Impact of Prenatal Alcohol Exposure on Receptor Targeting and Functioning

产前酒精暴露对受体靶向和功能的影响

• 批准号: 8026833
• 负责人: Kevin K. Caldwell
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8026833
• 关键词: Impact; Prenatal; Alcohol; Exposure; Receptor

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).

描述（由申请人提供）：在人类和实验动物模型中，发育过程中接触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，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发挥着关键作用，因此一直是研究的焦点，旨在确定产前酒精暴露 (PAE) 对认知产生有害影响的机制。拟议的研究旨在检验以下假设：PAE 改变 NMDAR 亚基在突触和突触外区室之间的分布（目标 1）和/或 NMDAR 通道复合体的特性（目标 2），导致小鼠齿状回中 NMDAR 功能受损。我们制定了两个具体目标来检验这一假设： 目标 1：PAE 改变齿状回突触和突触外区室之间 NMDAR 的分布 目标 1a：确定对照组和 FASD 小鼠在基础和激活状态下突触和突触外 NMDAR 亚基的水平。 目标 1b：评估 PAE 对基础和激活条件下控制 NMDAR 亚基定位的机制的影响。 目标 1b1：确定对照小鼠和 FASD 小鼠中 NMDA 受体亚基与突触支架蛋白（PSD-95、PSD-93 和 SAP-102）的关联。 目标 1b2：评估 PAE 对对照和 FASD 小鼠中 NMDAR 亚基的磷酸化和总（磷酸化 + 非磷酸化）形式水平的影响。目标 2：齿状回颗粒细胞中的 NMDAR 功能受损 目标 2a：在穿孔通路刺激后，测量对照和 FASD 小鼠制备的海马切片中的全细胞突触 NMDAR 依赖性电流。 目标 2b：测量对照小鼠和 FASD 小鼠海马切片中的全细胞 NMDA 依赖性突触和突触外电流。 公共健康相关性：已证明在发育过程中接触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。这些影响表现为一系列身体、行为、认知和社会功能障碍。该资助提出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，从而确定胎儿酒精谱系障碍（FASD）治疗干预的新靶点。