L.A. Martin1*; G. Mittleman2, and D. Goldowitz11Dept. Anat & Neurobiology, Univ Tenn. Health Sci. Ctr., Memphis, TN, 381632Dept. of Psych., Univ. Memphis, Memphis, TN, 38152
Post-mortem studies of human autistic brains have consistently revealed a partial loss of the Purkinje cells in the cerebellum. In addition, several fMRI studies have linked cerebellar abnormality with autism. The influence of the cerebellum on behavior has begun to be redefined in recent years to include non-motoric and cognitive behaviors. In order to study the role of cerebellar neuropathology in autistic behavior, we created an animal model with varying loss of cerebellar Purkinje cells by making aggregation chimeras between heterozygous lurcher (Lc/+) mutant embryos and wildtype (+/+) embryos. Lc/+ mice undergo a complete loss of Purkinje cells during postnatal development as a result of a mutation in the d2 glutamate receptor gene. Chimeric mice have varying amounts of Purkinje cells, depending on the degree of incorporation of cells from the +/+ lineage. In contrast to the ataxia shown by Lc/+ mice, chimeras have no obvious motor dysfunction. Using this chimeric model of cerebellar neuropathology, we conducted a series of investigations into the behavioral effects associated with Purkinje cell loss. We have assessed motivation through a progressive-ratio operant conditioning paradigm, working memory through a delayed-matched-to-position task (DMTP), spatial navigation abilities with the use of the Morris water maze, and social behavior with a series of simple screens. We have found that chimeras with a substantial loss of Purkinje cells acquired deficits in motor function as evidenced by multiple measures. We also found a relationship between "time-out" (perseverative) responses and the number of Purkinje cells in posterior lobules. Using the Morris water maze, we find that a loss of Purkinje cells is correlated with a deficit in spatial behavior. We have also found an unusual occurrence of repetitive behavior in a subset of chimeric mice in the social behavior screen. Finally, preliminary results from the DMTP task indicate a deficit in working memory associated with Purkinje cell loss. Thus, we are finding multi-dimensional impairments in behavior (motor and cognitive functions) associated with a depletion of cerebellar Purkinje cells that finds homology with human autism. Supported by Cure Autism Now (CAN).
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