Olivocerebellar Circuitry in Autism

自闭症患者的橄榄小脑回路

• 批准号: 6474157
• 负责人: GENE J BLATT
• 金额: $ 24.1万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6474157
• 关键词: GABA receptor; autism; autoradiography; benzodiazepine receptor; biological signal transduction; calcium binding protein; cell morphology; cell population study; cerebellar Purkinje cell; cerebellar nuclei; clinical research; enzyme biosynthesis; genetic transcription; glutamate decarboxylase; human tissue; immunocytochemistry; in situ hybridization; isozymes; ligands; mossy fiber; neuroanatomy; neurofilament; neuropathology; olivary body

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.

描述（由申请人提供）：自闭症中的电动机功能障碍很明显 特征性低下和运动计​​划困难（Bauman，1999） 自闭症大脑中的关键神经病理学研究报告了选择性 各种边缘系统结构和结构中的细胞改变 在橄榄球连接性中。在后方半球 小脑皮层，浦肯野细胞（PC）的数量明显减少， 在下橄榄核（IO）中也发现了细胞变化，并且 小脑核（CN），后者显示成人细胞损失。飞行员 在4个自闭症和3个对照的海马中的研究已显示 仅在GABA能受体系统中具有统计学意义的差异 （苯二氮嗪结合位点和GABAA受体）首次标记 这种中心效应在GABA自闭症系统中很明显。扰动 在自闭症小脑中的GABA系统中，由于 PC赤字和某些成年CN细胞的丢失，但干扰的性质 尚未解决。该提议的长期目标是确定 通过现代方法，如何缺乏这些GABA能的主要目标 橄榄球攀爬纤维（CFS）影响小脑电路 自闭症大脑以及这是否会产生谷氨酸能的“错误” IO-PC和I0-CN连接和/或GABA能PC-CN和CN-IO电路。到 这样做，我们将使用（1）免疫细胞化学来确定 CFS的分布：并获得有价值的定量见解 PC损失； （2）原位杂交研究 GABA合成的关键酶的两个同工型（谷氨酸脱羧酶或 gad）在PC中；与两种类型的钙结合蛋白一起定位 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 三种类型的GABA能的密度改变和/或结合亲和力 小脑皮层，CN和IO中的受体。数据将被比较 神经病理学的变化以及每个自闭症病例的临床数据， 根据传入目标有效连通性解释并观察到 每个感兴趣区域的细胞变化。这些研究的发现 希望能为开发早期干预的新方向 为了提高生活质量的自闭症患者 受影响的人。