Young ceruloplasmin knock-out mice exhibit increased neuronal vulnerability and increased anxiety: Roles for iron and BDNF

Ceruloplasmin (Cp) is a ferroxidase involved in iron metabolism by converting Fen2+ to Fen3+, and thereby regulating cellular iron efflux. In theceruloplasmin knockout (CpKO) mouse, the deregulation of iron metabolism is highlighted by liver and spleen hemosiderosis. Previous findings suggest that the proper regulation and subcellular localization of iron are very important in brain cell function and viability, however, the impact of Cp deficiency on brain neurochemistry, behavior and neuronal vulnerability is unknown. We found that in contrast to the observations in peripheral tissues, young (3 month old) CpKO mice exhibit decreased iron levels in the hippocampus cortex and striatum. We found that levels of serotonin and norepinephrine, known to be affected by iron concentration, are significantly reduced in these brain areas of the CpKO mice. Additionally in these brain areas we found reductions in the expression of the neurotrophin brain derived neurotrophic factor (BDNF) and its receptor trkB. BDNF levels have been shown to be affected by serotonin and norepinephrine levels, but we also demonstrated through chelator-mediated depletion of iron in cultured neural cells, a causal link between low brain iron levels and reduced BDNF expression. Behavior analysis of young CpKO mice revealed heightened anxiety-like behavior in the open field and elevated plus maze tests associated with elevated levels of plasma corticosterone. CpKO mice exhibited no deficits in motor function or learning and memory. In addition, when the young CpKO mice were subjected to middle cerebral artery occlusion, a model of focal ischemic stroke, we found increased brain damage compared to WT controls. Common stroke parameters such as lipid peroxidation measures, cytokine levels and astrocyte reactivity were not different between the two animal groups. The findings described above demonstrate that lack of Cp results in decreases in levels of iron, serotonin, norepinephrine and BDNF in multiple brain regions, that in the hippocampus (a modulator of emotional behavior) contributes to the anxiety phenotype and in the cortex and striatum leads to increased neuronal vulnerability to ischemia. This research highlights the importance of Cp in brain iron maintenance and suggests that even small decreases in brain iron levels can lead to behavioral abnormalities and render neurons vulnerable to degeneration.