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Abstract Details

Autistic-Like Behavior and Cerebellar Dysfunction in Purkinje Cell Tsc1 Mutant Mice
Child Neurology/Developmental Neurobiology
S15 - (-)
001
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.
We generated mice lacking Tsc1, one of the genes mutated in Tuberous Sclerosis, in cerebellar Purkinje cells.
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.
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.
Authors/Disclosures
Peter Tsai, MD, PhD (UT Southwestern)
PRESENTER 		The institution of Dr. Tsai has received research support from once upon a time foundation.
No disclosure on file
YunXiang Chu No disclosure on file
No disclosure on file
Mustafa Sahin, MD, PhD (Boston Children'S Hospital) Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Regenxbio . Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Centene. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for PTEN Research. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Sahin has received research support from NIH. The institution of Dr. Sahin has received research support from Tuberous Sclerosis Alliance. The institution of Dr. Sahin has received research support from Charities Aid Foundation. The institution of Dr. Sahin has received research support from Simons Foundation Autism Research Initiative. The institution of Dr. Sahin has received research support from Aucta Pharmaceuticals . The institution of Dr. Sahin has received research support from Loulou Foundation.
Hubert H. Fernandez, MD, FAAN (Center for Neurological Restoration, Cleveland Clinic) Dr. Fernandez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Fernandez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amneal. Dr. Fernandez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Intrance. Dr. Fernandez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Fernandez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Dr. Fernandez has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Fernandez has received publishing royalties from a publication relating to health care. Dr. Fernandez has received personal compensation in the range of $10,000-$49,999 for serving as a Steering Committee/Advisory Committee Member with Parkinson Study Group.