Authors :
Presenting Author: Ashwini Sri Hari, ME, PhD – University of Utah
Yunuen Coria, BS, MS – Senior Lab Specialist, Pharm/Tox, University of Utah; Ryan Cotter, BS – Lab Specialist, Pharm/Tox, University of Utah; Laura Handy, BS – Senior Lab Specialist, Pharm/Tox, University of Utah; Kristina Johnson, BS – Lab Manager, Pharm/Tox, University of Utah; Cameron Metcalf, PhD – Research Assistant Professor, Pharm/Tox, University of Utah; Karen Wilcox, PhD – Professor and Chair, Pharm/Tox, University of Utah
Rationale:
Dravet Syndrome (DS) is a pediatric, epileptic encephalopathy that is caused by
de novo mutations in the gene
SCN1A encoding a voltage-gated sodium channel (Nav1.1) subunit. DS is characterized by early-life febrile seizures, psychomotor dysfunction, and pharmacoresistance. The
Scn1aA1783V/WT mouse model of DS is used by NINDS Epilepsy Therapy Screening Program’s (ETSP) contract testing site at the University of Utah to screen novel therapies for DS. This model carries a missense mutation in
SCN1A that occurs in some DS patients and results in pharmacoresistant hyperthermia-induced seizures, spontaneous recurrent seizures (SRS, ~1/day), high mortality rate, and behavioral comorbidities. The objective of the current study was to determine if a priming event such as hyperthermia or an infection like event in this model would increase frequency of SRS that would allow for increased screening throughput of novel therapies. Early-life bouts of hyperthermia and infectious events in DS patients are associated with SRSs in adulthood.
Methods:
Male and female
heterozygous (HET) mice (Scn1aA1783V/WT) were used.
Repeat hyperthermia (RHT): Two groups with N=17 HET mice/grp (age P20-30) were used. The control group did not receive hyperthermia. The treatment group received hyperthermia once a day for five consecutive days where the core body temperature of mice was gradually increased until the occurrence of a seizure. Mice (age ~P70) were implanted with cortical electrodes and video EEGs were recorded for 21 days.
LPS: Two groups with N=7 HET mice/grp (P20-30) were used. The mice received intraperitoneal injection of either saline or 1mg/kg LPS (strain O127:B8). Mice (~P70) were implanted with cortical electrodes and video EEGs were recorded for 60 days.
Results:
In the RHT study, the average (mean ± standard deviation) SRS/day for the control group was 0.923 ± 2.097 and the hyperthermia treatment group was 1.221 ± 3.121 (P= 0.226). The five day RHT paradigm did not alter the temperature threshold at which the Hets seized at day 5 (39.7 ± 1.354 oC) compared to day 1 (39.2 ± 1.553 oC) (P= 0.086). For the LPS study, an interim EEG analysis was performed at ~2 weeks which showed that the average SRSs/day for the control group was 1.118 ± 2.048 and the LPS group was 1.103 ± 2.499 (P= 0.970). Analysis of additional vEEG is ongoing.
Conclusions:
These results suggest that etiologically relevant ‘priming’ events such as repeat hyperthermia-induced seizures and LPS-induced systemic inflammation failed to increase daily average spontaneous seizure frequency in HETs during adulthood. Nevertheless, this animal model with the current SRS frequency can be used to identify novel therapies to treat DS associated SRS.
Funding:
This project has been partly funded by Federal funds from the National Institute of Neurological Disorders and Stroke, Epilepsy Therapy Screening Program, National Institutes of Health, and Department of Health and Human Services, under Contract No. HHS 75N95022C00007.