Induction by synaptic zinc of heat shock protein-70 in hippocampus after kainate seizures

Following seizures, heat shock protein (HSP)-70 is induced in various brain regions, Since zinc that can induce HSP-70 in various cell systems is enriched in certain glutamatergic terminals and translocates to postsynaptic neurons with seizures, we examined the possibility that HSP-70 induction in the epileptic brain is mediated by synaptic zinc. Adult rats were injected intraperitoneally with kainate to induce seizures. Seizures were halted 3 h after the kainate administration by the injection of phenytoin. Staining of brain sections with zinc-specific fluorescent dye Tn at 24 h after the kainate injection revealed a one-to one correlation between dense Tn fluorescence and acidophilic neuronal degeneration in the hippocampus. Subsequent staining with anti-HSP-70 antibody, however, revealed that more numerous neurons than degenerating neurons exhibited HSP-70 immunoreactivity, Most of the HSP-70(C) neurons were not stained with acid fuchsin but exhibited mild zinc fluorescence in the cytoplasm, Intraventricular injection of CaEDTA attenuated neuronal death as well. as the HSP-70 induction in a dose-dependent manner. Supporting the specificity of zinc rather than calcium as the inducer of HSP-70 in neurons, exposure to zinc but not to a calcium ionophore or excitotoxins increased expression of HSP-70 mRNA and protein in cultured cortical neurons. The present results suggest that not only selective neuronal death, but also HSP-70 induction in neurons after seizures, is mediated by the translocation of endogenous synaptic zinc. (C) 2000 Academic Press.