Determining Changes in Neural Circuits in Tuberous Sclerosis
Abstract
The purpose of our research proposal is to unravel how neural circuits and neuronal physiology of the thalamus contribute to brain dysfunction in Tuberous Sclerosis. The major findings during the research period are that we temporally controlled Tsc1 gene deletion at two distinct time points in thalamus development. Our strategy results in a mosaic distribution of mutant neurons in adult mice. Using genetic circuit mapping along with temporal gene deletion, we show that early Tsc1 deletion results in ectopic parvalbumin-expressing thalamic axons that exit the thalamus and coalesce in the striatum. In addition, mutant thalamic axons reach, but do not properly innervate, the cerebral cortex. These alterations underlie aberrant repetitive grooming abnormalities and seizures that were present in all eleven conditional mutant mice. Importantly, the early deletion of Tsc1 in the thalamus mimicked salient features of human Tuberous Sclerosis including mosaicism, autism and epilepsy. In contrast, later Tsc1 deletion did not cause repetitive grooming abnormalities and seizures in only two of seventeen mice. We have determined base line physiological properties from thalamic neurons in which one copy of Tsc1 is deleted. Therefore, a novel and significant finding is that we identified a short temporal developmental window where Tsc1 deletion in the embryonic thalamus causes deficits in thalamocortical neural circuit architecture concomitant with behavioral abnormalities.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2012
- Accession Number
- ADA590824
Entities
People
- Mark Zervas
Organizations
- Brown University