Presenting Author:

Nicole Hawkins, Ph.D.

Principal Investigator:

Jennifer Kearney

Department:

Pharmacology

Keywords:

Epilepsy, seizures, anticonvulsants, mouse models,Dravet syndrome,

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B154 - Basic Science

Systematic Screening of Anticonvulsants in a Genetic Model of Epilepsy

Epilepsy is a common neurological disorder affecting 1% of the world population. While some individuals achieve adequate seizure control with typical anticonvulsant drugs, approximately 30% remain refractory to treatment, highlighting the need for novel compounds. Anticonvulsant development has relied on screening in acute seizure models, including pentylenetetrazole (PTZ) and maximal electroshock. These acute seizure models are limited by not being etiologically relevant to the approximately 2/3 of epilepsies categorized as genetic. Genetic epilepsy models exhibit spontaneous seizures and therefore increase the potential to enhance compound screening and development processes. Dravet syndrome is a severe epileptic encephalopathy, often resulting from de novo SCN1A mutations. Seizure onset begins in the first year of life, often provoked by fever and subsequently develop into multiple seizure types that are refractory to treatment. Dravet syndrome also includes an increased risk for sudden unexpected death in epilepsy (SUDEP). The Scn1a+/- heterozygous null mouse model recapitulates many features of Dravet syndrome, including spontaneous seizures, seizures provoked by hyperthermia and premature mortality. The Scn1a+/- Dravet mouse provides an ideal platform to test therapeutic agents. We sought to conduct a comprehensive anticonvulsant screen at therapeutically-relevant doses in Scn1a+/- mice to determine which phenotypic measure(s) (survival, spontaneous seizures or hyperthermia-induced seizures) correlate best with human therapeutic response. Furthermore, we wanted to demonstrate more generally the utility of a genetic epilepsy model in anticonvulsant drug screening.