Medically intractable temporal lobe epilepsy (TLE) is often treated by surgical removal of the anterior tip of the temporal lobe and the entire hippocampus. This tissue affords an unique opportunity for examining the characteristics of a human epileptogenic focus. Such information could also proove useful to the surgeon for development new strategies for in activating a seizure focus. This proposal aims at examining human epileptogenic tissue and testing the hypothesis that its increased excitability could be found in the reorganization of its neurotransmitter systems and/or the processes that mediate neurotransmitter action. To this and the distribution of nertotransmitter receptor systems for glutamate (GLU), GABA, somatostatin (SOM), neuropeptide Y (NPY) and dynorphin (DYN) will be studied with autoradiographic methods. The 2nd messenger adenylate cyclase and phosphoinositide systems will be localized with (3H)PDBu to label protein kinase C, (3H)IP3 to tag the IP3 receptor, and (3H)-forskolin to label the Gs adenylate cyclase complex. In order to assess the biosynthesis of the peptides SOM, NPY and DYN, in situ hybridization experiments will be done. Further, the distribution of the protooncogene protein c-fos will be examined immunocytochemically to determine if it is involved in human seizures as in animals. Giant 2D gel electrophoresis of epileptogenic tissue will attempt to identify any proteins unit to the seizure focus. Rats with heat induced seizures will be evaluated is a model for human TLE of non-tumor origin, and for the study of febrile seizures and the developmental outcome of such seizures. 2-deoxyglucose mapping of metabolic activity and for expression will be used to determine the origin and spread of seizures in these rats. Neuronal counts; light and electron microscopic immunocytochemical localization of neuroactive substances (GABA, Glutamate, SOM, NPY, DYN); autoradiographic mapping of the receptors for these substances; and second messenger systems; along with in situ hybridization experiments for peptide biosynthesis will determine the similarity of the changes induced by seizures in the rat to those of the human. The consequences of seizures induced in neonatel rats on their adult hippocampal organization will be evaluated to determine if there are sensitive periods during which febrile seizures lead to adult onset seizures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS027081-01
Application #
3413257
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1989-04-01
Project End
1992-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Xie, H; Brines, M L; de Lanerolle, N C (1998) Transcripts of the transposon mariner are present in epileptic brain. Epilepsy Res 32:140-53
O'Connor, E R; Sontheimer, H; Spencer, D D et al. (1998) Astrocytes from human hippocampal epileptogenic foci exhibit action potential-like responses. Epilepsia 39:347-54
Brines, M L; Sundaresan, S; Spencer, D D et al. (1997) Quantitative autoradiographic analysis of ionotropic glutamate receptor subtypes in human temporal lobe epilepsy: up-regulation in reorganized epileptogenic hippocampus. Eur J Neurosci 9:2035-44
de Lanerolle, N C; Williamson, A; Meredith, C et al. (1997) Dynorphin and the kappa 1 ligand [3H]U69,593 binding in the human epileptogenic hippocampus. Epilepsy Res 28:189-205
Brines, M L; Dare, A O; de Lanerolle, N C (1995) The cardiac glycoside ouabain potentiates excitotoxic injury of adult neurons in rat hippocampus. Neurosci Lett 191:145-8
de Lanerolle, N C; Brines, M L; Kim, J H et al. (1992) Neurochemical remodelling of the hippocampus in human temporal lobe epilepsy. Epilepsy Res Suppl 9:205-19;discussion 220
de Lanerolle, N C; Brines, M; Williamson, A et al. (1992) Neurotransmitters and their receptors in human temporal lobe epilepsy. Epilepsy Res Suppl 7:235-50