The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is caused by heterozygous mutations in either the TSC1 (hamartin) or the TSC2 (tuberin) gene. Among the multisystemic manifestations of TSC, the neurodevelopmental features cause the most morbidity and mortality, presenting a considerable clinical challenge. Hamartin...

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Bibliographic Details
Published in:Human molecular genetics 2012-07, Vol.21 (14), p.3226-3236
Main Authors: WAY, Sharon W, ROZAS, Natalia S, WU, Henry C, MCKENNA, James, REITH, R. Michelle, HASHMI, S. Shahrukh, DASH, Pramod K, GAMBELLOL, Michael J
Format: Article
Language:English
Subjects:
Animal models
Animals
Biological and medical sciences
Brain
Brain - drug effects
Brain - embryology
Brain - growth & development
Brain - metabolism
Cell physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Children
Cognition - drug effects
Cognitive ability
Cortex
Disease Models, Animal
Fundamental and applied biological sciences. Psychology
Genetics of eukaryotes. Biological and molecular evolution
Hamartin
Hippocampus
Humans
Learning
Learning - drug effects
Mechanistic Target of Rapamycin Complex 1
Medical sciences
Memory
Mice
Mice, Knockout
Molecular and cellular biology
Morbidity
Mortality
Multiprotein Complexes - genetics
Multiprotein Complexes - metabolism
Mutation
Neuroglia - drug effects
Neuroglia - metabolism
Neurology
Rapamycin
Sirolimus - administration & dosage
TOR protein
TOR Serine-Threonine Kinases - genetics
TOR Serine-Threonine Kinases - metabolism
Translation
Tuberin
tuberous sclerosis
Tuberous Sclerosis - drug therapy
Tuberous Sclerosis - embryology
Tuberous Sclerosis - psychology
Tuberous sclerosis 2 protein
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Tumors of the nervous system. Phacomatoses
Weaning
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Summary:Tuberous sclerosis complex (TSC) is caused by heterozygous mutations in either the TSC1 (hamartin) or the TSC2 (tuberin) gene. Among the multisystemic manifestations of TSC, the neurodevelopmental features cause the most morbidity and mortality, presenting a considerable clinical challenge. Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin complex 1 (mTORC1) kinase, a major cellular regulator of protein translation, cell growth and proliferation. Hyperactivated mTORC1 signaling, an important feature of TSC, has prompted a number of preclinical and clinical studies with the mTORC1 inhibitor rapamycin. Equally exciting is the prospect of treating TSC in the perinatal period to block the progression of brain pathologies and allow normal brain development to proceed. We hypothesized that low-dose rapamycin given prenatally and/or postnatally in a well-established neuroglial (Tsc2-hGFAP) model of TSC would rescue brain developmental defects. We developed three treatment regimens with low-dose intraperitoneal rapamycin (0.1 mg/kg): prenatal, postnatal and pre/postnatal (combined). Combined rapamycin treatment resulted in almost complete histologic rescue, with a well-organized cortex and hippocampus almost identical to control animals. Other treatment regimens yielded less complete, but significant improvements in brain histology. To assess how treatment regimens affected cognitive function, we continued rapamycin treatment after weaning and performed behavioral testing. Surprisingly, the animals treated with the combined therapy did not perform as well as postnatally-treated animals in learning and memory tasks. These results have important translational implications in the optimization of the timing and dosage of rapamycin treatment in TSC affected children.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/dds156