Mutations in the SCN1A voltage-gated sodium channel (VGSC) are responsible for a growing number of disorders, including genetic epilepsy with febrile seizures plus (GEFS+), Dravet syndrome (DS, or severe myoclonic epilepsy of infancy), and familial hemiplegic migraine. To better understand the mechanism by which SCN1A dysfunction leads to epilepsy, we generated transgenic and knock-in mice with the human SCN1A mutation R1648H. These mutants exhibit spontaneous seizures, reduced seizure thresholds, and shortened life spans. Electrophysiological analysis of cortical neurons revealed reduced function in both excitatory and inhibitory neurons, but the biophysical mechanisms were different - negatively shifted voltage dependence of fast inactivation in excitatory neurons versus slowed recovery from inactivation in inhibitory neurons. Our results and data from other groups led to the hypothesis that reduced GABAergic inhibition plays the major role in the pathogenesis of GEFS+ and DS. However, a direct causal link between SCN1A function in interneurons or pyramidal cells and seizure generation has not yet been established.
In Aim 1, we will selectively delete Scn1a from either interneurons or pyramidal cells to directly establish the relative contribution of each cell type to seizure generation.
In Aim 2, we will test the hypothesis that early-life febrile seizures (FSs), which are a prominent clinical feature of both GEFS+ and DS, have an impact on disease progression. We will also explore the mechanistic basis for the relationship between FSs and disease outcome and possible pharmacological interventions. Of further relevance to our ultimate goal of finding better treatments for epilepsy is our observation that altered function of the Scn8a VGSC can restore normal seizure thresholds and life spans to an Scn1a knockout model of DS. This observation led us to hypothesize that selective targeting of SCN8A may make an effective treatment for DS, which is often refractory to available medications.
In Aim 3 we will investigate whether altering Scn8a function can also ameliorate other genetic forms of epilepsy and types of seizures. This study will provide important information on the role of VGSCs in the maintenance of normal neuronal excitability and in the development of epilepsy. These experiments are innovative, clinically relevant, and will stimulate much-needed translational research.
Approximately 40% of patients with epilepsy do not achieve adequate seizure control and a better understanding of the mechanisms that lead to seizure generation will facilitate the development of more effective treatments. In this study we will examine the contribution of the voltage-gated sodium channel genes, SCN1A and SCN8A, to seizure generation and seizure protection, respectively. This study will provide important, clinically relevant information on the mechanisms of epilepsy and the range of different epilepsy subtypes that can be potentially treated by selectively targeting SCN8A. )
| Makinson, Christopher D; Tanaka, Brian S; Sorokin, Jordan M et al. (2017) Regulation of Thalamic and Cortical Network Synchrony by Scn8a. Neuron 93:1165-1179.e6 |
| Dutton, Stacey B B; Dutt, Karoni; Papale, Ligia A et al. (2017) Early-life febrile seizures worsen adult phenotypes in Scn1a mutants. Exp Neurol 293:159-171 |
| Lamar, Tyra; Vanoye, Carlos G; Calhoun, Jeffrey et al. (2017) SCN3A deficiency associated with increased seizure susceptibility. Neurobiol Dis 102:38-48 |
| Rha, Jennifer; Jones, Stephanie K; Fidler, Jonathan et al. (2017) The RNA-binding protein, ZC3H14, is required for proper poly(A) tail length control, expression of synaptic proteins, and brain function in mice. Hum Mol Genet 26:3663-3681 |
| Wong, Jennifer C; Dutton, Stacey B B; Collins, Stephen D et al. (2016) Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice. Front Pharmacol 7:357 |
| Makinson, Christopher D; Dutt, Karoni; Lin, Frank et al. (2016) An Scn1a epilepsy mutation in Scn8a alters seizure susceptibility and behavior. Exp Neurol 275 Pt 1:46-58 |
| Sawyer, N T; Helvig, A W; Makinson, C D et al. (2016) Scn1a dysfunction alters behavior but not the effect of stress on seizure response. Genes Brain Behav 15:335-47 |
| Makinson, Christopher D; Tanaka, Brian S; Lamar, Tyra et al. (2014) Role of the hippocampus in Nav1.6 (Scn8a) mediated seizure resistance. Neurobiol Dis 68:16-25 |
| Gilchrist, John; Dutton, Stacey; Diaz-Bustamante, Marcelo et al. (2014) Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents. ACS Chem Biol 9:1204-12 |
| Sawyer, Nikki T; Papale, Ligia A; Eliason, Jessica et al. (2014) Scn8a voltage-gated sodium channel mutation alters seizure and anxiety responses to acute stress. Psychoneuroendocrinology 39:225-36 |
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