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Updated: May 21, 2025

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Somatic mosaicism and interneuron involvement in mTORopathies

Lilian G Jerow1, Darcy A Krueger2, Christina Gross3

  • 1Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH, USA; Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Trends in Neurosciences
|March 22, 2025
PubMed

Insights

Somatic mutations in the mechanistic target of rapamycin (mTOR) pathway can cause neurological disorders. This review highlights the critical role of interneurons in these conditions, suggesting new therapeutic avenues.

Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • Somatic mutations in mechanistic target of rapamycin (mTOR) pathway genes are linked to epilepsy, autism, and cognitive dysfunction.
  • Research has primarily focused on mTOR's role in excitatory neurons, overlooking potential interneuron involvement.

Purpose of the Study:

  • To review clinical evidence and potential mechanisms of interneuron involvement in mTOR-related neurological disorders.
  • To explore how mTOR hyperactivation in interneurons contributes to disease pathogenesis using mouse models.

Main Methods:

  • Review of clinical data implicating interneurons in mTOR-related disorders.
  • Analysis of studies involving selective disruption of mTOR signaling in interneurons and their progenitors in mouse models.

Main Results:

  • Dysregulated mTOR signaling in interneurons is a critical factor in neurological dysfunction.
  • Studies in mouse models demonstrate that mTOR hyperactivation in interneurons drives disease pathology.

Conclusions:

  • Interneuron dysfunction due to mTOR hyperactivation is a significant contributor to epilepsy, autism, and cognitive deficits.
  • Cellular mosaicism and dual roles of mTOR signaling present challenges for developing effective treatments.
Keywords:
epilepsyfocal cortical dysplasiaparvalbuminsomatostatintuberous sclerosis complex

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