Behavioral and Neurochemical Effects of Cortical NMDA Receptor Dysfunction: Impli

描述（申请人提供）：皮层谷氨酸传入和传出投射功能的改变被认为与精神分裂症的病理生理有关。特别是，注意力集中在前额皮质（PFC）中谷氨酸n -甲基- d -天冬氨酸（NMDA）受体的可能改变上。单个NMDA受体由一个共同的NR1亚基（功能性NMDA受体所必需的）和NR2A-D亚基的组合组成。最近的尸检研究发现，精神分裂症患者PFC中NR1转录减少的证据。我们的研究目标是检查PFC区域限制性NR1功能丧失是否导致与该疾病相关的认知和神经化学缺陷。本研究将在小鼠模型中进行，其中loxP位点位于NR1亚基的功能必需外显子（fNR1小鼠）的侧面。基因缺失将通过腺相关病毒Cre重组酶的局部管理进行。我们之前的研究表明，fNR1小鼠内侧PFC和CA3海马NR1亚基功能受损分别对持续注意和工作记忆造成不同程度的破坏。本研究的目的1是进一步探讨PFC和CA3海马NR1亚基局部破坏对成年fNR1小鼠认知功能的影响。认知功能将通过延迟空间win-shift，非延迟随机觅食和视觉持续注意任务来检查。目的2将评估PFC中NR1功能障碍是否会导致中前额叶多巴胺（DA）神经元神经化学活性的继发性破坏。中前额叶DA神经元功能障碍一直被认为是精神分裂症患者认知缺陷的原因之一。此外，大量实验证据支持PFC中谷氨酸-DA相互作用的存在，反过来，我们的假设是慢性NR1功能障碍会损害中皮层DA神经元的功能能力。局部PFC NR1功能障碍对局部细胞外DA调节的影响将通过体内微透析进行研究。我们实验室的初步数据支持在fNR1小鼠中进行微透析的可行性。本研究的总体目标是研究前额叶皮质（PFC）中谷氨酸n -甲基- d -天冬氨酸（NMDA）受体功能障碍的行为和神经化学作用，以进一步了解精神分裂症相关认知缺陷的神经生物学基础。与AREA资助机制的目标一致，本提案中描述的所有初步和未来的实验都涉及并将继续涉及我们在西华盛顿大学新成立的行为神经科学专业的本科生。

DESCRIPTION (provided by applicant): Altered function of cortical glutamate afferent and efferent projections is thought to contribute to the pathophysiology of schizophrenia. In particular, attention has focused on possible alterations in glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC). Individual NMDA receptors are comprised of a common NR1 subunit (necessary for functional NMDA receptors) together with a combination of NR2A-D subunits. Recent postmortem studies have found evidence of decreased NR1 transcript in the PFC of schizophrenic subjects. A goal of our research is to examine whether regionally restricted loss of NR1 function in the PFC contributes to cognitive and neurochemical deficits associated with the illness. The present studies will be performed in a mouse model in which loxP sites flank a functionally requisite exon of the NR1 subunit (fNR1 mice). Gene deletions will be performed by local administration of adeno-associated-virus Cre recombinase. Our previous studies indicate that impaired function of the NR1 subunit in the medial PFC and CA3 hippocampus of fNR1 mice differentially disrupts sustained attention and working memory, respectively. Aim 1 of the present proposal is to further explore the effects of localized disruptions of the NR1 subunit in the PFC and CA3 hippocampus on cognitive function in adult fNR1 mice. Cognitive function will be examined using delayed spatial win-shift, non-delayed random foraging, and visual sustained attention tasks. Aim 2 will assess whether NR1 dysfunction in the PFC results in secondary disruptions in the neurochemical activity of mesoprefrontal dopamine (DA) neurons. Dysfunction of mesoprefrontal DA neurons has long been thought to contribute to cognitive deficits in schizophrenia. Furthermore, considerable experimental evidence supports the existence of a glutamate-DA interaction in the PFC and, in turn, our hypothesis that chronic NR1 dysfunction will impair the functional capacity of mesocortical DA neurons. The effects of localized PFC NR1 dysfunction on regulation of local extracellular DA will be examined using in vivo microdialysis. Preliminary data from our lab supports the feasibility of performing microdialysis in fNR1 mice. The overall goal of the proposed research is to examine the behavioral and neurochemical effects of dysfunction of glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC) in an effort to further understand the neurobiological basis of cognitive deficits associated with schizophrenia. Consistent with the objective of the AREA grant mechanism, all preliminary and future experiments described in this proposal have involved and will continue to involve undergraduate students in our newly established behavioral neuroscience major at Western Washington University. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating disease affecting ~1% of the population. Cognitive deficits associated with the disease are the most disruptive and unfortunately, the least responsive to currently available treatments. The proposed research endeavors to further our understanding of the neurobiological basis of these deficits in the hopes of ultimately, contributing to ongoing efforts to develop novel treatments for the cognitive impairment.