Temporal lobe epilepsy (TLE), the most common form of partial epilepsy, remains the cause of seizures most resistant to treatment. Understanding its pathophysiology is fundamental to designing more effective therapies. The hippocampus is a site of major pathology in TLE and has been the major focus of intense research, but the pathophysiology of this disorder remains unknown. The entorhinal cortex (EC) is intimately involved in hippocampal function and has pathological changes in TLE and experimental epilepsy. EC layer IV receives major inputs from the hippocampus, and layer II provides major output to the hippocampus, creating a potential reverberatory circuit to initiate or propagate seizures. EC neurons are clearly hyperexcitable in animal models, which may contribute to its propensity for seizures. This proposal examines inhibition in the EC as one cause of hyperexcitability, using an animal model of chronic epilepsy exhibiting spontaneous seizures and similar to human TLE. Three fundamental concepts are considered: 1)Hyperexcitability of layer II in epileptic rats is associated with altered inhibition, but this has not been explored in layer IV. WE will examine layer IV cells for electrophysiologic evidence of altered inhibition associated with chronic epilepsy to determine if altered inhibition is a general finding in this disorder. 2)Loss of inhibitory interneurons has been implicated in altered inhibition in the hippocampus, but not the EC. WE will examine the EC for anatomic evidence of layer specific selective loss of GABAergic inhibitory interneurons 3)Gaba receptors mediate inhibitory neurotransmission and are altered in the hippocampus. We will examine layer specific GABA alpha and GABA beta receptor density in the EC and potential alterations in GABA alpha receptor subunit expression by in situ hybridization. The information obtained by these studies will outline the nature of altered inhibition in EC associated with spontaneous seizures and will assist in the development of new and more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001992-02
Application #
2891449
Study Section
NST-2 Subcommittee (NST)
Program Officer
Jacobs, Margaret
Project Start
1998-04-15
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Virginia
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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