Kainate-induced zinc translocation from presynaptic terminals causes neuronal and astroglial cell death and mRNA loss of BDNF receptors in the hippocampal formation and amygdala.

To evaluate the potential role of endogenous zinc in the pathophysiology of epilepsy, we injected kainic acid into the medial septum, which evokes seizure activity and delayed hippocampal degeneration. Different approaches were used. In the hippocampus, we found a movement of zinc from the synaptic compartment to CA1 pyramidal neurons and astrocytes after kainate. The same was true in the amygdala. We found that in those areas showing intense zinc bleaching there was also a loss of reactive astrocytes, which supports the view that release of synaptic zinc induces astrocytic cell death. We have also tested whether the kainate-induced zinc movement from the synaptic compartment to neuronal or glial cells alters the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, trkB. There was a prominent loss of expression of trkB mRNA in areas that coincided precisely with those displaying astrocyte loss and zinc bleaching. In the amygdala, these events were accompanied by a high upregulation of BDNF mRNA. To demonstrate further a role of synaptic zinc in hippocampal pathology, we used two different approaches. We first injected different doses of zinc chloride in the CA1 area. At lower doses (0.1-10 nmol), zinc chloride selectively induced apoptosis in CA1 pyramidal neurons and dentate granular neurons. In a second approach, we found that hippocampal zinc chelation was effective in protecting CA1 pyramidal neurons against kainate-induced cell death.