Sexual Dimorphic Differences in a Mouse Model of Scn1b-linked Epilepsy with Cardiac Arrhythmia
Abstract number :
2.443
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2023
Submission ID :
1330
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Luis Lopez-Santiago, PhD – University of Michigan Medical School
Lori Isom, PhD – Professor, Pharmacology, University of Michigan; Roberto Ramos-Mondragon, PhD – Research Investigator, Pharmacology, University of Michigan; Joe Milton, MS – Pharmacology – University of Michigan
Rationale:
Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of neuronal and cardiac action potentials (APs). Pathogenic variants in VGSC genes are associated with epilepsy syndromes like Dravet syndrome, cardiac arrythmias like Brugada syndrome and Long QT syndrome, and sudden death syndromes like Sudden Unexpected Death in Epilepsy (SUDEP) and Sudden Cardiac Death. Because VGSCs are expressed in both brain and heart, neuro-cardiac mechanisms are proposed to contribute to SUDEP. While sex differences in biology are critical, historically they have been discounted, resulting in health disparities in female healthcare. We previously showed sex-specific behavioral differences in mice haploinsufficient for Scn1b (encoding VGSC b 1 subunits) in collaboration with the laboratory of Dr. Ivan Soltesz (Neuron. 2023 May 3;111(9):1440-1452). Here, we investigated sex-specific differences in Scn1b function in heart.
Methods:
We compared cardiac electrophysiology in male versus female Scn1b+/+ (WT) and Scn1b+/- adult mice.
Results:
We found that acutely dissociated ventricular myocytes from female Scn1b+/- mice have decreased transient sodium current (INa) density compared to WT females. In contrast, we found no differences between male Scn1b+/- and WT myocytes. Small, but significant, changes were found in resting membrane potential and action potential duration for female Scn1b+/- ventricular myocytes compared to female WT cells. No differences were found between male Scn1b+/- and WT myocytes. Telemetric ECG analysis in freely moving animals showed that female Scn1b+/- mice have increased heart rate (HR) compared to female WT while male Scn1b+/- mice have reduced HR compare to male WT. Finally, while both female and male Scn1b+/- mice have longer QTc intervals compared to WT mice of both sexes, we found larger magnitudes and variability of the QTc in females, which may increase their risk for cardiac arrhythmias and contribute to SUDEP.
Conclusions:
Taken together, this work suggests that there are critical sexual dimorphic differences in Scn1b function in both brain and heart in a mouse model of developmental and epileptic encephalopathy.
Funding: NIH R37-NS076752 (to LLI) and R01-HL149363 (to LLI and JMP)
Basic Mechanisms