Behavioral phenotype of a mouse model of the voltage-gated sodium channel patient variant SCN1B-p.R89C
Abstract number :
1.421
Submission category :
2. Translational Research / 2D. Models
Year :
2022
Submission ID :
2232957
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:28 AM
Authors :
Bryana Sandy, – Michigan State University; Samantha Hodges, PhD – Department of Pharmacology, University of Michigan Medical School, 1150 W Medical Center D., Ann Arbor, MI, 48109 – University of Michigan; Joe Minton, MS – Department of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109 – Universitiy of Michigan; Caroline Scheuing, n/a – Department of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109 – University of Michigan; Chloe Moore, n/a – Department of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109 – University of Michigan; Chunling Chen, MD – Department of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109 – University of Michigan; Lori Isom, PhD – Department of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109;Department of Neurology, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109;Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109 – University of Michigan
Rationale: Developmental and epileptic encephalopathies (DEEs) are a class of pediatric epilepsies characterized by severe seizures, early onset developmental delays, cognitive and behavioral impairments, and increased risk of sudden unexpected death in epilepsy. Inherited, biallelic variants in SCN1B, encoding the voltage-gated sodium channel β1/β1B subunits, are linked to early infantile developmental and epileptic encephalopathy and Dravet syndrome. Our lab has recently developed a mouse model that expresses the homozygous patient variant SCN1B-p.Arg89Cys containing an in-frame C-terminal V5 epitope tag (p.R89C-V5). The goal of the current study is to characterize the cognitive and behavioral phenotypes of Scn1b-p.R89C-V5 homozygous vs. wildtype (WT) mice. _x000D_
Methods: Adult male and female homozygous Scn1b-p.R89C-V5 and WT littermate mice (129 x C57Bl6/J mixed background) were tested in a series of behavioral tasks over a two-week testing period starting at approximately postnatal day 60. Mice were tested in tasks in order from least to most invasive (open field, elevated plus maze, novel object recognition, three chamber social task), with at least a 48 h break in between each task. All behavioral tasks were video-recorded and analyzed off-line with Ethovision software (EthoVision XT 7.0, Noldus Technology). Sexes were combined for preliminary behavioral analysis, however, differences between male and female mice will be examined upon completion of the study. Current sample sizes for behavioral tasks are as follows: Scn1b-p.R89C-V5 mice: n = 5-9, WT mice: n = 5–8. The study remains on-going to increase the sample size._x000D_
Results: While both male and female Scn1b-p.R89C-V5 mice were observed to have spontaneous generalized seizure activity, female Scn1b-p.R89C-V5 mice exhibited higher rates of seizure activity (83%, 5/6 mice) than male Scn1b-p.R89C-V5 mice (33%, 2/6 mice). Mice that exhibited seizure activity during habituation or testing were removed from analyses for that task. When combining sexes, Scn1b-p.R89C-V5 mice exhibited hyperactivity in the open field task, as detected by a significant increase in distance moved (p < 0.01) and velocity (p < 0.01) in comparison to WT mice. Scn1b-p.R89C-V5 mice also had an increased number of clockwise rotations in the open field task (p < 0.01), indicative of repetitive behavior. In the elevated plus maze, Scn1b-p.R89C-V5 mice spent a longer time in the open arms of the maze compared to WT mice (p < 0.01), indicating reduced anxiety-like behavior. No differences in sociability or social novelty were detected between Scn1b-p.R89C-V5 and WT mice in the three chamber social task (p > 0.05)._x000D_
Conclusions: These preliminary findings provide insight into the cognitive and behavioral impairments associated with the biallelic SCN1B-p.R89C variant. Characterizing the Scn1b-p.R89C-V5 mouse model will inform our understanding of the mechanisms underlying the complex phenotypes associated with SCN1B-linked DEEs._x000D_
Funding: American Epilepsy Society
Translational Research