Impact of Prenatal Alcohol Exposure on Receptor Targeting and Functioning

描述(申请人提供)：在人类和实验动物模型中，在发育过程中接触酒精已被证明对中枢神经系统的结构和功能造成大量剂量依赖的影响，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-天冬氨酸受体(NMDAR)在学习和记忆中起着关键作用，因此一直是研究的重点，目的是确定产前酒精暴露(PAE)对认知的有害影响的机制。本研究旨在验证PAE改变NMDAR亚单位在突触和突触外隔间的分布(Aim 1)和/或NMDAR通道复合体的性质(Aim 2)导致小鼠齿状回NMDAR功能受损的假说。目的1：PAE改变NMDAR在齿状回突触和突触外亚区的分布。目的1a：测定基础状态和激活状态下对照组和FASD小鼠突触和突触外NMDAR亚单位的水平。目的1b：评估PAE在基础和激活条件下对NMDAR亚基定位控制机制的影响。目的1b1：研究正常和FASD小鼠NMDA受体亚基与突触支架蛋白(PSD-95、PSD-93和SAP-102)的相关性。目的1b2：评估PAE对对照组和FASD小鼠NMDAR亚基磷酸化和总(磷酸化非磷酸化)亚基水平的影响。目的2：齿状回颗粒细胞NMDAR功能受损目的2a：测定正常小鼠和FASD小鼠海马片穿支通路刺激后全细胞突触NMDAR依赖电流。目的2b：测定正常小鼠和FASD小鼠海马片上全细胞NMDA依赖的突触和突触外电流。 与公共健康相关：在发育过程中暴露于酒精已被证明对中枢神经系统的结构和功能造成多种剂量依赖性影响。这些影响表现为一系列的身体、行为、认知和社交功能障碍。这项拨款建议的研究旨在确定产前酒精暴露对认知造成损害的神经化学机制，从而确定治疗胎儿酒精谱系障碍(FASD)的新靶点。

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).