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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

基本信息

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
项目类别：
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

项目摘要

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.

持续的阴性和认知症状是慢性残疾和长期不良的主要原因