LAGS+ an LAGS- two New Mouse Models Based on Bidirectional Genetic Selection to Identify Sudep-associated Genes
Abstract number :
3.07
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2024
Submission ID :
175
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Benoît Martin, PhD – 1Univ Rennes, CHU Rennes, INSERM, Laboratoire de Traitement de Signal et d’Image - UMR 1099, 35000 Rennes, France
Esther Zeitoun, BS – 1Univ Rennes, CHU Rennes, INSERM, Laboratoire de Traitement de Signal et d’Image - UMR 1099, 35000 Rennes, France
Gabriel Dieuset, BS – 1Univ Rennes, CHU Rennes, INSERM, Laboratoire de Traitement de Signal et d’Image - UMR 1099, 35000 Rennes, France
Violaine Latapie, BS – Univ Paris Est Créteil, INSERM, IMRB, Neuropsychiatrie Translationnelle, 94010 Créteil, France
Stéphane Jamain, PhD – Univ Paris Est Créteil, INSERM, IMRB, Neuropsychiatrie Translationnelle, 94010 Créteil, France
Arnaud Biraben, MD – 1Univ Rennes, CHU Rennes, INSERM, Laboratoire de Traitement de Signal et d’Image - UMR 1099, 35000 Rennes, France
Rationale: The audiogenic seizure (AGS) is a widely used model for preclinical studies of sudden unexpected death in epilepsy (SUDEP), as it relies on the non-invasive induction of a potentially lethal convulsion. Immediately after exposure to the sound, the mouse manifests a stereotyped behavior, which can be successively characterized by a wild running, clonic seizures, a tonic-clonic seizure in which the mouse falls onto its flanks, and a tonic seizure with an extension of the limbs towards the tail, followed or not by death. However, only a few inbred strains of mice are susceptible to AGS, and then only without full penetrance. To compensate for this limitation, our laboratory has recently developed two genetic mouse lines, LAGS+ and LAGS-, based on a bidirectional genetic selection on phenotypic criteria. Now, both LAGS+ and LAGS- present 100% of tonic seizures when stimulated with a white noise sound above 110 dB. However, they diverge on pronostic. Effectively, after 13 generations of selection, LAGS+ (for lethal audiogenic seizure), presents >99% of lethal AGS while LAGS- (for non-lethal audiogenic seizure) presents < 3% of lethal AGS. With the aim of identifying chromosomal regions contributing to AGS-related mortality, we have genotyped LAGS+ and LAGS- mice and compared their allelic frequencies.
Methods: Directional selection was initiated by a four-way cross derived from the audiogenic susceptible strains DBA/1J, DBA/2J, BALB/cJ and 129/SvTer. At each generation, 10 couples were constituted. At generation 11 for LAGS+ and generation 10 for LAGS-, we genotyped the 10 couples of each line using Illumina GGP GIGA-MUGA Arrays allowing the genotyping of more than 143,000 SNPs. We then performed a homozygosity mapping to identify shared genomic regions between animals with the same phenotype. In addition, we studied SUDEP-associated genes reported in humans.
Results: Our data showed that some genes known to be involved in seizures in different mouse models also appeared associated to mortality in our models. Additional chromosomal regions without candidate gene were also shown to be associated with mortality.
Conclusions: This work reinforces the interest of this new model for studying SUDEP. Further investigations should enable us to identify genes involved in the lethality process in this model.
Funding: NA
Basic Mechanisms