INJURY-INDUCED HIPPOCAMPAL EPILEPTOGENESIS IN EXPERIMENTAL MODELS OF TEMPORAL LOBE EPILEPSY IN THE RAT
AuthorBumanglag, Argyle V.
AdvisorSloviter, Robert S.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
EmbargoEmbargo: Release after 12/9/2011
AbstractThe mechanism by which brain injuries cause temporal lobe epilepsy is unknown. Suspected epileptogenic insults include neuron loss and secondary processes triggered by injury. Difficulties in determining which abnormalities precede the onset of seizures, and could play a causal epileptogenic role, have been a major obstacle to progress. Chemoconvulsant-induced status epilepticus in animals has been widely used to induce epilepsy experimentally, but it has been impossible to determine when epileptogenesis occurs because early seizures could be the result of residual drug. As an alternative to chemoconvulsants, perforant pathway stimulation-induced status epilepticus was used to produce limited brain injury and to initiate hippocampal epileptogenesis. Continuous video monitoring and granule cell layer recording determined the latencies to hippocampal epileptiform events and clinical seizures. Spontaneous hippocampal epileptiform discharges and behavioral seizures were recorded during the first three days post-injury, indicating that hippocampal epileptogenesis is a rapid process coincident with neuron loss, and that the short latency to clinical epilepsy might be due to damage to all brain regions that normally act as barriers to seizure spread. To test this hypothesis, a less injurious stimulation paradigm was developed. Histological analysis confirmed neuronal injury mainly limited to the hippocampus and entorhinal cortex. Continuous monitoring after twenty-four hours of stimulation revealed that whereas spontaneous hippocampal granule cell population spikes and focal epileptiform discharges were coincident with initial neuron loss, the latency to the first clinical behavioral seizure was 14-35 days. Early focal seizures were associated with brief granule cell layer epileptiform discharges that lasted 34.7 ± 3.0 seconds, whereas generalized motor seizures were associated with longer granule cell layer epileptiform discharges 126.0 ± 12.8 seconds in duration. These results indicate that hippocampal epileptogenesis is an immediate network defect coincident with initial neuron loss, rather than with delayed secondary processes, and that the "latent period," when one exists, may represent a "kindling" process in which initially focal seizures slowly overcome undamaged barriers to seizure spread. The finding that hippocampal epileptogenesis develops coincident with the initial injury, rather than with slower secondary processes, suggests that neuroprotection in the immediate post-injury period may be the most effective anti-epileptogenic strategy.
Degree ProgramGraduate College