Biomarkers of NMDA dysfunction and D-serine effects

NMDA 功能障碍和 D-丝氨酸效应的生物标志物

• 批准号: 7426298
• 负责人: JOSEPH T. COYLE
• 金额: $ 23.27万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426298
• 关键词: Acute; Agonist; Animals; Attention; Auditory; Award; Binding; Biological Markers; Brain; Chronic; Clinical Data; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Complex; Cycloserine; Etiology; Functional disorder; Funding; GLYT1; Genes; Glutamate Metabolism Pathway; Glutamates; Glycine; Grant; Human; Impaired cognition; Institutes; Link; Measures; Mediating; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NRG1 gene; Neuregulin 1; Neurobehavioral Manifestations; Neurocognition; Neurocognitive; Neurocognitive Deficit; Operative Surgical Procedures; Outcome; PLAB Protein; Pathogenesis; Patients; Pattern; Personal Satisfaction; Phencyclidine; Primates; Process; Process Measure; Range; Rodent; Rodent Model; Role; Sarcosine; Schizophrenia; Sensory; Sensory Process; Serine; Short-Term Memory; Site; Structure; Symptoms; Transgenic Mice; Transgenic Organisms; behavior measurement; cognitive change; disability; drug development; genetic manipulation; in vivo; inhibitor/antagonist; mouse model; neurophysiology; neurotransmission; prevent

Persistent negative and cognitive symptoms are a primary cause of chronic disability and poor long-term outcome in schizophrenia. Deficits involve sensory-level disturbances, as well as abnormalities of higher level cognition. Phencyclidine (PCP) and other antagonists of N-methyl-D-aspartate (NMDA)-mediated neurotransmission induce symptoms and cognitive deficits that closely resemble those of schizophrenia and incorporate sensory, as well as higher cognitive changes, indicating a potentially critical role of NMDA receptors in the etiopathology of negative symptoms and cognitive dysfunction. NMDA receptors are modulated in vivo by glycine and D-serine, which bind to the glycine modulatory site (GMS) of the NMDA receptor complex. Clinical trials with GMS agonists have yielded highly encouraging clinical data with regard to negative symptoms, although effects on neurocognition remain to be determined. The present project will investigate effects of D-serine on neurocognitive deficits associated with schizophrenia, using both eventrelated potential (ERP) and behavioral measures sensitive to bottom-up effects of early cortical dysfunction. The project consists of two components. First, neurocognitive measures will be added to a recently funded study of D-serine treatment in both chronic and prodromal subjects in order to evaluate the degree to which GMS agonist treatment can reverse or prevent neurocognitive deficits associated with schizophrenia. Second, parallel studies in transgenic mouse models will evaluate the degree to which ERP deficits in schizophrenia can be reproduced by genetic manipulations aimed at the NMDA GMS.

持续的负性和认知症状是慢性残疾和长期不良的主要原因 精神分裂症的结局。缺陷包括感觉水平的紊乱，以及更高级的 层次认知。苯环利定等N-甲基-D-天冬氨酸拮抗剂介导的 神经传递导致的症状和认知障碍与精神分裂症和 合并感觉以及更高级的认知变化，表明NMDA可能起着关键作用 阴性症状和认知功能障碍的病因病理中的受体。NMDA受体是 在体内受甘氨酸和D-丝氨酸的调节，它们与NMDA的甘氨酸调节位点(GMS)结合 受体复合体。GMS激动剂的临床试验在以下方面产生了非常令人鼓舞的临床数据 对阴性症状的影响，尽管对神经认知的影响仍有待确定。本项目将 研究D-丝氨酸对精神分裂症相关神经认知功能障碍的影响 对早期皮质功能障碍的自下而上影响敏感的潜在事件相关电位(ERP)和行为测量。 该项目由两个部分组成。首先，神经认知测量将被添加到最近资助的 D-丝氨酸治疗慢性和先证者的研究 GMS激动剂治疗可以逆转或预防与精神分裂症相关的神经认知缺陷。 其次，在转基因小鼠模型中的平行研究将评估ERP缺陷的程度。 精神分裂症可以通过针对NMDAGMS的基因操作来复制。