Prenatal ethanol exposure effects on NMDA receptor localization and function

产前乙醇暴露对 NMDA 受体定位和功能的影响

• 批准号: 8123036
• 负责人: Megan L Brady
• 金额: $ 3.1万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123036
• 关键词: Adult; Animal Model; Animals; Applications Grants; Behavioral; Biochemical; Brain; Cell Fractionation; Cell membrane; Cell physiology; Cells; Cognition; Cognitive; Consumption; D Aspartate; Data; Development; Dose; Electric Stimulation; Electrophysiology (science); Experimental Designs; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Hippocampal Formation; Hippocampus (Brain); Human; Immunoblotting; Impaired cognition; Knowledge; Laboratory Animal Models; Learning; Life; Long-Term Potentiation; Measures; Membrane; Memory; Mitogen-Activated Protein Kinases; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neuraxis; Pathway interactions; Play; Population; Presynaptic Terminals; Property; Relative (related person); Research; Research Project Grants; Role; Secondary to; Structure; Synapses; Synaptic plasticity; Techniques; Testing; Therapeutic Intervention; Training; Training Programs; Treatment outcome; Work; adverse outcome; alcohol exposure; aspartate receptor; channel blockers; density; dentate gyrus; design; granule cell; improved; in utero; mature animal; mouse model; neurochemistry; neuromechanism; novel; patch clamp; postsynaptic; prenatal exposure; presynaptic; receptor function; research study; skills; social; therapy development

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.

描述（由申请人提供）：本资助申请中概述的培训计划是专门为申请人设计的，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研究在胎儿酒精暴露（PAE）小鼠模型中，发育暴露于酒精的破坏性影响的神经化学机制。在两种人群和动物模型中，PAE与一系列身体、认知和行为异常有关，在这些人群中，PAE被称为胎儿酒精谱系障碍（FASD）。在动物模型中，PAE已被证明对包括n -甲基- d -天冬氨酸（NMDA）受体（NMDAR）在内的多种认知重要脑结构和功能产生影响。拟进行的研究将采用生化和电生理技术分别检测NMDARs在小鼠齿状体中的分布和性质。由于齿状回是海马皮层的主要输入通路，因此在发育过程中对齿状回的损伤可能会产生长期和深远的影响。据推测，PAE导致齿状回突触外膜中含有NR1/ nr2a的NMDA受体的存在增加，这与突触外室中NMDA依赖性活性的增加有关。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新的靶点。