In Vivo Characterization of Epilepsy After Postnatal Cerebral Deletion of TSC2 in Mice
Abstract number :
3.015
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2023
Submission ID :
727
Source :
www.aesnet.org
Presentation date :
12/4/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Zin-Juan Klaft, MD, Doctorate Degree Neurophysiology – Department of Neuroscience, Tufts University
Mary Sommer, MSc – Department of Neuroscience, Tufts U; Shilpa Prabhakar, MSc – Massachusetts General Hospital, Neurology Research; Edwina Abou Haidar, MD – Massachusetts General Hospital, Neurology Research; Kristi Viles, PhD – BridgeBio Inc.; David Scott, PhD – BridgeBio Inc.; Xandra Breakefield, PhD – Harvard Medical School / Massachusetts General Hospital; Chris Dulla, PhD – Department of Neuroscience, Tufts University
Rationale: Tuberous sclerosis (TSC) patients suffer from a high seizure burden that cannot be sufficiently controlled with current anticonvulsants in a majority of patients. TSC mouse models to test therapeutic interventions are needed. Here, we characterize the seizure burden in juvenile mice with postnatal TSC2 deletion induced by exposure to Cre recombinase at P0 in TSC2fl/fl C57BL6 mice.
Methods: Intraventricular injections of AAV1-Cre were performed at postnatal day 0 in TSC2fl/fl C57BL6 mice. Mice were implanted with ECoG electrodes during postnatal week three and recordings were performed during postnatal weeks four through seven. Survival of mice was monitored, and electrographic recordings were analyzed for epileptiform activity to assess seizure burden after postnatal deletion of TSC2.
Results: Median survival of AAV1-cre (P0) treated mice was 51 days with no deaths recorded in no-virus TSC2 fl/fl control animals. This allowed for ECoG implant surgery and monitoring of seizure activity during postnatal weeks four through seven. Epileptiform activity was recorded in all mice that received intraventricular AAV1-cre at P0 and presented as seizures and arrays of electrographic events with variable duration. Mean seizure incidence was 3.7 ± 0.8 (± SD) per hour during postnatal week four and five and 2.1 ± 0.9 per hour in weeks six and seven. Behavioral seizures were of tonic-clonic nature. Interestingly, aberrant electrographic activity was highly prevalent during recordings with a mean of 51.6 ± 15.7 % of time spent with epileptiform ECoG during weeks four and five and 43.1 ± 17.5 % for weeks six and seven. No seizures were detected in control animals implanted with ECoG.
Conclusions: Postnatal, stochastic viral deletion of TSC2 at P0 leads to severe seizure phenotypes and severely diminished survival times in mice. Time courses of survival, seizure development, and epileptiform load of mice in this TSC2 model enable upcoming studies assessing treatment efficacy of novel, causal therapeutic approaches against pharmacoresistant seizures found in TSC2.
Funding: research agreement BridgeBio Inc.
Basic Mechanisms