Identifying the temporal electrophysiological and molecular changes that contribute to TSC-associated epileptogenesis

Tuberous sclerosis complex (TSC), caused by heterozygous mutations in TSC1 or TSC2, frequently results in intractable epilepsy. Here, we made use of an inducible Tsc1-knockout mouse model, allowing us to study electrophysiological and molecular changes of Tsc1-induced epileptogenesis over time. We recorded from pyramidal neurons in the hippocampus and somatosensory cortex (L2/L3) and combined this with an analysis of transcriptome changes during epileptogenesis. Deletion of Tsc1 resulted in hippocampus-specific changes in excitability and adaptation, which emerged before seizure onset and progressed over time. All phenotypes were rescued after early treatment with rapamycin, an mTOR inhibitor. Later in epileptogenesis, we observed a hippocampal increase of excitation-to-inhibition ratio. These cellular changes were accompanied by dramatic transcriptional changes, especially after seizure onset. Most of these changes were rescued upon rapamycin treatment. Of the genes encoding ion channels or belonging to the Gene Ontology term action potential, 27 were differentially expressed just before seizure onset, suggesting a potential driving role in epileptogenesis. Our data highlight the complex changes driving epileptogenesis in TSC, including the changed expression of multiple ion channels. Our study emphasizes inhibition of the TSC/mTOR signaling pathway as a promising therapeutic approach to target epilepsy in patients with TSC.