NEURONAL STRESS AND INJURY IN C57 BL MICE AFTER SYSTEMIC KAINIC ACID ADMINISTRATION/

Kainate-induced seizures are widely studied as a model of human tempor al lobe epilepsy due to behavioral and pathological similarities. whil e kainate-induced neuronal injury is well characterized in rats, relat ively little data is available on the use of kainate and its consequen ces in mice. The growing availability of genetically altered mice has focused attention on the need for well characterized mouse seizure mod els in which the effects of specific genetic manipulations can be exam ined. We therefore examined the kainate dose-response relationship and the time-course of specific histopathological changes in C57/BL mice, a commonly used founder strain for transgenic technology. Seizures we re induced in male C57/BL mice (kainate 10-40 mg/kg i.p.) and animals were sacrificed at various time-points after injection. Seizures were graded using a behavioral scale developed in our laboratory. Neuronal injury was assayed by examining DNA fragmentation using in situ nick t ranslation histochemistry. In parallel experiments, we examined the ex pression an inducible member of the heat shock protein family, HSP-72, another putative marker of neuronal injury, using a monoclonal antibo dy. Seizure severity paralleled kainate dosage. At higher doses DNA fr agmentation is seen mainly in hippocampus in area CA3, and variably in CA1, thalamus and amygdala within 24 h, is maximal within 72 h, and i s largely gone by 7 days after administration of kainate. HSP-72 expre ssion is also highly selective, occurring in limbic structures, and it evolves over a characteristic time-course. HSP-72 is expressed mainly in structures that also manifest DNA fragmentation. Using double-labe ling techniques, however, we find essentially no overlap between neuro ns expressing HSP-72 and DNA fragmentation. These findings indicate th at DNA fragmentation and HSP-72 expression are complementary markers o f seizure-induced stress and injury, and support: the notion that HSP- 72 expression is neuroprotective following kainate-induced seizures. ( C) 1998 Elsevier Science B.V. All rights reserved.