Epilepsy is a significant neurological disorder characterized by recurrent spontaneous seizures. It is estimated that over 2.3 million Americans have epilepsy with 200,000 new cases of epilepsy being diagnosed each year. Epilepsy is a factor in the deaths of between 25,000 to 50,000 patients each year and is estimated to cost the US $12.5 billion each year. Epilepsy therefore, is a major economic and personal burden for the American public. Unfortunately, antiepileptic drugs (AEDs) are ineffective in approximately 30% of patients. Too often treatment is associated with adverse side effects which may be the result of the AEDs affecting their targets in regions outside the seizure onset zone. In order to develop more effective treatments with fewer side effects there has been a concerted effort to understand the underlying mechanisms by which neurons become hyperexcitable in epilepsy. In chronic epilepsy molecular and cellular changes occur within the seizure onset zone, making it capable of generating spontaneous seizures. It has become clear that these changes have an altered pharmacology so that the development of new therapies that are more specific for the causes of epilepsy will be greatly aided by identifying important changes that are unique to the seizure onset zone. In this proposal we will examine the changes in sodium (Na) channels in epileptogenesis. Na channels play a critical role in controlling neuronal excitability, and so changes in Na channel thresholds and firing patterns would have significant effects on system excitability. Alterations in Na channel behavior, as a result of Na channel mutations, are known to be responsible for a number of inherited forms of generalized epilepsy. Our central hypothesis is that alterations in the expression and physiology of Na channels that make neurons more excitable are found broadly in the limbic system seizure onset zone. To help support the hypothesis that these changes contribute to the development of epilepsy it is necessary to show that the changes occur before the onset of spontaneous seizures and are thus not a consequence of the seizures. Our proposal will focus on medial entorhinal cortex (mEC) and subiculum neurons using an animal model of temporal lobe epilepsy (TLE), a common form of adult pharmaco-resistant epilepsy. We provide preliminary data demonstrating that mEC layer II neurons are intrinsically hyperexcitable in epileptic animals and that Na channel physiology is also altered. We show that changes in neuronal excitability and Na channel behavior occur before the appearance of spontaneous seizures. These findings support our central hypothesis that changes in Na channel expression and physiology contribute to the development of epilepsy.

Public Health Relevance

Epilepsy is a neurological disorder and is a major public health issue affecting over 2 million Americans. Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy that is difficult to treat pharmacologically. The limbic system is known to be heavily implicated in seizure generation in TLE. In this proposal we will determine the changes in sodium channel activity within the limbic system during the development of epileptic seizures in an animal model of TLE. Since Na channels are the target for many clinically used anticonvulsant drugs a better understanding of the importance of Na channels in epileptogenesis could provide a target for therapy development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075157-02
Application #
8412774
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Whittemore, Vicky R
Project Start
2012-02-01
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$325,085
Indirect Cost
$113,991
Name
University of Virginia
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Hargus, Nicholas J; Nigam, Aradhya; Bertram 3rd, Edward H et al. (2013) Evidence for a role of Nav1.6 in facilitating increases in neuronal hyperexcitability during epileptogenesis. J Neurophysiol 110:1144-57