Delayed Onset of the Epilepsy Phenotype and Mortality with Mtor Inhibition in a Mouse Model of TSC
Abstract number :
3.012
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2022
Submission ID :
2204374
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Luis Martinez, PhD – Baylor College of Medicine/Texas Children's Hospital; Anne Anderson, MD – Baylor College of Medicine; Vishnu Susheer, N/A – Baylor College of Medicine; Wai Lee, PhD – Baylor College of Medicine
This abstract is a recipient of the Young Investigator Award
Rationale: Tuberous Sclerosis Complex (TSC) is a genetic disorder characterized by brain malformations and severe epilepsy in up to 90% of patients. Mutations in TSC1 or TSC2 genes result in dysregulation of the mTOR pathway and TSC. Brain malformations in TSC are highly epileptogenic. mTOR inhibitors are promising therapeutic agents and are predicted to function as anti-epileptogenic agents. Clinical studies have shown that mTOR inhibitors can reduce seizure burden in some TSC patients, however this therapy may not have a disease modifying effect. Here we treated a mouse model of TSC with the mTOR inhibitor RAD001 (Everolimus) and tracked EEG and mTOR activity during treatment.
Methods: Littermate mouse pups with conditional forebrain deletion of the Tsc2 gene in excitatory neurons [Wild type, (WT) NEX-Cre+/Tsc2WT/WT; Knockout (KO), NEX-Cre+/Tsc2flox/flox] were treated with vehicle or 6mg/kg RAD001 by intraperitoneal route every other day postnatally. Video electroencephalography (vEEG) activity was recorded. EEG analysis of epileptiform and seizure activity was performed offline. Molecular analysis of mTOR signaling was carried out using western blotting of cortical tissue harvested from the treated animals at various time points.
Results: Early, chronic treatment with the mTOR inhibitor RAD001 normalized pS6 levels, abolished seizure activity, and prolonged the lifespan of NEX-Tsc2 mice (p < 0.001). vEEG recordings revealed Tsc2 KO mice treated with RAD001 beginning early in postnatal development exhibit a significant delay in the development of seizures from P12 to approximately P50. During inhibitor treatment there is a seizure-free interval of normal EEG activity followed by an incremental rise in epileptiform activity leading up to the appearance of seizures by P50 which is markedly delayed compared to the vehicle treated group. pS6 levels were reduced and comparable to vehicle treated WT (p >0.05) starting as early as the first day of treatment with RAD001 (P8) and up to P35 but were significantly increased at P45 (p < 0.05).
Basic Mechanisms