(Investigator s Abstract). This project is designed to study in vivo molecular mechanisms in the hippocampus which initiate and guide new, aberrant synaptic connections that may lead to chronic seizure in human epilepsy by inducing and following the time course of cell loss and sprouting in a rat model. The neurobiology of aberrant synaptic reorganization in hippocampal sclerosis will be compared to similar molecular mechanism of axon growth and synaptogenesis seen during development. This proposal will answer two biologically significant questions: 1) Do the cellular, molecular, and axon growth patterns after damage follow the developmental programs or retain other mature programs? 2) Does chronic hippocampal rat epilepsy model true human hippocampal epilepsy in its interictal EEG spikes, focal EEG seizures, synaptic reorganizations, and molecular expressions? These experiments will test for molecular mechanisms that correlate with several unexplained phenomena in epilepsy: 1) What is the developmentalcritical period for susceptibility to damaged-induced epilepsy?2) What causes the long latent period between acute injury/acute seizures and eventual chronic seizures? 3) Are neurotrophic factors upregulated to maintain epileptic neoinnervation and/or to maintain synaptic hyperexcitability? Temporal lobe epilepsy is the most frequent form of human epilepsy, and in surgical series 65% of patients have hippocampal sclerosis. There is a pattern of cell loss and sprouting characterized by an aberrant monosynaptic feedback of mossy fibers on granule cells of the dentate gyrus which apparently contributes to intractable seizures.Little is known about the mechanisms causing the synaptic reorganization.The proposed research will map the molecular signals in the postnatal to adult developmental sequence in rats using modern in vivo probes for: 1) axonal growth patterns, 2) extrinsic tropic and trophic factors, and 3) target neurotrophic factors. In situ hybridization of messenger ribonucleic acids (mRNA) will be used to further confirm significant changes in the developmental expressions of these growth promoting molecules and synaptogenesis. These studies will be compared to true human epileptic neurons and circuits, an opportunity underway in our lab and critical next step for understanding human epileptogenesis. To compare with normally-developed connections in the rat dentate gyrus, aberrant reactive synaptogenesis will be induced by intrahippocampal damage in rats which will cause hyperexcitability and seizures that often develop into chronic seizures. Simultaneous studies with identical molecular probes will be used in epileptic rats from early postnatal to adult ages to compare the eventual chronic EEG patterns between epileptic rat and man and relate these epileptic changes to alterations or expression of critical proteins involved in different reorganizations. These results may suggest antecedent mechanisms involved in progressive damage in human sclerotic epileptic hippocampus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031655-05
Application #
2379680
Study Section
Neurology A Study Section (NEUA)
Program Officer
Jacobs, Margaret
Project Start
1994-04-01
Project End
2001-02-28
Budget Start
1997-03-01
Budget End
2001-02-28
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Mikuni, N; Babb, T L; Wylie, C et al. (2000) NMDAR1 receptor proteins and mossy fibers in the fascia dentata during rat kainate hippocampal epileptogenesis. Exp Neurol 163:271-7
Babb, T L; Ying, Z; Mikuni, N et al. (2000) Brain plasticity and cellular mechanisms of epileptogenesis in human and experimental cortical dysplasia. Epilepsia 41 Suppl 6:S76-81
Mikuni, N; Babb, T L; Ying, Z et al. (1999) NMDA-receptors 1 and 2A/B coassembly increased in human epileptic focal cortical dysplasia. Epilepsia 40:1683-7
Ying, Z; Babb, T L; Mikuni, N et al. (1999) Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in dysplastic neurons of human epileptic cortex. Exp Neurol 159:409-18
Mikuni, N; Nishiyama, K; Babb, T L et al. (1999) Decreased calmodulin-NR1 co-assembly as a mechanism for focal epilepsy in cortical dysplasia. Neuroreport 10:1609-12
Mikuni, N; Babb, T L; Christi, W (1999) Increased NR1-NR2A/B coassembly as a mechanism for rat chronic hippocampal epilepsy. Neurosci Lett 267:165-8
Babb, T L (1999) Synaptic reorganizations in human and rat hippocampal epilepsy. Adv Neurol 79:763-79
Ying, Z; Babb, T L; Hilbig, A et al. (1999) Hippocampal chemical anatomy in pediatric and adolescent patients with hippocampal or extrahippocampal epilepsy. Dev Neurosci 21:236-47
Mikuni, N; Babb, T L; Chakravarty, D N et al. (1999) Time course of transient expression of GDNF protein in rat granule cells of the bilateral dentate gyri after unilateral intrahippocampal kainic acid injection. Neurosci Lett 262:215-8
Hilbig, A; Babb, T L; Najm, I et al. (1999) Focal cortical dysplasia in children. Dev Neurosci 21:271-80

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