Astrocyte‐specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures

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Abstract
Persons affected with tuberous sclerosis complex (TSC) develop a wide range of neurological abnormalities including aberrant neuronal migration and seizures. In an effort to model TSC‐associated central nervous system abnormalities in mice, we generated two independent lines of astrocyte‐specific Tsc1 conditional knockout mice by using the Cre‐LoxP system. Astrocyte‐specific Tsc1‐null mice exhibit electroencephalographically proven seizures after the first month of age and begin to die at 3 to 4 months. Tsc1‐null mice show significant increases in astrocyte numbers throughout the brain by 3 weeks of age and abnormal neuronal organization in the hippocampus between 3 and 5 weeks. Moreover, cultured Tsc1‐null astrocytes behave similar to wild‐type astrocytes during log phase growth but demonstrate increased saturation density associated with reduced p27Kip1 expression. Collectively, our results demonstrate that astrocyte‐specific disruption of Tsc1 in mice provides a context‐dependent growth advantage for astrocytes that results in abnormalities in neuronal organization and epilepsy.