The voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are key regulators of neuronal excitability in the central nervous system (CNS). Mutations in SCN1A, SCN2A, and SCN3A are associated with several epilepsy subtypes, including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI), a debilitating childhood disorder characterized by refractory seizures, mental retardation, and ataxia. In striking contrast, we have observed elevated seizure thresholds in mice with mutations in Scn8a. Furthermore, we were able to restore normal seizure thresholds and lifespans in Scn1a mutants that model GEFS+ and SMEI by genetically altering the activity of Scn8a. Based on these observations, we hypothesize that neuronal excitability can be modulated by selectively reducing the expression level of Scn8a, thereby providing a potentially new approach to the treatment of epilepsy. Since current anti- epilepsy drugs (AEDs) cannot selectively target SCN8A, we will evaluate the possibility of altering neuronal excitability by selectively reducing the expression level of Scn8a using an in vivo shRNA interference strategy. This will be accomplished in two specific aims. In the first aim we will generate an adeno-associated virus (AAV) short-hairpin RNA (shRNA) expression vector against Scn8a (AAV- sh8a). The delivery of this reagent into the mouse hippocampus will be optimized to achieve maximum knockdown of Scn8a expression. In the second aim we will evaluate the ability of AAV-sh8a to ameliorate the seizure phenotype in a mouse model of SMEI. If successful, this proof-of-principle R21 proposal would open up an important new direction for the treatment of refractory epilepsy subtypes.

Public Health Relevance

Despite advances in anti-epilepsy drug development, 20-40% of epilepsy patients still do not achieve adequate seizure control or do not respond to treatment at all. In this proof-of-principle study, we will develop and test a potential new strategy for the treatment of severe epilepsy. If successful, this study may offer new hope for the treatment of epilepsy subtypes that do not respond to current medications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS066155-01
Application #
7708046
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Fureman, Brandy E
Project Start
2009-07-20
Project End
2011-06-30
Budget Start
2009-07-20
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$232,500
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Dutton, Stacey B B; Sawyer, Nikki T; Kalume, Franck et al. (2011) Protective effect of the ketogenic diet in Scn1a mutant mice. Epilepsia 52:2050-6
Escayg, Andrew; Goldin, Alan L (2010) Sodium channel SCN1A and epilepsy: Mutations and mechanisms. Epilepsia :
Sawyer, Nikki T; Escayg, Andrew (2010) Stress and epilepsy: multiple models, multiple outcomes. J Clin Neurophysiol 27:445-52