Olivocerebellar Circuitry in Autism

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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.