Epilepsy is a common neurological disorder that affects 50 million people worldwide. Approximately 30% of epileptic patients have treatment resistant (refractory) seizures, thereby presenting a major clinical challenge and burden. The most common form of refractory epilepsy is mesial temporal lobe epilepsy (MTLE), characterized by spontaneous seizures, neuropsychological deficits, and hippocampal sclerosis. At present, surgical resection of the epilepsy focus is the best treatment strategy for this disorder; however, this procedure is only used in a subset of cases. Consequently, there is an urgent need to develop alternative treatments. Mutations in the voltage-gated sodium channels (VGSCs) SCN1A, SCN2A, and SCN3A are associated with several epilepsy subtypes including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Gain of function mutations in the VGSC SCN8A have recently identified in individuals with epileptic encephalopathies. However, our laboratory has demonstrated that mice with Scn8a mutations that reduce channel activity or expression are more resistant to induced seizures when compared to their wild-type littermates. In addition, we were able to dramatically ameliorate seizure severity and restore normal lifespans to Scn1a mutants that model DS and GEFS+ by either co-segregation of an Scn8a mutation or hippocampal knockdown of Scn8a expression. Since the hippocampus is the major site of seizure generation and morphological changes in MTLE, we hypothesize that selective reduction of SCN8A expression in the hippocampus will provide an effective strategy for the treatment of MTLE. We will test this hypothesis with three specific aims.
In Aim 1, we will establish the effect on spontaneous seizure frequency and severity of reducing hippocampal Scn8a expression in the widely used intra-hippocampal kainic acid mouse model of MTLE. Reduced Scn8a expression will be achieved by hippocampal injection of an adeno-associated viral vector expressing a short hairpin RNA against Scn8a (AAV-3). Seizure activity will be monitored in AAV-3 treated mice using continuous video/EEG analysis and will be compared to control mice injected with a scrambled construct (AAV-GFP).
In Aim 2, we will determine if hippocampal reduction of Scn8a expression could also prevent or ameliorate the changes in behavior and hippocampal morphology and that are observed in this model of MTLE. Finally, in Aim 3, we compare the biophysical properties of hippocampal slices from the AAV-3 and AAV-GFP treated mice in order to directly examine neuronal excitability. We will also test if partial pharmacological block of Nav1.6, using novel compounds, can reduce seizure-like bursting activity in hippocampal slices from the MTLE mouse model, and we will explore the contribution of the different VGSCs to the development of MTLE. This clinically relevant proposal will provide important insight into the feasibility of targeting SCN8A as a treatment for MTLE, and more broadly, for other forms of refractory epilepsy.
Mice with reduced activity of the sodium channel gene Scn8a are more seizure resistant, suggesting that selective targeting of the human SCN8A gene might provide a novel treatment for human epilepsy. In this study we will use mice to explore the clinical potential of targeting SCN8A as a treatment for mesial temporal lobe epilepsy, the most common form of treatment resistant epilepsy.
|Wong, Jennifer C; Makinson, Christopher D; Lamar, Tyra et al. (2018) Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy. Sci Rep 8:126|
|Giddens, Michelle M; Wong, Jennifer C; Schroeder, Jason P et al. (2017) GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant. Neurobiol Dis 106:181-190|
|Butler, Kameryn M; da Silva, Cristina; Shafir, Yuval et al. (2017) De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Epilepsy Res 129:17-25|
|Lamar, Tyra; Vanoye, Carlos G; Calhoun, Jeffrey et al. (2017) SCN3A deficiency associated with increased seizure susceptibility. Neurobiol Dis 102:38-48|
|Meisler, Miriam H; Helman, Guy; Hammer, Michael F et al. (2016) SCN8A encephalopathy: Research progress and prospects. Epilepsia 57:1027-35|