Pharmacological inhibition of the mTOR pathway impairs hippocampal development in mice

Lakshmi Raman, Xiangmei Kong, Steven G. Kernie

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)9-14
Number of pages6
JournalNeuroscience Letters
Volume541
DOIs
StatePublished - Apr 29 2013

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Sirolimus
Stem Cells
Pharmacology
Dentate Gyrus
Green Fluorescent Proteins
Parahippocampal Gyrus
Bromodeoxyuridine
Astrocytes
Brain Injuries
Transgenic Mice
Apoptosis
Morbidity
Neurons
Population

Keywords

  • Dentate gyrus
  • MTOR
  • Neurogenesis
  • Rapamycin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Pharmacological inhibition of the mTOR pathway impairs hippocampal development in mice. / Raman, Lakshmi; Kong, Xiangmei; Kernie, Steven G.

In: Neuroscience Letters, Vol. 541, 29.04.2013, p. 9-14.

Research output: Contribution to journalArticle

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