Development of NMDAR hypofunction and cognitive deficits

点击翻译按钮获取中文摘要

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.