Sex and Temporal Influences on the Developmental Trajectory of Epilepsy in a Mouse Model of Dravet Syndrome
Abstract number :
1.137
Submission category :
2. Translational Research / 2D. Models
Year :
2022
Submission ID :
2204375
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Mustafa Hameed, MD – Boston Children's Hospital, Harvard Medical School; Sheryl Vermudez, PhD – Boston Children's Hospital; Benjamin Hui, BS – Research Assistant, Department of Neurology, Boston Children's Hospital; Rui Lin, MS – Research Assistant, Department of Neurology, Boston Children's Hospital; Gabrielle McGinty, BS – Research Assistant, Department of Neurology, Boston Children's Hospital; Alexander Rotenberg, MD, PhD – Professor, Department of Neurology, Boston Children's Hospital
Rationale: Dravet syndrome (DS) is a monogenic epilepsy associated with multiple comorbidities that results from haploinsufficiency of the SCN1A voltage-gated sodium channel gene, and which is faithfully modeled in Scn1atm1Kea mutant mice on an F1 hybrid C57x129S6 background. The epilepsy in these mice has been proposed to progress in multiple stages, with distinct clinical phenotypes at each stage. However, various aspects including sex and temporal variations in EEG metrics and comorbidities have not been fully described, particularly in mature adults. The aim of the present study was to characterize the developmental trajectory of DS in these mice.
Methods: Mortality in juvenile heterozygous F1 Scn1a+/- male (N=39) and female (N=47) mice was calculated across multiple litters. At P90, 11 male and 7 female F1 Scn1a+/- mice were implanted with wireless EEG transmitters. Recording electrodes were placed epidurally with active over left occipital lobe and reference over right olfactory bulb, and secured with skull screws. 1-channel continuous video-EEG (sampling rate, 1000 Hz) was recorded. EEG was analyzed for epileptic seizures using a semi-automated seizure detection algorithm, followed by manual review of video-EEG. Absolute spectral power in interictal EEG frequency bands was calculated and normalized to total EEG power (0.5-90 Hz). Total spectral power per frequency band was compared between groups.
Results: Fifteen percent of heterozygous F1 mice died by P30 (N=86). 92% of the deaths occurred post-weaning at P21. Females were at higher risk of unexpected death compared to males [♀: 23%, ♂: 5%; Fisher’s exact (FE), p < 0.05; relative risk (RR): 4.6, 95% CI: 1.2-17.8]. In surviving P90 F1 Scn1a+/- mice (N=18), 61% exhibited generalized tonic-clonic seizures (GTCS) with female mice now at lower risk of GTCS compared to males (♀: 29%, ♂: 82%; FE, p < 0.05; RR: 0.35, 95% CI: 0.10-0.9). Among epileptic F1 heterozygous animals, however, there was no effect of sex on average GTCS duration (♂: 45 ± 4s, ♀: 51 ± 6; ns). Regardless of GTCS occurrence, divergent interictal changes in total spectral power in distinct frequency bands were observed between sexes. Compared to their female counterparts, male F1 Scn1a+/- mice exhibited attenuated theta (5-12 Hz) (♂: 0.295 ± 0.031, ♀: 0.389 ± 0.018; p < 0.05) and attenuated high-gamma (60-90 Hz) power (♂: 0.032 ± 0.005, ♀: 0.058 ± 0.012; p < 0.05).
Translational Research