Prenatal ethanol exposure effects on NMDA receptor localization and function

描述(由申请者提供)：本资助申请中概述的培训计划是专门为申请者设计的，重点是获得多学科研究技能和专业发展。训练计划的研究部分将调查酒精暴露对胎儿期酒精暴露(PAE)小鼠模型的发育损害作用的神经化学机制。PAE与一系列的生理、认知和行为异常有关，在这两个人类群体中，它被称为胎儿酒精谱系障碍(FASD)，在动物模型中。在动物模型中，PAE已被证明对认知中重要的多种大脑结构和功能产生影响，包括N-甲基-D-天冬氨酸(NMDA)受体(NMDAR)。拟议的研究将使用生化和电生理学技术来分别检测NMDAR在小鼠齿状体内的分布和性质。在发育过程中，齿状回的损伤可能会产生长期而深远的后果，因为这一结构是进入海马体的主要皮质输入途径。据推测，PAE导致齿状回突触外膜上含有NR1/NR2A的NMDA受体的存在增加，这与突触外隔区NMDA依赖的活动增加有关。如果这种增加确实存在，它将为FASD认知功能障碍的治疗干预提供一个新的靶点。 公共卫生相关性：产前接触酒精会导致一系列终生的身体、行为、认知和社交异常，统称为胎儿酒精谱系障碍(FASD)。拟议培训计划的研究部分旨在增加我们对孕期酒精暴露对学习和记忆损害影响的神经化学机制的知识。对这些机制的更好理解将有助于开发新的疗法，从而改善FASD患者的治疗结果。

DESCRIPTION (provided by applicant): The training program outlined in this grant application was specifically designed for the applicant with focuses on the acquisition of multi-disciplinary research skills and professional development. The research component of the training program will investigate neurochemical mechanisms that underlie the damaging effects of developmental exposure to alcohol in a mouse model of prenatal alcohol exposure (PAE). PAE is associated with a range of physical, cognitive and behavioral abnormalities in both human populations, where it is termed fetal alcohol spectrum disorder (FASD), and in animal models. In animal models, PAE has been shown to exert effects on multiple brain structures and functions that are important in cognition, including the N-methyl- D-aspartate (NMDA) receptor (NMDAR). The proposed research studies will employ biochemical and electrophysiological techniques to examine the distribution and properties, respectively, of NMDARs in the mouse dentate. Damage to the dentate gyrus during development may have long-lasting and far-reaching consequences since this structure serves as a major cortical input pathway into the hippocampus. It is hypothesized that PAE leads to an increased presence of NR1/NR2A-containing NMDA receptors in the extrasynaptic membrane of the dentate gyrus, and this is associated with an increase in NMDA-dependent activity in the extrasynaptic compartment. If such an increase does exist, it will provide a novel target for therapeutic intervention in the treatment of cognitive dysfunctions in FASD. PUBLIC HEALTH RELEVANCE: Prenatal exposure to alcohol causes a multitude of life-long physical, behavioral, cognitive and social abnormalities, collectively termed fetal alcohol spectrum disorder (FASD). The research component of the proposed training program aims to increase our knowledge of neurochemical mechanisms that underlie the damaging effects of prenatal alcohol exposure on learning and memory. A better understanding of these mechanisms will assist in the development of novel therapies that could improve treatment outcomes for those afflicted with FASD.