RETT SYNDROME: INVESTIGATIONS OF CHOLINERGIC DYSFUNCTION

Rett综合征（RS）是一种神经发育障碍， 只有女童，发病率约为 每10，00 -15，000个活产婴儿中就有一个。其最典型的临床 表现为严重的发育和认知退化， 立体运动，不规则呼吸，自闭症行为， 癫痫发作神经化学评估表明， 皮质和皮质下区域的胆碱能功能， 是这些症状的基础本提案的目的是 研究这种受损的神经机制， 胆碱能功能这些机制的阐明将提供 这些信息对我们理解神经生物学至关重要， 卢比研究结果将为开发一种新型的 一种全新的RS研究方法，并将确定是否 RS的根本问题是神经元凋亡或受损 营养因子功能拟议的生物化学研究将提供 区域营养因子水平的重要信息， RS病例和女性对照的大脑。长期缺乏这种 营养因素，可能还有其他因素， 前脑的正常功能（以及可能的发育） RS脑中的胆碱能神经元。拟定的组织学研究 将调查程序性细胞死亡的证据此外，本发明还提供了一种方法， 这些研究将提供有关功能的定量信息， 乙酰胆碱能神经元的完整性位于脑内的 RS女孩。这些研究的成功完成将提供 对神经基础的基本见解， RS中的认知功能。此外，更好地了解 神经化学和病理学变化的基础， 这个神经系统，以及这些变化如何构成特定的临床 与RS相关的症状，可能导致改善诊断和/或 治疗方法。

Rett Syndrome (RS) is a neurodevelopmental disorder affecting almost exclusively female children with an incidence rate of approximately one in 1O,OO-15,OOO live births. Its most characteristic clinical manifestations are severe developmental and cognitive deterioration, sterotypic movements, irregular respiration, autistic behavior and seizures. Neurochemical evaluations have demonstrated a decrease in cholinergic function in cortical and subcortical regions that may underlie some of these symptoms. The goal of this proposal is to investigate the neural mechanisms responsible for this impaired cholinergic function. The elucidation of these mechanisms will provide information that is central to our understanding of the neurobiology of RS. The results will lay the foundation for the development of an entirely new approach to the study of RS and will determine whether the underlying problem in RS is one of neuronal apoptosis or impaired trophic factor function. The proposed biochemical studies will provide important information on regional levels of trophic factors in the brains of RS cases and female controls. The chronic lack of this trophic-factor, and possibly others, would have an enormous impact upon the normal function (and possibly development) of forebrain cholinergic neurons in the RS brain. The proposed histological studies will investigate for evidence of programmed cell death. In addition, these studies will provide quantitative information on the functional integrity of the acetylcholinergic neurons located within the brain of RS girls. The successful completion of these studies will provide fundamental insights into the neurological bases for the decline in cognitive function seen in RS. In addition, a better understanding of the neurochemical and pathological changes that underlie changes in this neural system, and how these changes underlie the specific clinical symptoms associated with RS, may lead to improved diagnostic and/or therapeutic approaches.