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Autistic-Like Behavior and Cerebellar Dysfunction in Purkinje Cell Tsc1 Mutant Mice

Friday, 3 May 2013: 14:45
Chamber Hall (Kursaal Centre)
P. Tsai1, C. Hull2, Y. Chu2, W. Regehr2 and M. Sahin1, (1)Boston Children's Hospital, Boston, MA, (2)Harvard Medical School, Boston, MA
Background:  Autism spectrum disorders are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Although implicated in these disorders, the contribution of cerebellar dysfunction to autism remains unclear. Tuberous Sclerosis is a genetic disorder associated with high rates of comorbid autism.

Objectives: To investigate the cerebellar contribution to autism, we generated a Purkinje cell specific mouse model of Tuberous Sclerosis Complex.

Methods: We generated mice lacking Tsc1, one of the genes mutated in Tuberous Sclerosis, in cerebellar Purkinje cells.  We examined social interaction, repetitive behaviors, and vocalizations in addition to evaluating cellular and electrophysiologic mechanisms contributing to behavioral phenotypes.  Lastly, we treated mice with the mTOR inhibitor, rapamycin, to evaluate whether cellular and behavioral phenotypes could be ameliorated with this therapy.

Results:  Homozygous, but not heterozygous, loss of Tsc1 in Purkinje cells resulted in increased neuronal stress, Purkinje cell loss, and motor deficits. However, both heterozygous and homozygous mutant animals displayed autistic-like behaviors, including abnormal social interaction, repetitive behavior, and abnormal vocalizations, in addition to decreased Purkinje cell excitability. Treatment of mutants with the mTOR inhibitor, rapamycin, prevented both pathological and behavioral deficits.

Conclusions: These findings demonstrate novel roles for Tsc1 in Purkinje cell function and define, for the first time, a molecular basis for a cerebellar contribution to cognitive disorders such as autism.

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