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

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

SUBMITTER: Afshar-Saber W 

PROVIDER: S-EPMC12865816 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature