Abstracts

RATIONALE: Previous studies have indicated that C57BL/6 mice are relatively resistant to neuronal loss following kainate induced status epilepticus (Schauwecker and Steward, [italic]Proc.Natl.Acad.Sci.USA[/italic], 94:4103-8, 1997). The goals of this study were to determine if this mouse strain is also resistant to neuronal damage following pilocarpine induced seizures and to compare the patterns of neuronal loss to those commonly found in pilocarpine treated rats.
METHODS: Seizures were induced in adult C57BL/6 mice by systemic injection of pilocarpine (320 mg/kg, i.p.). The distributions of degenerating neurons were examined at short intervals (24 hours - 1 week) with Fluoro-Jade methods. Patterns of neuronal loss were determined at 1-8 weeks by cresyl violet staining and immunohistochemical localization of NeuN, a general marker of neuronal nuclei.
RESULTS: Pilocarpine treatment produced sustained behavioral seizures in a high percentage of C57BL/6 mice. These mice resumed normal behavior within 1-2 days but then developed spontaneous seizures at 1-3 weeks following the induced seizures. Very close similarities were found between the brain regions that contained degenerating neurons at early time points, as identified by Fluoro-Jade, and the regions with neuronal loss that were evident in NeuN labeled specimens at later time points. In the hippocampal formation, the patterns of neuronal damage were similar to those observed in pilocarpine treated rats. Extensive damage was found consistently in the hilus and CA3, and more variable amounts of neuronal loss were observed in CA1 and CA2. Substantial neuronal degeneration was also evident in several amygdaloid nuclei. Within the thalamus of the C57BL/6 mice, severe neuronal loss was confined to specific nuclei that included the lateral dorsal, reuniens and intralaminar nuclei. Neuronal loss in many other thalamic nuclei was less severe than that in the rat. Interestingly, very little neuronal degeneration was observed in the piriform cortex where severe damage is generally found in the rat. Neuronal loss in other regions of the cerebral cortex was also less severe in the C57BL/6 mice than in Sprague-Dawley rats.
CONCLUSIONS: Extensive neuronal damage occurs in the hippocampus of C57BL/6 mice following pilocarpine induced status epilepticus, and this appears to contrast with the relative invulnerability of hippocampal neurons in this mouse strain to kainate induced seizure damage. However, the extent and location of neuronal damage in several other regions of the CNS appears to be less severe and more selective in the C57BL/6 mice than in Sprague-Dawley rats. The consistent development of spontaneous seizures in these mice, despite the more restricted neuronal loss, suggests that the pilocarpine treated C57BL/6 mouse could be a particularly useful animal model of temporal lobe epilepsy. These mice also could provide a baseline for evaluating the influence of various genetic alterations on neuronal damage and epileptogenesis in mice with a C57BL/6 genetic background.
[Supported by: VA Medical Research Funds.]