Abstract
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.
| Original language | English |
|---|---|
| Article number | e150120 |
| Journal | JCI insight |
| Volume | 6 |
| Issue number | 23 |
| DOIs | |
| Publication status | Published - 8 Dec 2021 |
Bibliographical note
Funding Information:The authors would like to acknowledge Minetta Elgersma-Hooisma for managing the mouse colony and carefully reading the manuscript. We would like to thank Geeske M. van Woerden for her scientific input and Eleonora Aronica and James Mills for providing access to the Human Tuber and cortex transcriptome data and for bioinformatical advice. We further thank Mirjam van den Hout-van Vroonhoven for her help with the RNA-Seq data. Last, we thank Freek van Hemert and Bram de Regt from Philips Research for performing the RNA-Seq. This work was supported by grants from the Dutch Epilepsy Foundation (Epilepsie fonds, grant number 16-09) and the Dioraphte foundation to YE.
Publisher Copyright:
© 2021, Koene et al.