2. Academic Validation
  3. Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models

Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models

  • Cell Rep. 2025 Dec 23;44(12):116664. doi: 10.1016/j.celrep.2025.116664.
Wardiya Afshar-Saber 1,  Juan F Ruiz 1,  Isabel Gisser 1,  Ziqin Yang 1,  Leena Mehendale 1,  Nicole A Teaney 1,  Rachel Hobson 1,  Madison R Glass 1,  Truc T Pham 1,  Elizabeth Bainbridge 1,  Mustafa Sahin 2,  Kellen D Winden 3
Affiliations

Affiliations

  • 1 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 2 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: [email protected].
  • 3 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 41379617 DOI: 10.1016/j.celrep.2025.116664
Abstract

Tuberous sclerosis complex (TSC) is caused by variants in either TSC1 or TSC2, which cooperate to inhibit the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with neurological disorders that are attributed to disinhibition of mTORC1, but the mechanisms connecting dysregulation of mTORC1 to molecular and physiological changes in neurons remain unclear. In this study, we aim to understand transcriptional changes in TSC and identify downregulation of the immediate-early gene EGR1 in TSC2-deficient excitatory neurons. Furthermore, we find that activity-dependent transcription is impaired in TSC due to abnormalities in maturation-dependent DNA demethylation. Finally, we determine that mTORC1 inhibition started late in neuronal maturation of human neurons is only partially effective in reversing gene expression changes and ineffective in reducing spontaneous neuronal hyperactivity in TSC. These data demonstrate a critical window in early brain development where mTORC1 dysregulation leads to transcriptional changes that contribute to persistent neuronal abnormalities.

Keywords

CP: molecular biology; CP: neuroscience; DNA methylation; activity-dependent transcription; mTOR complex 1; tuberous sclerosis complex.

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