Severe Myoclonic Epilepsy in Infancy (SMEI), also referred to as Dravet syndrome, is a childhood disorder associated with loss-of-function mutations in Scn1a that is characterized by frequent seizures and severe cognitive impairment. Patients are often intractable to anti-epileptic drugs and do not recover normal cognitive function later in life. In order to determine appropriate treatment strategies for improving cognitive outcomes, it is first necessary to understand the underlying biological contributions to cognitive dysfunction. Although the cognitive deficits in epilepsy are often attributed to the impact of seizures, we propose that the genetic deficit associated with SMEI leads to neurophysiological alterations in brain network activity and contributes to cognitive impairment independently of seizures. This possibility may hold important implications for investigating future treatments aimed to improve cognition. It would suggest that cognitive function may not fully recover by treating seizures alone. This investigation will therefore be important to determine if additional treatment strategies to the traditional anti-epileptic drugs should be pursued in the effort to develop therapies for improving cognitive outcome. The Scn1a gene encodes for the type I voltage-gated sodium channel. In the forebrain, Scn1a deficits cause impaired action potential firing of parvalbumin-positive (PV+) interneurons but not excitatory pyramidal cells. In addition to the contribution of this cell type to balancing excitation and inhibition in the brain, PV+ interneurons play critical roles in the spatiotemporal patterning of neural networks, especially during cognitive processes. In the septo-hippocampal system, these cells are required for brain network oscillations and temporal coding, and selective impairments in this interneuron population result in impaired cognitive performance on learning and memory tasks. Therefore, the septo-hippocampal system may be one network affected by Scn1a deficits. The goal of this proposal is to address the question of whether Scn1a deficits contribute to cognitive impairment. We hypothesize that Scn1a deficits in the septo-hippocampal system are sufficient to impair cognition independently of the seizure disorder. We will use in vivo electrophysiological and behavioral techniques combined with RNAi silencing of Scn1a expression in rats to test this hypothesis.
Our specific aims are to (1) determine the effects of Scn1a deficits in the septo-hippocampal system on cognition, and (2) to investigate the effects of Scn1a deficits on neural network oscillations and coding. These experiments will be important for elucidating a neural network mechanism that may contribute to impaired cognition caused by Scn1a gene mutations.

Public Health Relevance

Using a novel approach to investigate the effects of a genetic deficit on brain physiology, the goal of this research project is to determine the underlying mechanisms contributing to cognitive impairment in the severe childhood disorder of epilepsy, Dravet syndrome. Although cognitive impairment in epilepsy is typically attributed to seizures, our prior studies indicate that the genetic deficit found in patients with Dravet syndrome independently contributes to the decline in cognitive function. This investigation will therefore be important to determine if additional treatment strategies to the traditional anti-epileptic drugs should be pursued in the effort to develop therapies for improving cognitive outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS077537-02
Application #
8333561
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fureman, Brandy E
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$38,832
Indirect Cost
Name
Dartmouth College
Department
Neurology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Bender, Alex C; Natola, Heather; Ndong, Christian et al. (2013) Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol Dis 54:297-307
Bender, Alex C; Morse, Richard P; Scott, Rod C et al. (2012) SCN1A mutations in Dravet syndrome: impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav 23:177-86