Early Intervention in a mouse model of NMDA hypofunction

NMDA 功能减退小鼠模型的早期干预

• 批准号: 7620409
• 负责人: SHERYL S MOY
• 金额: $ 26.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-10 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620409
• 关键词: Acoustics; Adolescence; Adolescent; Age; Anhedonia; Animal Model; Antipsychotic Agents; Area; Behavior; Behavioral; Biological Assay; Brain; Brain region; Characteristics; Chronic; Clinical; Communication; Control Groups; Development; Diagnosis; Disease; Disease Progression; Dose; Drug Exposure; Drug usage; Early treatment; Exhibits; Exposure to; Food; Genetic; Glutamates; Goals; Haloperidol; Immediate-Early Genes; Impairment; Length; Link; Maps; Measures; Mediating; Mental disorders; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neonatal; Neurons; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Procedures; Proteins; Research; Research Personnel; Risperidone; Role; Schizophrenia; Social Behavior; Social Interaction; Social isolation; Staging; Sucrose; Surveys; Symptoms; Syndrome; System; Testing; Therapeutic Intervention; Time; Treatment Efficacy; Treatment Protocols; Ultrasonics; Validation; Withdrawal; atypical antipsychotic; cognitive function; design; drug efficacy; emerging adult; immunoreactivity; intervention effect; mouse model; neurodevelopment; neuromechanism; neuronal patterning; neuropsychiatry; neurotransmission; novel; olanzapine; postnatal; preference; prepulse inhibition; prevent; public health relevance; pup; receptor function; research study; response; social; vocalization; young adult

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.

描述（由申请人提供）：精神分裂症是一种特别残疾的精神疾病，与早期脑损伤，神经发育改变以及NMDA受体神经传递的内在功能不全有关。研究人员提出，在疾病的早期开始使用抗精神病药治疗，可能会减慢或停止精神分裂症的病理学大脑变化。我们已经开发了一种小鼠模型，即NMDA受体型（NR1 - / - ）小鼠，用于NMDA受体功能的内在缺陷，这可能是精神分裂症的症状。该模型具有反映临床疾病中观察到的变化的行为表型，包括习惯性缺陷和在预硫抑制测试中的感觉运动门控受损。此外，NR1 - / - 小鼠在直接社会互动​​中表现出低水平的社会偏好和深刻的改变。精神分裂症患者在社会互动和沟通方面也表现出缺陷，有时在其他疾病迹象出现之前。用于精神分裂症治疗的药物最有效地抵抗明显的阳性疾病症状，并且针对阴性症状（包括社交戒断和Anhedonia）有效。 NR1 - / - 小鼠提供了一个独特的系统，用于确定针对顽固性阴性症状和疾病进展的特定药物功效，并探索行为缺陷的神经机制。以下研究的第一个目标是研究出现异常行为的发展时间课程，包括社会反应障碍，感觉运动门控和习惯。该提案的第二个目标是绘制介导NR1 - / - 小鼠特征的特定社会反应的特定大脑区域。为此，将使用FOS和FOSB免疫反应性的度量来确定大脑特定区域的神经元激活。第三个目标是评估在断奶时期启动的奥氮平还是利培酮的慢性治疗，将延迟或防止在近似小鼠中观察到的社会行为，感觉运动门控和习惯性的缺陷。结果将与慢性氟哌啶醇治疗进行比较，以确定非典型药物是否对NR1型型小鼠的变化具有差异疗效。对于最终目标，将使用FOS和FOSB表达来确定抗精神病药对大脑多个地区异常神经活性的早期干预的影响。总体而言，这些研究将阐明内在的NMDA受体功能低下对行为和区域大脑活动的神经发育影响，以及对精神分裂症治疗干预的潜在机制以及潜在的靶标。公共卫生相关性：精神分裂症是一种严重的神经精神综合症，通常在青春期或成年初期首次诊断出。我们已经开发了一种遗传小鼠模型，即NR1型型小鼠，用于与精神分裂症相关的缺乏谷氨酸功能。该建议将确定小鼠模型中异常行为发作的发育时间过程，并检查青春期启动的抗精神病药治疗是否对NR1型型型小鼠的行为和脑活动有益影响。