4-(diethylamino)-benzaldehyde suppresses Epileptic Spike-wave Discharges in a Genetic Epilepsy Model of Dravet Syndrome
Abstract number :
3.014
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2022
Submission ID :
2204657
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:26 AM
Authors :
Chengwen Zhou, PhD – Vanderbilt University Medical Center; Gai-Linn Besing, B.S. – Neurology – Vanderbilt University Medical Center; Cobie Potesta, B.S. – Neurology – Vanderbilt University Medical Center; Hannah Higgins, B.S. – Vanderbilt University; Angelina Pranger, B.S. – Neurology – Vanderbilt University Medical Center; Martin Gallagher, M.D. – Associate Professor, Neurology, Vanderbilt University Medical Center; Robert Macdonald, MD. Ph.D – professor, Neurology, Vanderbilt University Medical Center
Rationale: Seizure activity incidence in human epileptic patients exhibits NREM sleep preference. Our previous works (AES 2019, 3.026) indicate that slow-wave oscillations (SWOs, 0.5 Hz) induced in vivo can trigger spike-wave-discharges (SWDs) in a genetic epilepsy (GE) mouse model. The incidence of epileptic SWDs depends on sleep-related homeostatic synaptic potentiation in cortical neurons. 4-(diethylamino)-benzaldehyde (DEAB) has been shown to suppress homeostatic synaptic potentiation in cortical neurons. Thus, using a GE Gabrg2+/Q390X Dravet syndrome mouse model, we hypothesized that suppressing the homeostatic synaptic plasticity in vivo would attenuate SWD incidences in this mouse model.
Methods: In accordance with guidelines set by VUMC IACUC, both wt and het Gabrg2+/Q390X knock-in (KI) mice (P60-120) underwent craniotomy surgery, and three EEG screw electrodes (Pinnacle Technology) were implanted in the skulls over somatosensory cortex and cerebellum (ground). EMG wires were inserted in the neck trapezius muscles. After surgery, mice were allowed to recover for at least 1 week with normal day-light and dark circadian cycle. After recovery, DEAB was injected (dosage 100 mg/kg, i.p.) for consecutive 5 days. Before and after the DEAB injection in mice, EEG (0.1~100 Hz) and EMG activity (10~400 Hz) were recorded using two Multiclamp 700B amplifiers and one DigiData 1400 digitizer (at 20 KHz) (Molecular Device Inc.). Epileptic behaviors in mice were also simultaneously video-recorded for Racine-staging. The data were expressed as mean ± SEM.
Results: Our results revealed that het KI mice exhibited significantly more epileptic SWDs in het KI mice than wt mice [SWD#/hr, wt 7.85 ± 0.86 (n=7 mice) vs het 163.85 ± 32.05, (n=9 mice), t-test p=0.0001] [total SWD duration(s)/hr: wt 13.58 ± 1.94 vs. het 556.87 ± 82.81, t-test p=0.001], which is consistent with our previous findings using this Dravet syndrome mouse model. After consecutive 5 days of DEAB injections (i.p.), SWD incidence drastically decreased in het mice. Moreover, only the het mice exhibited significantly less epileptic SWDs and shorter SWD duration, compared to pre-DEAB injection [SWD #/hr, wt (n=7) pre-DEAB 7.85 ± 0.86 vs post-DEAB 8.54 ± 2.30, paired t-test p=0.751; het (n=9) pre-DEAB 163.85 ± 32.05 vs post-DEAB 47.03 ± 7.63, paired t-test p=0.007] [SWD duration (s)/hr, wt (n=7) pre-DEAB 13.58 ± 1.94 vs post-DEAB 17.88 ± 5.79, paired t-test p=0.413; het (n=9) pre-DEAB 556.87 ± 82.81 vs post-DEAB 176.80 ± 41.06, paired t-test p=0.0009].
Conclusions: Consistent with our previous findings on epileptic SWD incidence in the het Gabrg2+/Q390X KI mice, more epileptic SWDs occurred in the het KI mice. DEAB injection (i.p.) significantly suppresses the SWD incidences in this GE Dravet syndrome mouse model, offering a potential novel treatment for epileptic SWDs during NREM sleep.
Funding: NIH R01 NS107424-01, R0 1NS107424-03S (NINDS/NIA)
Basic Mechanisms