Olivocerebellar Circuitry in Autism

描述（由申请人提供）：运动功能障碍在自闭症中很明显 具有特征性张力减退和运动规划困难（Bauman，1999） 对自闭症患者大脑的关键神经病理学研究表明， 各种边缘系统结构和结构中的细胞改变 在橄榄小脑的连接中。在大脑后外侧半球， 小脑皮质，浦肯野细胞（PC）的数量显着减少， 在下橄榄核（IO）也发现了细胞变化， 小脑核（CN），后者在成人中显示细胞丢失。试点 对4名自闭症患者和3名对照者海马体的研究表明， 仅在GABA能受体系统中存在统计学显著差异 (both苯二氮平结合位点和GABAA受体）， 孤独症患者GABA系统中枢效应明显。扰动 在自闭症患者小脑中的GABA系统中也是明显的， PC缺陷和一些成年CN细胞的损失，但干扰的性质 尚未得到解决。本提案的长期目标是确定 通过现代方法，如何缺乏这些GABA能的主要目标， 橄榄小脑攀爬纤维（CF）影响小脑回路， 自闭症的大脑，以及这是否会造成自闭症的“错误连接”， IO-PC和I 0-CN连接和/或GABA能PC-CN和CN-IO电路。到 为了实现这一点，我们将使用（1）免疫细胞化学来确定 CF的分布：并获得有价值的定量见解的时间 （2）原位杂交研究PC丢失的水平和表达， GABA合成关键酶的两种同工型（谷氨酸脱羧酶或 GAD）;两种类型的钙结合蛋白与 PC中的GAD;以及细胞中关键GABA能转运蛋白（GAT-1-3）的表达 CN和（3）定量受体放射自显影定位任何 三种类型的GABA能蛋白的密度和/或结合亲和力的改变 小脑皮质的CN和IO受体。数据将与 神经病理学变化和临床数据，从每个自闭症病例， 基于传入-靶-传出连接性进行解释并观察 每个感兴趣区域的细胞变化。这些研究的结果 希望能为早期干预的发展指明新的方向 为自闭症患者提供服务，旨在改善他们的生活质量， 受影响的个人。

DESCRIPTION (provided by applicant): Motor dysfunction is evident in autism with characteristic hypotonia and motor planning difficulties (Bauman, 1999) Key neuropathological studies in autistic brains have reported selective cellular alterations in a variety of limbic system structures and in structures within olivocerebellar connectivity. In the posterolateral hemisphere of the cerebella cortex, Purkinje cells (PCs) were markedly reduced in number and cellular changes were also found in the inferior olivary nuclei (IO) and cerebellar nuclei (CN) with the latter showing cell loss in adults. Pilot studies in the hippocampus of 4 autistics and 3 controls, have shown statistically significant differences only in the GABAergic receptor system (both benzodiazpine binding sites and GABAA receptors) marking the first time that central effect were evident in the GABA system of autistics. Perturbations in the GABA system in the cerebellum of autistics are also evident due to the PC deficit and a loss of some adult CN cells but the nature of the disturbances has not been addressed. The long term goal of this proposal is to determine through modern methods, how the absence of these GABAergic primary targets of olivocerebellar climbing fibers (CFs) affects cerebellar circuitry in the autistic brain and whether this creates a "miswiring" of the glutamatergic IO-PC and I0-CN connectivity and/or the GABAergic PC-CN and CN-IO circuitry. To accomplish this, we will use (1) immunocytochemistry to determine the distribution of CFs: and gain valuable quantitative insights into the timing of the PC loss; (2) in situ hybridization to study the levels and expression of two isoforms of a key enzyme for GABA synthesis (glutamate decarboxylase or GAD) in PCs; the co localization of two types of calcium binding proteins with GAD in PCs; and the expression of key GABAergic transporters (GAT-1-3) in cells of the CN and (3) quantitative receptor autoradiography to localize any alterations in the density, and/or binding affinity of three types of GABAergic receptors in the cerebellar cortex, CN and IO. Data will be compared to neuropathological changes and to clinical data from each autistic case and interpreted based on afferent-target-efferent connectivity and observed cellular changes in each region of interest. Findings from these studies hopefully will lead to new directions for the development of early intervention for autistic individuals with an aim to improve the quality of life for affected individuals.