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Autism in Tuberous Sclerosis: The Case for the Cerebellum

Friday, 3 May 2013: 16:00
Auditorium (Kursaal Centre)
M. Sahin, Boston Children's Hospital, Boston, MA
Background: The pathogenesis of autism remains poorly understood, and contribution of cerebellar dysfunction to these disorders is unclear. Tuberous sclerosis complex (TSC) provides an ideal model for autism research, given the very high rates of autism spectrum disorders associated with TSC and its increasingly well-characterized genetic and molecular basis. TSC is caused by mutations in either the TSC1 or TSC2 genes. Both genes encode for proteins that are upstream of mammalian target of rapamycin (mTOR) and mutations in TSC1 or TSC2lead to upregulation of mTOR. Excessive mTOR activation is believed to be pathogenic in this disease.

Objectives: We asked whether cerebellar TSC1/2 dysfunction contributes to the pathogenesis of ASDs. In particular, we focused on the main output neuron of the cerebellar cortex, the Purkinje cells.

Methods: To investigate the role that cerebellar Tsc1/2 dysfunction plays in autism, we generated Purkinje cell Tsc1 mutant mice (Tsai et al., Nature 2012). We examined the effects of Tsc1 loss specifically in Purkinje cells of the cerebellum using immunohistochemistry, electrophysiology and behavioral analyses.

Results: Purkinje cell Tsc1 mutant mice displayed pathologic features seen in autism, including Purkinje cell loss and elevated markers of neuronal stress. Mutant Purkinje cells had aberrant morphology in terms cell size, axonal projections and dendritic spine structure and density. Furthermore, both heterozygous and homozygous loss of Tsc1in mouse cerebellar PCs led to autistic-like behaviors – social impairment, restrictive/repetitive behaviors, and abnormal vocalizations – in addition to excitability defects. Importantly, treatment of mutants with the mTOR inhibitor, rapamycin, starting in early development 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 investigating the cerebellar contribution to cognitive disorders such as autism. They also provide us with a mouse model in which we can test novel hypotheses with respect to the neuronal circuitry and developmental time windows associated with autistic-like behaviors.

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