Selective activation of mTORC1 signaling recapitulates microcephaly, tuberous sclerosis, and neurodegenerative...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mammalian target of rapamycin (mTOR) is linked to neurological disorders like tuberous sclerosis complex (TSC), neurodegeneration, and autism.
• Understanding mTOR's role in disease pathogenesis is limited by a lack of models that directly increase its activity.

Purpose of the Study:

• To investigate the temporal role of mTORC1 in neurological disease pathogenesis.
• To develop and utilize a novel transgenic mouse model with temporally controlled mTOR gain-of-function in the forebrain.

Main Methods:

• Generated transgenic mice with temporally controlled gain-of-function mTOR mutations in the forebrain.
• Analyzed the effects of selective mTORC1 activation during embryonic development and adulthood on cortical structure and function.
• Assessed neuronal apoptosis, progenitor cell activity, HIF-1α levels, and neurodegenerative markers.

Main Results:

• Embryonic mTORC1 activation caused cortical atrophy and neuronal progenitor apoptosis, linked to HIF-1α upregulation.
• Adult mTORC1 activation led to cortical hypertrophy, fatal epileptic seizures, and recapitulated features of human TSC.
• Activated mTORC1 in adult brains induced cytoplasmic inclusions and microglial activation, indicating progressive neurodegeneration.

Conclusions:

• mTORC1 exhibits distinct roles in brain development versus adulthood.
• Temporal activation of mTORC1 contributes to diverse neurological conditions, including developmental disorders and neurodegeneration.
• This study provides critical insights into mTORC1-mediated pathogenesis of human neurological diseases.