Mouse Models of NMDAR Hypofunction

NMDAR 功能减退小鼠模型

基本信息

批准号：
8074008
负责人：
JOSEPH T. COYLE
金额：
$ 30.45万
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/8074008
关键词：
Affect Agonist Alzheimer&apos s Disease Astrocytes Behavior Behavioral Brain Cells Chemistry Clozapine Code Cognitive Cognitive deficits Collaborations Complementary DNA Cycloserine D-Amino Acid Dehydrogenase Dopamine D2 Receptor Electrophysiology (science)Enhancers Genes Genetic Genomics Glial Fibrillary Acidic Protein Glutamate Carboxypeptidase II Glutamates Glycine Haloperidol High Pressure Liquid Chromatography Hippocampus (Brain)Human Activities Impaired cognition In Vitro Measurement Measures Modeling Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors N-acetylaspartate N-acetylaspartylglutamate Pathology Patients Pharmaceutical Preparations Physiology Plasma Proteins Recombinants Reporting Risk Role Sarcosine Schizophrenia Serine Site Synapses Techniques Tetracyclines Transgenic Mice Transgenic Organisms Ursidae Family Variant adeno-associated viral vector in vivo inhibitor/antagonist link protein metabotropic glutamate receptor 3 mouse model mutant neurochemistry novel promoter protein expression psychopharmacologic receptor function research study serine racemase tissue culture

项目摘要

Genetic, post-mortem and psychopharmacologic findings support the hypothesis that hypofunction of NMDA receptors may contribute symptomatic manifestations of schizophrenia. One potential mechanism is through the glycine modulatory site on the NMDA receptor, which must be occupied by glycine/D-serine, for the NMDA receptor to function. The association of the risk for schizophrenia with the gene encoding G72, a protein that activates D-amino acid oxidase that degrades D-serine, suggests low D-serine, which has been reported in schizophrenia, could be one cause of NMDA receptor hypofunction. To understand better the role of D-serine in hippocampal physiology and behavior, we will pursue two strategies. First, we will use our mice with floxed serine racemase gene to suppress its expression at 4 weeks pot-partum and characterize the neurophysiologic and behavioral consequences. Secondly, we will characterize the effects of transfected G72 on D-amino acid oxidase activity and D-serine levels in vitro, in tissue culture and in vivo using transgenic techniques. Finally, N-acetyl aspartyl glutamate (NAAG) is catabolized by glutamate Carboxypeptidase II (GCPII). NAAG is a selective agonist at mGluR3 (GRM3), whose gene has been associated with risk for schizophrenia; and GCPII expression is reduced in schizophrenia. We will use our mice with floxed GCPII to suppress its expression at 4 weeks post-partum and characterize the neurophysiologic and behavioral consequences. We believe that these experiments should provide informative mutant mice that should share homologies in behavior and synaptic chemistry to schizophrenia and will permit correlating cognitive deficits defined by the same tasks in patients and mice to hippocampal electrophysiology.

遗传、尸检和精神药理学结果支持 NMDA 功能减退的假设受体可能导致精神分裂症的症状表现。一种潜在的机制是通过 NMDA 受体上的甘氨酸调节位点，必须被甘氨酸/D-丝氨酸占据， NMDA 受体发挥作用。精神分裂症风险与编码 G72 的基因的关联激活可降解 D-丝氨酸的 D-氨基酸氧化酶的蛋白质表明 D-丝氨酸水平较低，这已被据报道，精神分裂症可能是 NMDA 受体功能减退的原因之一。为了更好地理解 D-丝氨酸在海马生理和行为中的作用，我们将采取两种策略。首先，我们将使用我们的带有 floxed 丝氨酸消旋酶基因的小鼠在产后 4 周时抑制其表达并表征神经生理学和行为后果。其次，我们将表征转染后的效果 G72 对体外、组织培养和体内 D-氨基酸氧化酶活性和 D-丝氨酸水平的影响转基因技术。最后，N-乙酰天冬氨酰谷氨酸（NAAG）被谷氨酸分解代谢羧肽酶 II (GCPII)。 NAAG 是 mGluR3 (GRM3) 的选择性激动剂，其基因已被与精神分裂症的风险有关；精神分裂症中 GCPII 的表达降低。我们将使用我们的使用 floxed GCPII 的小鼠在产后 4 周抑制其表达并表征神经生理和行为后果。我们相信这些实验应该提供信息丰富的突变小鼠应该与精神分裂症在行为和突触化学方面具有同源性并将允许将患者和小鼠中由相同任务定义的认知缺陷与海马体相关联电生理学。