Early Intervention in a mouse model of NMDA hypofunction

描述（由申请人提供）：精神分裂症是一种特别致残的精神疾病，与早期脑损伤、神经发育改变和NMDA受体神经传递的内在功能减退有关。研究人员提出，在疾病的早期阶段开始使用抗精神病药物治疗，可能会减缓或停止精神分裂症的病理性大脑变化。我们已经开发了一种小鼠模型，NMDA受体亚型（NR 1-/-）小鼠，NMDA受体功能的内在缺陷，可能是精神分裂症症状的基础。该模型具有反映在临床病症中观察到的改变的行为表型，包括在前脉冲抑制测试中的习惯化缺陷和受损的感觉运动门控。此外，NR 1-/-小鼠表现出低水平的社会偏好和直接社会互动的深刻变化。精神分裂症患者也表现出社会互动和沟通方面的缺陷，有时在其他症状出现之前。用于治疗精神分裂症的药物对明显的阳性疾病症状最有效，而对阴性症状（包括社交退缩和快感缺乏）效果较差。NR 1-/-小鼠提供了一个独特的系统，用于确定针对非特异性阴性症状和疾病进展的特定药物疗效，并用于探索行为缺陷的神经机制。以下研究的第一个目标是调查异常行为出现的发展时间过程，包括社会反应，感觉运动门控和习惯化的损伤。该提案的第二个目标是绘制NR 1-/-小鼠介导异常社会反应特征的特定大脑区域。为此，Fos和FosB免疫反应性的测量将用于确定大脑中特定区域的神经元激活。第三个目标是评估在断奶后阶段开始的奥氮平或利培酮长期治疗是否会延迟或预防在低形态小鼠中观察到的社会行为、感觉运动门控和习惯化缺陷。将结果与长期氟哌啶醇治疗进行比较，以确定非典型药物是否对NR 1低形态小鼠的变化具有不同的疗效。对于最终目标，Fos和FosB表达将用于确定抗精神病药物早期干预对大脑多个区域异常神经元活动的影响。总之，这些研究将阐明内在NMDA受体功能减退对行为和区域脑活动的神经发育影响，作为精神分裂症治疗干预的潜在机制和潜在靶点。精神分裂症是一种严重的神经精神综合征，通常在青春期后期或成年早期首次诊断。我们已经开发了一种遗传小鼠模型，NR 1亚型小鼠，缺乏谷氨酸功能相关的精神分裂症。该建议将确定小鼠模型中异常行为发生的时间进程，并检查在青春期开始的抗精神病药物治疗是否对NR 1亚型小鼠的行为和大脑活动产生有益影响。

DESCRIPTION (provided by applicant): Schizophrenia, a particularly disabling psychiatric disorder, has been linked to early brain insult, altered neurodevelopment, and an intrinsic hypofunction of NMDA receptor neurotransmission. Researchers have proposed that treatment with antipsychotic drugs, initiated in the early stages of the disease, might slow or halt pathological brain changes in schizophrenia. We have developed a mouse model, the NMDA receptor hypomorphic (NR1-/-) mouse, for the intrinsic deficits in NMDA receptor function that may underlie symptoms in schizophrenia. This model has a behavioral phenotype that reflects alterations observed in the clinical disorder, including deficits in habituation and impaired sensorimotor gating in tests of prepulse inhibition. In addition, NR1-/- mice exhibit low levels of social preference and profound alterations in direct social interaction. Schizophrenia patients also exhibit deficits in social interaction and communication, sometimes well before the emergence of other signs of the disorder. Drugs used for treatment in schizophrenia are most effective against the overt, positive disease symptoms, and less efficacious against negative symptoms, including social withdrawal and anhedonia. The NR1-/- mouse provides a unique system for determining specific drug efficacy against recalcitrant negative symptoms and against disease progression, and for exploring neural mechanisms for behavioral deficits. The first goal of the following studies is to investigate the developmental time course for the emergence of aberrant behaviors, including impairments in social responses, sensorimotor gating, and habituation. The second goal of the proposal is to map the specific brain regions mediating the abnormal social responses characteristic of the NR1-/- mice. For this goal, measures of Fos and FosB immunoreactivity will be used to determine neuronal activation in specific regions in brain. A third goal is to evaluate whether chronic treatment with olanzapine or risperidone, initiated in the post- weanling period, will delay or prevent the deficits in social behavior, sensorimotor gating, and habituation observed in the hypomorphic mice. Results will be compared with chronic haloperidol treatment, to determine if the atypical drugs have differential efficacy against changes in the NR1 hypomorphic mice. For the final goal, Fos and FosB expression will be used to determine the effects of early intervention with antipsychotics on aberrant neuronal activity across multiple regions in brain. Overall, these studies will elucidate the neurodevelopment effects of intrinsic NMDA receptor hypofunction on behavior and regional brain activity, as possible underlying mechanisms and potential targets for therapeutic intervention in schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a severe neuropsychiatric syndrome, usually first diagnosed in late adolescence or early adulthood. We have developed a genetic mouse model, the NR1 hypomorphic mouse, for deficient glutamate function relevant to schizophrenia. This proposal would determine the time course in development for the onset of abnormal behavior in the mouse model, and examine whether treatment with antipsychotic drugs, initiated in adolescence, could have beneficial effects on behavior and brain activity in the NR1 hypomorphic mice.