Pharmacological inhibition of the mTOR pathway impairs hippocampal development in mice

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• Infant brain injury from chronic hypoxia is a significant concern.
• The mammalian target of rapamycin (mTOR) pathway is implicated in regulating progenitor stem cells in the dentate gyrus.
• Previous studies showed chronic hypoxia decreases hippocampal progenitor stem cells via mTOR inhibition.

Purpose of the Study:

• To investigate the effects of pharmacological mTOR pathway inhibition using rapamycin on the progenitor stem cell pool and dentate gyrus development.
• To determine if mTOR inhibition impacts neurogenesis and glial cell populations in the developing hippocampus.

Main Methods:

• Utilized a transgenic mouse model expressing green fluorescent protein (GFP) to track progenitor cells.
• Administered rapamycin for prolonged inhibition of the mTOR pathway.
• Assessed progenitor cell pool size (GFP+), proliferation (BrdU+), apoptosis, and mature neuron markers (NeuN+).
• Examined astrocyte and microglial populations in the dentate gyrus.

Main Results:

• Prolonged mTOR inhibition led to a persistent decrease in the early progenitor stem cell pool (GFP+).
• Increased proliferation (BrdU+) was observed, but coupled with elevated apoptosis, resulting in fewer mature neurons (NeuN+).
• Inhibition of mTOR pathway also caused depletion of astrocyte and microglial cells in the dentate gyrus.

Conclusions:

• Pharmacological inhibition of the mTOR pathway impairs dentate gyrus development by affecting progenitor cells, neurogenesis, and glial populations.
• These findings raise concerns about potential negative impacts on cognitive development in young children due to mTOR pathway alterations.