Development of NMDAR hypofunction and cognitive deficits

NMDAR 功能减退和认知缺陷的发展

• 批准号: 8761553
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761553
• 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; 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; gene repression; genetic risk factor; human FRAP1 protein; insight; interest; mTOR Signaling Pathway; memory process; methylazoxymethanol; mutant; mutant mouse model; neurodevelopment; postnatal; prenatal; prevent; public health relevance; 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 在精神分裂症病理生理过程中的作用 摘要精神分裂症 (SZ) 越来越被认为是一种神经发育障碍，通常在精神病发作之前出现认知障碍，而 N-甲基-D-天冬氨酸受体 (N-甲基-D-天冬氨酸受体) NMDAR）长期以来一直与学习和记忆过程、神经发育和 SZ 相关。然而，认知缺陷的原因以及引发病理过程的原因尚不完全清楚。鉴于 NMDAR 对认知功能的重要性，NMDAR 失调/功能障碍很可能在 SZ 的病理过程中发挥关键作用。在过去的二十年里，SZ 和人类尸检研究的几种动物模型观察到的一个非常一致的现象是 NMDAR 功能减退的现象。然而，绝大多数与 SZ 相关的研究都集中在成人的 NMDAR 功能上，而没有探索 NMDAR 在大脑发育过程中的作用。下一步重要的一步是确定在发育过程中通过不同的损伤导致 NMDAR 功能障碍的机制。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，前额皮质和海马中 NMDAR 亚基的蛋白质水平从青少年时期开始显着降低，并在青少年时期变得更加突出。此外，在发育早期阶段，暴露于甲基偶氮甲醇 (MAM) 的大鼠和 DISC1 突变小鼠模型的前额叶神经元中 NMDAR 介导的电流存在明显变化。基于这些观察结果，我们假设 NMDAR 功能低下始于出生后发育的早期阶段，并一直发展到成年。这个过程对于不同的动物模型是通用的。在早期（幼年期）纠正 NMDAR 功能低下将有效恢复谷氨酸能突触传递，从而挽救认知缺陷。目标 1 结合分子、生化和生理学技术以及行为测试，我们将确定出生后发育过程中前额皮质和海马 NMDAR 错误表达和功能障碍的时间过程；以及测试 MAM 暴露大鼠和诱导 DISC1 突变小鼠的学习和记忆功能。在目标 2 中，我们将研究出生后发育过程中 NMDAR 功能障碍的潜在机制，重点关注表观遗传重塑的转录抑制和参与 NMDAR 下调的信号通路。在目标 3 中，我们将确定在发育早期（幼年期）通过药物纠正 NMDAR 功能减退是否能够恢复 NMDAR 功能，从而挽救 MAM 暴露大鼠和 DISC1 突变小鼠的学习和记忆缺陷。我们相信这些实验将阐明 NMDAR 功能减退的进展，提供对其原因的机制洞察，并为治疗干预产生可能的新途径。此外，这些结果将为探索早期 NMDAR 功能减退如何导致 SZ 认知缺陷提供一个有趣的平台，并将解决早期治疗是否能够阻止进展或逆转与该疾病相关的认知缺陷这一非常重要的概念问题。