期刊
JOURNAL OF COMPARATIVE NEUROLOGY
卷 518, 期 16, 页码 3381-3407出版社
WILEY
DOI: 10.1002/cne.22406
关键词
hippocampus; epileptogenesis; rat; dentate gyrus
资金
- National Institute of Neurological Disorders and Stroke, National Institutes of Health [NS 18201]
- Fondazione Cariverona
- European Community [LSH-CT-2006-037315]
In refractory temporal lobe epilepsy, seizures often arise from a shrunken hippocampus exhibiting a pattern of selective neuron loss called classic hippocampal sclerosis. No single experimental injury has reproduced this specific pathology, suggesting that hippocampal atrophy might be a progressive endstage pathology resulting from years of spontaneous seizures. We posed the alternative hypothesis that classic hippocampal sclerosis results from a single excitatory event that has never been successfully modeled experimentally because convulsive status epilepticus, the insult most commonly used to produce epileptogenic brain injury, is too severe and necessarily terminated before the hippocampus receives the needed duration of excitation. We tested this hypothesis by producing prolonged hippocampal excitation in awake rats without causing convulsive status epilepticus. Two daily 30-minute episodes of perforant pathway stimulation in Sprague-Dawley rats increased granule cell paired-pulse inhibition, decreased epileptiform afterdischarge durations during 8 hours of subsequent stimulation, and prevented convulsive status epilepticus. Similarly, one 8-hour episode of reduced-intensity stimulation in Long-Evans rats, which are relatively resistant to developing status epilepticus, produced hippocampal discharges without causing status epilepticus. Both paradigms immediately produced the extensive neuronal injury that defines classic hippocampal sclerosis, without giving any clinical indication during the insult that an injury was being inflicted. Spontaneous hippocampal-onset seizures began 16-25 days postinjury, before hippocampal atrophy developed, as demonstrated by sequential magnetic resonance imaging. These results indicate that classic hippocampal sclerosis is uniquely produced by a single episode of clinically cryptic excitation. Epileptogenic insults may often involve prolonged excitation that goes undetected at the time of injury. J. Comp. Neural. 518:3381-3407, 2010. (C) 2010 Wiley-Liss, Inc.
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