Pharmacological and Genetic Rescue of Idiopathic Epilepsies
Anderson, Lyndsey Leigh
PHARMACOLOGY Pharmacological and Genetic Rescue of Idiopathic Epilepsies Lyndsey Leigh Anderson Dissertation under the direction of Professor Alfred George, Jr. Epilepsy is a common neurological disorder affecting approximately 1% of the population worldwide. Many epilepsy patients achieve complete seizure control with current antiepileptic drugs; however, these medications fail to control seizures in 30% of patients, highlighting the need for novel treatments and for research into the underlying molecular mechanisms of epilepsy. Mutations within voltage-gated sodium channels have been identified in association with epilepsy and several mouse models have been generated to understand how these disease-associated mutations manifest in epilepsy development. The genetically engineered mouse line, Scn2aQ54, expresses a transgene encoding an inactivation-impaired neuronal Nav1.2 channel. Mice expressing the Scn2aQ54 transgene exhibit a severe epilepsy phenotype correlated with increased persistent sodium current in hippocampal neurons. We investigated the antiepileptic potential of preferential persistent sodium current inhibition using ranolazine and the novel compound, GS967. We observed that both ranolazine and GS967 reduced seizure frequency in Scn2aQ54 mice, and GS967 inhibited spontaneous action potential firing in neurons isolated from Scn2aQ54 mice. GS967 was also effective at protecting against seizures in the maximal electroshock model. Additionally, we found that long-term treatment with GS967 improved survival, prevented neuron loss and suppressed mossy fiber sprouting in Scn2aQ54 mice. Heterozygous Scn1a knockout (Scn1a+/-) mice recapitulate the phenotype of Dravet syndrome such as spontaneous seizures and premature lethality. Electrophysiological studies in dissociated hippocampal neurons from Scn1a+/- mice have shown a reduced sodium current density and impaired excitability in GABAergic interneurons suggesting that impaired GABA-mediated inhibition underlies the pathophysiology of Dravet syndrome. We generated a mouse line in which SCN1A is selectively expressed in GABAergic interneurons to directly test the hypothesis that the epilepsy phenotype in Scn1a+/- mice can be rescued by restoring SCN1A in GABAergic interneurons. Utilizing this genetic approach, we were not able to attenuate the reduced lifespan of Scn1a+/- mice by restoring SCN1A selectively in interneurons, suggesting that additional mechanisms may contribute to the reduced survival of Dravet syndrome. However, pharmacological intervention with GS967 was able to successfully rescue the lifespan of Scn1a+/- mice. These results suggest that GS967 is an effective novel antiepileptic drug that can be utilized to probe the pathophysiology of epilepsy.