Impact of Prenatal Alcohol Exposure on Receptor Targeting and Functioning

描述（由申请人提供）：在人类和实验室动物模型中，已证明发育期间暴露于酒精会对中枢神经系统的结构和功能产生多种剂量依赖性影响，导致一系列身体、行为、认知和社会功能障碍，统称为胎儿酒精谱系障碍（FASD）。N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）已被证明在学习和记忆中起着关键作用，因此一直是旨在确定产前酒精暴露（PAE）对认知有害影响的机制的研究焦点。所提出的研究旨在检验以下假设：PAE改变突触和突触外隔室之间NMDAR亚基的分布（Aim 1）和/或NMDAR通道复合物的性质（Aim 2），导致小鼠齿状回中NMDAR功能受损。已经开发了两个具体的目的来测试这一假设：目的1：PAE改变突触和突触外隔室之间的齿状回NMDAR的分布目的1a：确定对照和FASD小鼠在基础和激活状态下的突触和突触外NMDAR亚基的水平。 目的1b：评估PAE对基础和活化条件下NMDAR亚基定位控制机制的影响。 目标1b 1：确定对照组和FASD小鼠中NMDA受体亚单位与突触支架蛋白（PSD-95、PSD-93和SAP-102）的相关性。 目标1b 2：评估PAE对对照和FASD小鼠中NMDAR亚基磷酸化和总（磷酸化+非磷酸化）形式水平的影响。目标二：目的2a：测量在穿通通路刺激后从对照和FASD小鼠制备的海马切片中的全细胞突触NMDAR依赖性电流。 目的2b：测量从对照和FASD小鼠制备的海马切片中的全细胞NMDA依赖性突触和突触外电流。 公共卫生相关性：在发育过程中暴露于酒精已被证明会对中枢神经系统的结构和功能产生多种剂量依赖性影响。这些影响表现为一系列身体、行为、认知和社会功能障碍。这项研究旨在确定产前酒精暴露对认知的损害作用的神经化学机制，从而确定治疗胎儿酒精谱系障碍（FASD）的治疗干预的新目标。

DESCRIPTION (provided by applicant): In both humans and laboratory animal models, exposure to alcohol during development has been shown to cause a multitude of dose-dependent effects on the structure and function of the central nervous system, resulting in a range of physical, behavioral, cognitive and social dysfunctions that are collectively termed fetal alcohol spectrum disorders (FASD). The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has been shown to play a critical role in learning and memory, and consequently has been a focus of studies aiming to identify mechanisms that underlie the detrimental effects of prenatal alcohol exposure (PAE) on cognition. The proposed studies aim to test the hypothesis that PAE alters the distribution of NMDAR subunits between synaptic and extrasynaptic compartments (Aim 1) and/or the properties of the NMDAR-channel complex (Aim 2) leading to impaired NMDAR function in the mouse dentate gyrus. Two specific aims have been developed to test this hypothesis: Aim 1: PAE alters the distribution of NMDAR between synaptic and extrasynaptic compartments in the dentate gyrus Aim 1a: Determine the levels of synaptic and extrasynaptic NMDAR subunits in control and FASD mice under basal and activated states. Aim 1b: Assess the impact of PAE on mechanisms controlling the localization of NMDAR subunits under basal and activated conditions. Aim 1b1: Determine the associations of NMDA receptor subunits with synaptic scaffolding proteins (PSD-95, PSD-93, and SAP-102) in control and FASD mice. Aim 1b2: Assess the impact of PAE on the levels of phosphorylated and total (phosphorylated + non- phosphorylated) forms of NMDAR subunits in control and FASD mice. Aim 2: NMDAR function is impaired in the dentate gyrus granule cells Aim 2a: Measure whole-cell synaptic NMDAR-dependent currents in hippocampal slices prepared from control and FASD mice following perforant pathway stimulation. Aim 2b: Measure whole-cell NMDA-dependent synaptic and extrasynaptic currents in hippocampal slices prepared from control and FASD mice. PUBLIC HEALTH RELEVANCE: Exposure to alcohol during development has been shown to cause a multitude of dose-dependent effects on the structure and function of the central nervous system. These effects are manifested as a range of physical, behavioral, cognitive and social dysfunctions. The studies proposed in this grant aim to identify neurochemical mechanisms that underlie the damaging effects of prenatal alcohol exposure on cognition, and thus identify novel targets for therapeutic intervention in the treatment of fetal alcohol spectrum disorders (FASD).