Analysis of the dopamine system in Rett syndrome

描述(申请人提供)：雷特综合征(RTT，MIM 312750)是一种X连锁的神经发育疾病，以各种临床特征为特征，最显著的是在6-18个月的生命中失去双手和语言。此外，受影响的个人有突出的手部刻板印象、发育障碍、认知障碍、自主神经功能障碍和癫痫发作。RTT是由编码甲基CpG结合蛋白2(MECP2)的基因突变引起的。佐格比博士的实验室制作的动物模型概括了RTT的许多临床特征，因此是一个有用的疾病模型。重要的是，在人类疾病中看到的许多运动异常在动物模型中都存在。这一建议是基于这样一个假设，即RTT的特定临床特征可归因于特定神经元群体中的MeCP2功能障碍。具体地说，黑质纹状体多巴胺能系统内的MeCP2功能障碍是该病运动异常的原因。因此，这项建议试图探索RTT动物模型中的多巴胺能系统。这笔拨款的具体目的是：1)通过研究RTT小鼠的神经化学组成和对药物挑战的行为反应，表征RTT小鼠的多巴胺能系统；2)确定MeCP2功能丧失的后果；3)分析RTT小鼠模型突触前和突触后多巴胺神经元内基因表达的变化。这些研究将探索RTT中多巴胺系统的功能障碍，并将阐明RTT综合征中发现的运动异常的可能治疗策略。此外，他们还将阐明导致运动障碍的一般遗传机制。这一见解可能会为未来治疗其他运动障碍的策略铺平道路，例如帕金森氏病或亨廷顿病。

DESCRIPTION (provided by applicant): Rett Syndrome (RTT, MIM 312750) is an X-linked neuro-developmental condition characterized by a variety of clinical features, most notably loss of hand use and language between 6-18 months of life. Furthermore, affected individuals have prominent hand stereotypes, growth failure, cognitive impairment, autonomic dysfunction and seizures. RTT is caused by mutations in the gene encoding Methyl-CpG Binding Protein 2 (MECP2). An animal model generated in the laboratory of Dr. Zoghbi recapitulates many of the clinical features of RTT and thus is a useful disease model. Importantly, many of the movement abnormalities seen in the human disease are present in the animal model. This proposal is based on the hypothesis that specific clinical features in RTT are attributable to MeCP2 dysfunction within specific neuron populations. Specifically, MeCP2 dysfunction within the nigrostriatal dopaminergic system is the cause of the movement abnormalities in the disease. Therefore, this proposal seeks to explore the dopaminergic system in an animal model of RTT. The Specific Aims of this grant are to: 1) Characterize the dopaminergic system in RTT mice by studying the neurochemical composition and behavioral response of RTT mice to pharmacological challenge; 2) Determine the consequence of loss of MeCP2 function exclusively in the dopaminergic system; 3) Analyze gene expression changes within pre- and post-synaptic dopamine neurons in the RTT mouse model. These studies will explore the dysfunction of the dopamine system in RTT and will illuminate possible therapeutic strategies for the movement abnormalities found in RTT syndrome. Furthermore, they will shed light on the genetic mechanisms generating movement disorders in general. This insight may pave the way for future therapeutic strategies for other movement disorders such as: Parkinson's disease or Huntington's disease.