Temporal lobe epilepsy, the most common form of adult focal epilepsies, is often resistant to anticonvulsant therapy. Recently, surgery outcome has been improving, however, 15 - 30% of patients still report having seizures 5 years after surgery. Although it is generally agreed that epilepsy results from a disruption of the balance between excitation and inhibition, genetic and environmental factors and possibly a brain insult such as anoxia, infection or head injury may be involved in the expression of TIE. In many cases, the precipitating brain insult cannot be clinically recognized, and thus epileptogenesis may be difficult to detect and stop, prior to the development of the first spontaneous seizure. Thus, one line of treatment should involve cessation of spontaneous seizures once they occur. Anticonvulsants used to limit or prevent acute seizures might not prevent seizures in a chronic epilepsy. This indicates that mechanisms involved in generating acute seizures may be different from those involved in maintaining a chronic epileptic state. To develop drugs against a chronic epileptic state, the mechanisms involved in spontaneous seizures generation and maintenance after the latent phase should be elucidated. Synaptic activation of NMDA receptors has been reported to be increased after kindling. The high sensitivity of NMDA receptor activation to afferent firing rate raises the possibility that enhanced NMDA receptor responses to low frequency afferent firing in the epileptic state contributes to reduced seizure threshold. Increased expression of postsynaptic glutamate receptors would increase the degree of depolarization during repetitive stimulation. NMDA receptor activity in the hippocampus is altered after kindling, but the nature of the changes in NMDA receptors after epileptogenesis has not been elucidated. NMDA receptors bind glutamate with a higher affinity than AMPA receptors and lengthen the EPSP time course. Differences in biophysical properties of different receptor subtypes such as glutamate dissociation rates and magnesium binding affinities can also contribute to increased depolarization in the postsynaptic cell. We plan to determine if temporal summation of EPSPs is increased in CA1 pyramidal cells of the hippocampus in chronically epileptic rats, and if such increases are mediated by NMDA receptors. Seizures associated with Temporal Lobe Epilepsy are often generated in the hippocampus. This project focuses on determining how glutamate receptor mediated excitation changes in seizure prone CA1 pyramidal cells in the hippocampus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Minority Biomedical Research Support Thematic Project Grants (S11)
Project #
5S11NS055883-05
Application #
8097411
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Stewart, Randall R
Project Start
2007-08-15
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$245,000
Indirect Cost
Name
Morehouse School of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
102005451
City
Atlanta
State
GA
Country
United States
Zip Code
30310
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