Region & Developmental Stage Specific Deletion of MeCP2 in Mouse Brain

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• 批准号: 7256736
• 负责人: LISA M MONTEGGIA
• 金额: $ 20.96万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256736
• 关键词: Accounting; Acute; Adult; Affect; Age; Amygdaloid structure; Animals; Anxiety; Appearance; Autistic Disorder; Behavior; Behavioral; Behavioral Model; Behavioral Paradigm; Binding Proteins; Birth; Brain; Brain region; Child; Cognitive; Defect; Dependovirus; Development; Disease; Disease regression; Exhibits; Female; Gait; Genes; Goals; Hand; Hippocampus (Brain); Impairment; Individual; Injection of therapeutic agent; Knock-out; Link; Mediating; Mental Retardation; Methyl-CpG-Binding Protein 2; Motor; Motor Cortex; Movement; Mus; Mutation; Neuraxis; Neurodevelopmental Disorder; Neurologic; Neurons; Pathogenesis; Pathway interactions; Patients; Phenotype; Prosencephalon; Rett Syndrome; Role; Seizures; Sleep Disorders; Social Behavior; Social Interaction; Specificity; Staging; Symptoms; System; Testing; Time; Tissues; Work; autistic behaviour; behavior test; critical developmental period; experience; loss of function; motor impairment; mouse methyl CpG binding protein 2; neural circuit; recombinase; research study; social; targeted delivery

DESCRIPTION (provided by applicant): The major objective of this proposal is to delineate the role of MeCP2 in specific brain regions and at distinct developmental time points in mediating behavioral phenotypes observed in individuals patients afflicted with Rett Syndrome (RTT). We have recently developed a system in which genes in the mouse brain can be knocked out by targeted delivery of an adeno-associated virus (AAV) encoding Cre recombinase in a regional and temporal specific manner. We hypothesize that cessation of MeCP2 expression in specific brain regions (hippocampus, amygdala and motor cortex) will cause them to: 1) exhibit alterations in specific behaviors depending on the brain region targeted; and 2) provide a framework of the neural circuitry that is involved in mediating aspects of RTT. In these experiments, in addition to regional specificity, we will be able to deliver AAV- CRE at two distinct stages of development (1 month after birth or 4 months after birth.). One month after birth corresponds to a time before appearance of symptoms in mice. In this way, we will be able to see whether deletion of MeCP2 in a specific brain region after birth can recapitulate specific symptoms associated with the disease. Region specific deletion of MeCP2 four months after birth (a time point after emergence of symptoms) will enable us to find out if there is a developmental critical period for appearance of the symptoms. If symptoms still emerge after this late deletion, this would suggest that loss of MeCP2 at any developmental stage causes functional deficiencies indicating a role for MeCP2 in acute neuronal function in addition to a role in neuronal development. This information is important because it may provide a framework whereby particular pathways or specific brain regions can be targeted for the treatment of Rett Syndrome by taking advantage of their distinctive pharmacological profiles. Rett's syndrome (RTT) is a neurodevelopmental disorder that accounts for one of the leading causes of mental retardation and autistic behavior in females. In general, individuals affected with RTT experience normal development up to the age of 5-48 months at which time developmental problems occur. Most RTT defects are predominantly expressed in the CNS, including mental retardation, autism-like behavior, seizures, disturbances of sleep, problems with gait, and stereotypical hand movements. Recent work has demonstrated that RTT is an X-linked dominant disorder that in most instances (at least 76%) results from mutations in the Methyl-CpG-binding protein (MeCP2) gene that are predicted to result in loss of function of MeCP2. While these mutations have been identified in the majority of RTT cases, there is currently no direct link between loss of function of MeCP2 and the pathogenesis of RTT. To better understand the role of MeCP2 in mediating the behavioral phenotypes observed in RTT individuals, we propose to delete MeCP2 in specific regions of the brain and then examine these animals in a broad array of behavioral paradigms. We will also delete the MeCP2 gene in developing mice (before the appearance of a behavioral phenotype) and in adult mice (after the appearance of a behavioral phenotype) and then assess these animals in a broad array of behavioral models. This approach will allow a clearer interpretation of MeCP2's role in specific brain regions as well as in developmental time points in mediating behavioral phenotypes similar to those observed in RTT patients. The proposed studies should increase our understanding of the role of MeCP2 in mediating certain RTT associated behaviors as well as identify neural circuits that mediate these abnormalities.

描述（由申请人提供）：该提案的主要目的是描述MECP2在特定的大脑区域和不同发育时间点的作用，并在患有RETT综合征（RTT）患者的个体患者中观察到的介导行为表型中。我们最近开发了一个系统，在该系统中，可以通过区域和时间特异性的方式靶向递送腺体相关病毒（AAV）来淘汰小鼠脑中的基因。我们假设在特定的脑区域（海马，杏仁核和运动皮层）中MECP2表达停止会导致它们：1）根据针对性的大脑区域表现出特定行为的改变； 2）提供了与RTT介导各个方面有关的神经回路的框架。在这些实验中，除了区域特异性外，我们还将能够在两个不同的发育阶段（出生后1个月或出生后4个月）提供征服。出生后一个月对应于小鼠症状出现之前的时间。这样，我们将能够查看出生后特定大脑区域中MECP2的缺失是否可以概括与疾病相关的特定症状。出生后四个月（出现症状后的时间点），MECP2的区域特异性缺失将使我们能够找出出现症状是否存在发育的关键时期。如果在此迟到后仍会出现症状，这将表明，在任何发育阶段，MECP2的丧失会导致功能缺陷，表明MECP2在急性神经元功能中起作用，除了在神经元发育中作用。该信息很重要，因为它可以提供一个框架，即可以通过利用其独特的药理特征来将特定途径或特定的大脑区域用于治疗RETT综合征。 RETT综合征（RTT）是一种神经发育障碍，是女性心理迟缓和自闭症行为的主要原因之一。通常，患有RTT的人经历了正常发展，直到5-48个月，在此期间发生了发育问题。大多数RTT缺陷主要在中枢神经系统中表达，包括智力低下，自闭症行为，癫痫发作，睡眠障碍，步态问题和刻板印象的手动运动。最近的工作表明，RTT是一种X连锁的显性疾病，在大多数情况下（至少76％）是由于甲基-CPG结合蛋白（MECP2）基因的突变导致的，预计会导致MECP2功能的丧失。尽管这些突变已在大多数RTT病例中鉴定出来，但目前MECP2功能丧失与RTT发病机理之间尚无直接联系。为了更好地理解MECP2在RTT个体中观察到的行为表型中的作用，我们建议在大脑的特定区域删除MECP2，然后在广泛的行为范式中检查这些动物。我们还将在发育中的小鼠（行为表型出现之前）和成年小鼠（行为表型出现之后）中删除MECP2基因，然后在一系列行为模型中评估这些动物。这种方法将允许对MECP2在特定大脑区域以及与RTT患者中观察到的行为表型相似的介导行为表型中的作用以及在发育时间点中进行更清晰的解释。拟议的研究应增加我们对MECP2在介导某些RTT相关行为的作用的理解，并确定介导这些异常的神经回路。