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Neuronal hyperactivity becomes mTORC1 independent due to epigenetic changes in Tuberous Sclerosis Complex

GSE286912 Mus musculus Expression profiling by high throughput sequencing 8 samples Submitted 2025/10/25 Platform GPL19057
Summary
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 have been attributed to disinhibition of mTORC1, but mechanisms connecting dysregulation of mTORC1 to molecular and physiological changes in neurons remain unclear. In this study, we sought to understand transcriptional changes in TSC and identified down-regulation of the immediate early gene, EGR1, in TSC2-deficient excitatory neurons. Furthermore, we found that activity-dependent transcription is impaired in TSC due to abnormalities in epigenetic maturation. Finally, we determined 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 epigenetic changes that contribute to persistent neuronal abnormalities.
Published in
Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models
Afshar-Saber W, Ruiz JF, Gisser I et al. · Cell reports 2025 · PMID 41379617 · doi:10.1016/j.celrep.2025.116664
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Also filed as BioProject PRJNA1210536 and SRA study SRP557315. Searching any of these in the dataset finder brings you back here.

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