期刊
CEREBRAL CORTEX
卷 22, 期 9, 页码 2111-2119出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhr300
关键词
epilepsy; GABA; hamartin; mTOR; mTORC1
资金
- American Epilepsy Society/Milken Family Early Career Award
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health (NIH) [5K08NS050484]
- Tuberous Sclerosis Alliance Postdoctoral Fellowship award
- National Institute of Mental Health, NIH [T32 MH065215-07]
- Vanderbilt Ingram Cancer Center [P30 CA68485]
- Vanderbilt Digestive Disease Research Center [DK058404]
Tuberous sclerosis complex (TSC) is a genetic disease with severe neurologic and psychiatric manifestations including epilepsy, developmental delay, and autism. Despite much progress in defining abnormal signaling pathways including the contribution of increased mTORC1 signaling, specific abnormalities that underlie the severe neurologic features in TSC remain poorly understood. We hypothesized that epilepsy and autism in TSC result from abnormalities of gamma-aminobutyric acidergic (GABAergic) interneurons. To test this hypothesis, we generated conditional knockout mice with selective deletion of the Tsc1 gene in GABAergic interneuron progenitor cells. These interneuron-specific Tsc1 conditional knockout (CKO) mice have impaired growth and decreased survival. Cortical and hippocampal GABAergic interneurons of CKO mice are enlarged and show increased mTORC1 signaling. Total numbers of GABAergic cells are reduced in the cortex with differential reduction of specific GABAergic subtypes. Ectopic clusters of cells with increased mTORC1 signaling are also seen suggesting impaired interneuron migration. The functional consequences of these cellular changes are evident in the decreased seizure threshold on exposure to the proconvulsant flurothyl. These findings support an important role for the Tsc1 gene during GABAergic interneuron development, function, and possibly migration.
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