Development of NMDAR hypofunction and cognitive deficits

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伴有认知障碍，而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有关。然而，认知缺陷的原因和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，在几个动物模型的SZ和人类死后研究中，一个非常一致的观察结果是NMDAR功能减退现象。然而，绝大多数与SZ相关的研究都集中在成人的NMDAR功能上，未探索NMDAR在大脑发育中的作用。一个重要的下一步是确定在发育过程中不同损伤导致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，NMDAR亚基在前额叶皮层和海马中的蛋白质水平显著降低，从青少年时期开始，在青少年时期变得更加突出。此外，暴露于甲基氧化甲醇（MAM）的大鼠和DISC1突变小鼠模型中，在发育早期，前额叶神经元中nmda介导的电流都有明显的改变。基于这些观察，我们假设NMDAR功能减退始于出生后发育的早期阶段，并一直发展到成年。这个过程在不同的动物模型中是普遍的。早期（少年期）纠正NMDAR功能减退可有效恢复谷氨酸能突触传递，从而挽救认知缺陷。在Aim 1中，我们将结合分子、生化和生理技术，以及行为测试，确定NMDAR在出生后发育期间前额叶皮层和海马中的错误表达和功能障碍的时间过程；以及测试mam暴露大鼠和诱导型DISC1突变小鼠的学习和记忆功能。在Aim 2中，我们将研究NMDAR在出生后发育过程中功能障碍的机制，重点关注通过表观遗传重塑和NMDAR下调的信号通路进行转录抑制。在Aim 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，为其原因提供机制见解，并为治疗干预提供可能的新途径。此外，该结果将为探索早期NMDAR功能障碍如何导致SZ的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预防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。

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.