Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex
Open Access
- 1 September 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 20 (23), 4597-4604
- https://doi.org/10.1093/hmg/ddr393
Abstract
Epileptic seizures, particularly infantile spasms, are often seen in infants with tuberous sclerosis complex (TSC) soon after birth. It is feared that there are long-term developmental and cognitive consequences from ongoing, frequent epilepsy. In addition, the hallmark brain pathology of TSC, cortical tubers and giant cells are fully developed at late gestational ages. These observations have led us to examine the benefit of prenatal rapamycin in a new fetal brain model of TSC. In this Tsc1ccNes-cre+ mouse model, recombination and loss of Tsc1 in neural progenitor cells leads to brain enlargement, hyperactivation of mTOR, and neonatal death on P0 due to reduced pup–maternal interaction. A single dose of prenatal rapamycin given to pregnant dams (1 mg/kg, subcutaneous) rescued the lethality of mutant mice. This one dose of prenatal rapamycin treatment reduced hyperactivation of the mTOR pathway in the mutant brain without causing apparent pregnancy loss. Continued postnatal rapamycin beginning at day 8 extended the survival of these mice to a median of 12 days with complete suppression of hyperactive mTOR. However, the rapamycin-treated mutants developed enlarged brains with an increased number of brain cells, displaying marked runting and developmental delay. These observations demonstrate the therapeutic benefit and limitations of prenatal rapamycin in a prenatal-onset brain model of TSC. Our data also suggest the possibility and limitations of this approach for TSC infants and mothers.Keywords
This publication has 32 references indexed in Scilit:
- Efficacy and Safety of Sirolimus in LymphangioleiomyomatosisNew England Journal of Medicine, 2011
- Biallelic TSC gene inactivation in tuberous sclerosis complexNeurology, 2010
- Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complexHuman Genetics, 2010
- An Emerging Role of mTOR in Lipid BiosynthesisCurrent Biology, 2009
- Signaling Events Downstream of Mammalian Target of Rapamycin Complex 2 Are Attenuated in Cells and Tumors Deficient for the Tuberous Sclerosis Complex Tumor SuppressorsCancer Research, 2009
- Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosisMolecular Cancer, 2009
- Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouseHuman Molecular Genetics, 2009
- Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosisNature Medicine, 2008
- Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or LymphangioleiomyomatosisNew England Journal of Medicine, 2008
- mTOR and cancer: insights into a complex relationshipNature Reviews Cancer, 2006