Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex

• Published in: Human molecular genetics Vol. 20; no. 23; pp. 4597 - 4604
• Main Authors: Anderl, Stefanie, Freeland, Megan, Kwiatkowski, David J., Goto, June
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.12.2011
• Subjects: Animal models; Animals; Animals, Newborn; Biological and medical sciences; Birth; Brain; Brain - drug effects; Brain - growth & development; Brain - metabolism; Brain - pathology; Cell Count; Cell physiology; Cell Size; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cognitive ability; Cortex; Data processing; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy; Female; Fetuses; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Giant cells; Hamartin; Infants; Integrases - metabolism; Intermediate Filament Proteins - metabolism; Lethality; Medical sciences; Mice; Molecular and cellular biology; Nerve Tissue Proteins - metabolism; Nestin; Neural stem cells; Neurology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Phenotype; Pregnancy; Rapamycin; Recombination; Seizures; Signal Transduction - drug effects; Sirolimus - administration & dosage; Sirolimus - pharmacology; Sirolimus - therapeutic use; Survival Analysis; Time Factors; TOR protein; TOR Serine-Threonine Kinases - metabolism; tuberous sclerosis; Tuberous Sclerosis - drug therapy; Tuberous Sclerosis - pathology; Tumors of the nervous system. Phacomatoses; Antineoplastic agent; Animal model; Nervous system diseases; Sirolimus; Rodentia; Central nervous system; Genetic disease; Encephalon; Prenatal; Vertebrata; Antibiotic; Mammalia; Treatment; Mouse; Tumor; Genetics; Immunosuppressive agent; Bourneville syndrome
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddr393

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 Tsc1 cc Nes-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.