Development of NMDAR hypofunction and cognitive deficits

NMDAR 功能减退和认知缺陷的发展

• 批准号: 8898214
• 负责人: Wen-Jun Gao
• 金额: $ 38.38万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898214
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; Animal Model; Autopsy; Biochemical; Brain; Brain region; Cognitive deficits; Data; Development; Disease; Down-Regulation; Epigenetic Process; Failure; Functional disorder; Gene Silencing; Genetic Models; Glutamates; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Learning; Left; Life; Mediating; Memory; Memory impairment; Modeling; Molecular; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobehavioral Manifestations; Neurodevelopmental Disorder; Neurons; Onset of illness; Pathologic Processes; Perinatal; Pharmacological Treatment; Physiological; Pilot Projects; Play; Prefrontal Cortex; Process; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-akt; Psychotic Disorders; Rattus; Regulation; Research; Role; Schizophrenia; Short-Term Memory; Signal Pathway; Signal Transduction; Staging; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic Intervention; Time; Work; abstracting; base; behavior test; cognitive function; critical period; epigenetic regulation; gene repression; genetic risk factor; human FRAP1 protein; insight; interest; mTOR Signaling Pathway; memory process; methylazoxymethanol; mutant; mutant mouse model; neurodevelopment; postnatal; prenatal; prevent; receptor; receptor downregulation; receptor function; research study

DESCRIPTION (provided by applicant): The role of NMDAR in the pathophysiological process of schizophrenia Abstract Schizophrenia (SZ) is increasingly recognized as a neurodevelopmental disorder with cognitive impairments often preceding the onset of psychosis, while the N-methyl-D-aspartate receptor (NMDAR) has long been associated with learning and memory processes, neurodevelopment, and SZ. Yet, the cause of the cognitive deficits and what initiates the pathological process are incompletely understood. Given the importance of NMDARs for cognitive functions, it is likely that NMDAR mis-regulation/dysfunction plays a critical role in the pathological process of SZ. In the past two decades, a remarkably convergent observation across several animal models of SZ and human postmortem studies is the phenomenon of NMDAR hypofunction. However, the vast majority of SZ- related research has focused on NMDAR function in adults, leaving the role of NMDARs during brain development unexplored. An important next step is to identify the mechanisms that cause NMDAR dysfunction with different insults during development. To address this issue, we have conducted some pilot studies. Our preliminary data indicated that along with working memory and learning deficits, protein levels of NMDAR subunits are significantly reduced in the prefrontal cortex and hippocampus, starting from the juvenile period and becoming more prominent during the adolescent period. Furthermore, there is a clear alteration in NMDAR-mediated current in the prefrontal neurons in both methylazoxymethanol (MAM)-exposed rat and DISC1 mutant mouse models during the early stage of development. Based on these observations, we hypothesize that NMDAR hypofunction begins in the early stage of postnatal development and progresses until adulthood. This process is universal to different animal models. Correcting NMDAR hypofunction in the early stage (juvenile period) would be effective to restore glutamatergic synaptic transmission and thus to rescue cognitive deficits. Using a combination of molecular, biochemical, and physiological techniques, along with behavioral tests, in Aim 1 we will determine the time course of NMDAR mis-expression and dysfunction in the prefrontal cortex and hippocampus during postnatal development; as well as testing learning and memory functions in both MAM-exposed rats and inducible DISC1 mutant mice. In Aim 2 we will investigate the mechanisms underlying NMDAR dysfunction during postnatal development, focusing on transcriptional repression by epigenetic remodeling and signaling pathways involved in NMDAR downregulation. In Aim 3 we will determine whether pharmacologically correcting NMDAR hypofunction in the early stage (juvenile period) of development is able to restore NMDAR functions and thus rescue learning and memory deficits in MAM-exposed rats and DISC1 mutant mice. We believe that these experiments will elucidate the progression of NMDAR hypofunction, provide mechanistic insight into its cause, and generate possible new avenues for therapeutic intervention. Furthermore, the results would provide an interesting platform for exploring how early NMDAR hypofunction contributes to cognitive deficits in SZ and will address the very important conceptual question of whether early stage treatment is able to prevent the progression or reverse the cognitive deficits associated with this disease.

描述（由申请人提供）：NMDAR在精神分裂症摘要精神分裂症（SZ）的病理生理过程中的作用越来越多地被认为是一种神经发育障碍，并在精神病的发作之前通常在认知障碍之前，而n-methyl-d-d-d-d-d-opartate受体（NMDAR）与Learne and Memory and Memory and se and se and se and se相关。然而，认知缺陷的原因以及启动病理过程的原因是不完全理解的。鉴于NMDAR对认知功能的重要性，NMDAR错误调节/功能障碍可能在SZ的病理过程中起关键作用。在过去的二十年中，在几种SZ和人类后研究的动物模型中进行了明显收敛的观察是NMDAR功能障碍的现象。但是，绝大多数相关的研究都集中在成年人的NMDAR功能上，因此未探索NMDAR的角色。下一步的一个重要下一步是确定在发育过程中引起NMDAR功能障碍而引起不同侮辱的机制。为了解决这个问题，我们进行了一些试点研究。我们的初步数据表明，随着工作记忆和学习缺陷，前额叶皮层和海马的NMDAR亚基的蛋白质水平显着降低，从少年时期开始，并在青少年期间变得更加突出。此外，在发育的早期阶段，NMDAR介导的前额叶神经元中NMDAR介导的电流发生了明显改变。基于这些观察结果，我们假设NMDAR功能障碍始于产后发展的早期，并一直持续到成年。这个过程对于不同的动物模型是普遍的。在早期（少年时期）纠正NMDAR功能障碍将有效恢复谷氨酸能突触传播，从而挽救认知缺陷。在AIM 1中，使用分子，生化和生理技术以及行为测试的结合，我们将在产后发育过程中确定前额叶皮层和海马的NMDAR错误表达和功能障碍的时间过程；以及在暴露于MAM暴露的大鼠和诱导的盘状突变小鼠中的学习和记忆功能。在AIM 2中，我们将研究产后发育过程中NMDAR功能障碍的基础机制，重点是通过表观遗传重塑和涉及NMDAR下调的信号通路进行转录抑制。在AIM 3中，我们将确定在早期（少年时期）在药理学上纠正NMDAR功能障碍是否能够恢复NMDAR功能，从而在MAM暴露的大鼠和Disc1突变体小鼠中挽救学习和记忆缺陷。我们认为，这些实验将阐明NMDAR功能障碍的进展，提供对其原因的机械洞察力，并为治疗干预产生新的途径。此外，结果将提供一个有趣的平台，用于探索NMDAR早期功能障碍如何导致SZ认知缺陷，并将解决一个非常重要的概念问题，即早期治疗是否能够防止与该疾病相关的认知违规。