Site-specific neural hyperactivity via the activation of MAPK and PKA/CREB pathways triggers neuronal degeneration in methylmercury-intoxicated mice.

Methylmercury (MeHg) induces site-specific neurotoxicity in the adult brain. In this study, we investigated the site-specific expression of the signaling cascade related to neural activity in a mouse model of MeHg intoxication showing neurodegeneration only in the deep layer of the cerebral cortex, especially layer IV. We performed time course studies of c-fos and brain-derived neurotrophic factor (BDNF) expression levels which are proper markers of neural activity. We showed that upregulation of both markers preceded the neuronal degeneration in the cerebral cortex. Immunohistochemical analysis revealed the site-specific upregulation of c-fos in the deep layer of the cerebral cortex. Western blot analysis showed that c-fos and BDNF expression was associated with CREB phosphorylation, which was triggered by the activation of the p44/42 MAPK, p38 MAPK and PKA pathways. However, we did not detect any changes in the expression levels of c-fos and BDNF proteins and no signs of neuronal degeneration in the hippocampus and cerebellum, despite the fact that we could detect accumulation of MeHg in these two brain regions. These results suggested an intriguing possibility that MeHg-induced neuronal degeneration was caused by site-specific neural hyperactivity triggered by the activation of MAPK and PKA/CREB pathways followed by c-fos and BDNF upregulation.