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Neuronal subtypes in genetic disorder

Sep. 6, 2012, 7:00 AM

Tuberous sclerosis complex (TSC) is a genetic disorder that has severe neurologic consequences including epilepsy, developmental delay and autism. Although it is known that mutations in two genes (TSC1 or TSC2) cause the disorder, specific abnormalities that cause neurologic features are not clear.

(Wellcome Images)

Kevin Ess, M.D., Ph.D., assistant professor of Neurology, Cary Fu, M.D., assistant professor of Neurology, and colleagues proposed that defects in inhibitory interneurons that use the neurotransmitter GABA might play a role. They selectively deleted the mouse Tsc1 gene in these interneurons and found that the mice had impaired growth and decreased survival. Their studies, reported in the September issue of Cerebral Cortex, show that the GABA interneurons were enlarged, had increased mTORC1 signaling (which is regulated by TSC1 and TSC2), were fewer in number, and were clustered in ectopic locations. The mice also had lower thresholds for seizures.

Their findings support an important role for the Tsc1 gene during interneuron development and suggest that inhibitory GABA interneurons may contribute to the pathogenesis of epilepsy and autism in patients with TSC.

This research was supported by an American Epilepsy Society/Milken Family Early Career Award and by a grant from the National Institute of Neurological Disorders and Stroke (NS050484) of the National Institutes of Health.

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