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: 8074011
• 负责人: JOSEPH T. COYLE
• 金额: $ 23.76万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074011
• 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; Neurobehavioral Manifestations; Neurocognition; Neurocognitive; Neurocognitive Deficit; Outcome; Pathogenesis; Patients; Pattern; Phencyclidine; Primates; Process; Process Measure; Rodent; Rodent Model; Role; Sarcosine; Schizophrenia; Sensory; Sensory Process; Serine; Short-Term Memory; Site; Structure; Symptoms; Transgenic Mice; behavior measurement; cognitive change; disability; drug development; genetic manipulation; in vivo; inhibitor/antagonist; mouse model; neurophysiology; neurotransmission; operation; 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.

持续的负面和认知症状是慢性残疾和长期差的主要原因 精神分裂症的结果。赤字涉及感觉级别的干扰以及较高的异常 水平认知。 N-甲基-D-天冬氨酸（NMDA）介导的苯基二酮（PCP）和其他拮抗剂 神经传递引起症状和认知缺陷，与精神分裂症和认知缺陷非常相似 结合感觉以及更高的认知变化，表明NMDA的潜在至关重要 阴性症状和认知功能障碍的病理学中的受体。 NMDA受体是 通过甘氨酸和D丝氨酸调节体内，它们与NMDA的甘氨酸调节位点（GMS）结合 受体复合物。使用GMS激动剂进行的临床试验产生了极大的令人鼓舞的临床数据 尽管对神经认知的影响仍有待确定，但负面症状。本项目将 研究了D-丝氨酸对与精神分裂症相关的神经认知缺陷的影响 潜力（ERP）和行为措施对早期皮质功能障碍的自下而上的影响敏感。 该项目由两个组成部分组成。首先，神经认知措施将被添加到最近资助的 研究在慢性和前驱受试者中的D-丝氨酸治疗，以评估 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，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NMDA GM的遗传操作来再现。