Genomic coordinate 2:28,531,240
Here I present: “Tuberous Sclerosis (Mouse Model)”, Victor McKusick, Mendelian in Inheritance in Man’, 1966. icd10=Q85.1
Uhlmann et al. (2002) demonstrated that heterozygous Tsc1 and Tsc2 mice exhibit increased numbers of astrocytes, suggesting that hamartin and tuberin are important growth regulators for astrocytes. To study the consequence of hamartin loss on astrocyte function, Uhlmann et al. (2002) generated mice in which the Tsc1 gene was specifically inactivated in astrocytes. The mice demonstrated an age-dependent progression of increased astrocyte proliferation, abnormal neuronal organization in the hippocampus, seizures, and death, reminiscent of human tuberous sclerosis. The findings suggested that the increase in astrocyte proliferation preceded the neuronal abnormalities, causing mass effect changes or disturbance of complex astrocyte-neuron interactions. In culture, the Tsc1-null astrocytes grew in association with reduced expression of the cell cycle regulator p27(KIP1), suggesting disruption of a TSC-mediated growth regulation complex involving p27(KIP1).
Zeng et al. (2008) observed that mice with conditional Tsc1 inactivation primarily in glia developed glial proliferation, enlarged brain size, progressive epilepsy, and premature death. Treatment with rapamycin at postnatal day 14 before the onset of neurologic symptoms prevented the development of epilepsy and premature death. Treatment at 6 weeks after the onset of symptoms suppressed seizures and prolonged survival. Brain histology showed that treatment with rapamycin resulted in decreased abnormal astrocyte proliferation and increased neuronal organization compared to untreated mice, even at later treatment. Rapamycin caused a dose-dependent decrease in S6 phosphorylation, indicating inhibition of the MTOR pathway. Cessation of rapamycin treatment resulted in reappearance of seizures, progressive brain enlargement, and premature death, similar to untreated mice. concluded that rapamycin has strong efficacy for preventing seizures and prolonging survival in these transgenic mice.
