcohol syndrome (FAS) is characterized by a constellation of behavioral and physiological abnormalities in children, including learning, sensory and motor deficits. There is growing evidence that abnormalities of neocortical function and plasticity underlie these deficits. However, the cellular and molecular mechanisms by which prenatal alcohol exposure disrupts neocortical development remain elusive. Neuronal electrophysiological activity involving the N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to have a critical function in the circuit rearrangements that characterize the developing sensory neocortex. Moreover, inflow of calcium through the NMDA receptor activates the transcription factor cAMP/Calcium-dependent response element binding protein (CREB), which regulates gene expression required in neural plasticity. Alcohol is known to block NMDA receptors and there is increasing evidence that CREB activation is reduced following chronic alcohol exposure. The proposed studies will examine a series of interrelated hypotheses focused on effects of alcohol on NMDA receptor- and CREB-dependent mechanisms of neocortical development and plasticity. The studies will use molecular techniques, including in vivo antisense techniques and viral vectors for gene transfer, to examine the molecular mechanisms by which alcohol disrupts cortical development and plasticity. The first goal is to characterize abnormalities of function in sensory neocortex of animals exposed to alcohol during the third trimester equivalent of human gestation. Animals will be studied electrophysiologically and behaviorally following a period of one alcohol-free month. The second goal is to examine whether effects of alcohol on NMDA receptors underlie the disruption of cortical development. Alcohol is known to decrease, but not completely block, NMDA receptor function. Similarly to alcohol, antisense DNA suppresses but does not block cortical NMDA receptor function. Therefore, antisense DNA injected intracortically will be used to verify whether a partial blockade of cortical NMDA receptor function is sufficient to disrupt cortical development. The third goal of these studies is to elucidate whether reduction of CREB activation underlies the decreased cortical plasticity in FAS. To examine this hypothesis, a herpes simplex viral vector will be used to induce overexpression of CREB, compensating for the downregulation caused by the chronic alcohol treatment. Electrophysiological recordings will then be used to determine whether cortical plasticity is restored to its normal level by the overexpression of CREB. Finally, these studies will examine whether alcohol affects development of peripheral sites that influence cortical development. The visual cortex will be used as a model in these studies because it has been the most studied area of the neocortex. Moreover, visual cortical plasticity is thought to share some basic mechanisms with learning and memory, and there is substantial evidence that NMDA receptors and CREB are involved in this type of plasticity. The studies on this system should assess the effects of alcohol on prenatal cortical plasticity in general and the results should not be restricted to the visual cortex. This information may one day contribute to devise therapeutic interventions that will prevent or alleviate morbidity in FAS.