Mouse Models of NMDAR Hypofunction

遗传、尸检和精神药理学研究结果支持NMDA功能减退的假说， 受体可能有助于精神分裂症的症状表现。一个潜在的机制是通过 NMDA受体上的甘氨酸调节位点，其必须被甘氨酸/D-丝氨酸占据，用于 NMDA受体发挥作用。精神分裂症的风险与G72基因编码的关联， 一种激活降解D-丝氨酸的D-氨基酸氧化酶的蛋白质，表明D-丝氨酸含量低， 在精神分裂症中报道，可能是NMDA受体功能低下的原因之一。更好地了解 为了研究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 在产后4周时用floxed丝氨酸消旋酶基因抑制其表达的小鼠，并表征 神经生理和行为后果。其次，我们将描述转染的 G72对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-乙酰基谷氨酸酯（NAAG）被谷氨酸分解代谢 羧肽酶II（GCPII）。NAAG是mGluR 3（GRM 3）的选择性激动剂，其基因已被发现。 与精神分裂症的风险相关;并且GCPII表达在精神分裂症中降低。我们将用我们 在产后4周时用floxed GCPII抑制其表达，并表征 神经生理和行为后果。我们认为这些实验应该提供 信息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 电生理学

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.