title: Pharmacological inhibition of the mTOR pathway impairs hippocampal development in mice.
abstract: Brain injury is an important cause of morbidity in infants at risk for exposure to chronic hypoxia. Using a transgenic mouse that expresses green fluorescent protein (GFP) within this progenitor population we have previously shown that exposure to chronic hypoxia significantly decreases the progenitor stem cell pool in the dentate gyrus of the hippocampus that is in part mediated by inhibition of the mammalian target of rapamycin (mTOR) pathway. Hence we hypothesized that pharmacological inhibition of the mTOR pathway using rapamycin will alter the progenitor stem cell pool and impair the development of the dentate gyrus. We find that prolonged inhibition of the mTOR pathway causes a decrease in the early progenitor stem cell pool, demonstrated by decreased GFP-expressing progenitors, which persists long term. However there is a significant increase in proliferating progenitor cell pool, as seen by increased BrdU that is coupled with increased apoptosis thereby leading to fewer Neu N-expressing mature neurons. Further inhibition of the mTOR pathway leads to depletion of the astrocyte and microglial pool in the dentate gyrus as well. Overall our findings demonstrate that pharmacological inhibition of the mTOR pathway leads to impaired development of the DG, raising the concern that in young children could impair cognitive development.
authors: Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, United States. Lakshmi.Raman@UTSouthwestern.edu
authors: Lakshmi
authors: L
authors: Raman
authors: Xiangmei
authors: X
authors: Kong
authors: Steven G
authors: SG
authors: Kernie
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects; D055495:Neurogenesis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D049452:Green Fluorescent Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus