Genetic Analysis of Ethanol Sensitivity in Mice

描述(申请人提供)：我们实验室的长期目标是 了解乙醇神经毒性作用的分子机制 发育中的大脑。孕妇饮酒会导致 胎儿神经毒性，即胎儿酒精综合征(Fas)， 受影响儿童的后遗症包括多动，学习障碍， 智力低下、抑郁和精神错乱。以前的药理作用 有证据表明，N-甲基-D-天冬氨酸(NMDA)受体抑制是一种 乙醇的重要直接作用，以及对镇静剂的敏感性增加 乙醇的作用与cAMP第二信使通路的突变有关 果蝇。我们将利用基因缺陷的小鼠 钙刺激的腺酰环化酶I(AC1)和VIII型(AC8)，重要 N-甲基-D-天冬氨酸(NMDA)受体信号的介体，以确定是否 哺乳动物AC功能的改变在体内调节酒精敏感性。这个 这项提案的具体目标将检验AC1和/或AC8的假设 缺乏导致1)增加对细胞凋亡作用的敏感性。 酒精在大脑发育的突触发育期；增加 对乙醇作用的NMDA受体拮抗剂成分的敏感性；3) 类似程度的酒精介导的更大的长期行为缺陷 围产期神经元死亡。]这些基因的结果是， 药理学和分子生物学研究将进一步阐明 乙醇改变神经元生理和存活的分子机制 为考虑AC的异构体特异性调制提供了依据 作为治疗胎儿酒精综合征的靶点。

DESCRIPTION (provided by applicant): The long-term goals of our laboratory are to understand the molecular mechanisms for the neurotoxic effects of ethanol on the developing brain. Alcohol consumption by pregnant women can result in intrauterine fetal neurotoxicity, i.e. fetal alcohol syndrome (FAS), with sequelae in affected children including hyperactivity, learning disorders, mental retardation, depression, and psychosis. Previous pharmacological evidence has implicated N-methyl-D-aspartate (NMDA) receptor inhibition as an important direct effect of ethanol, and increased sensitivity to the sedative effect of ethanol occurs with mutations in the cAMP second messenger pathway in drosophila. We will utilize mice genetically deficient in the calcium-stimulated adenylyl cyclases type I (AC1) and VIII (AC8), important mediators of N-methyl-D-aspartate (NMDA) receptor signaling, to determine if alteration in mammalian AC function modulates ethanol sensitivity in vivo. The specific aims of this proposal will test the hypotheses that AC1 and/or AC8 deficiency results in 1) increased sensitivity to the apoptotic actions of ethanol during the synaptogenesis period of brain development; increase in sensitivity to the NMDA receptor antagonist component of ethanol action; and 3) greater long-term behavioral deficits for similar degrees of ethanol-mediated neuronal death in the perinatal period.] The results of these genetic, pharmacological, and molecular biological studies will further elucidate the molecular mechanisms by which ethanol alters neuronal physiology and survival and provide the basis for considering isoform-specific modulation of AC function as a therapeutic target for fetal alcohol syndrome.