Increases in Iron "Content" or Deposition in Folate Depletion; Folate Depletion Impairs Neurogenesis in Adult Mice

These are interesting articles. Both articles show that folate depletion impairs iron utilization, and this isn't that surprising. Heme formation in erythrocyte precursors is coupled to DNA replication and the cell cycle (I forget the details), and folate repletion restores DNA replication and cell division. But there could be other mechanisms. One interesting thing, something that makes me wonder if that simple explanation is adequate, is that the liver iron content was doubled in response to folate deficiency in this article:

http://www.ncbi.nlm.nih.gov/pubmed/1571542

Again, that could just be that less iron is being used for red blood cell formation in folate deficiency, but the magnitude of the effect is surprising to me. I can't get the full text of this article, at this point, but the magnitude of the increase in red blood cell ferritin (this is not the same as serum ferritin but is analogous to "tissue ferritin," the type(s) of ferritin chains that store iron in the liver or astrocytes or some other tissue) in folate or B12 deficiencies is really large. It's elevated like 60- or 70-fold, and the authors compare it to hemochromatosis:

http://www.ncbi.nlm.nih.gov/pubmed/6505636

An increase in the liver iron (bound to ferritin) content or red blood cell ferritin is not, by itself, evidence of hemochromatosis (that's a genetic difference that causes inappropriate increases in the intestinal absorption of iron), but elevations in the levels of tissue ferritin are not very desirable in the long term.

I suppose this type of thing could have some relevance to restless legs syndrome (RLS), given that both folic acid and iron have sometimes been used, albeit not very effectively, to treat RLS. But I don't know what the mechanism would be. Maybe folate repletion increases the mtDNA content or has another metabolic effect and improves iron utilization in neurons in the basal ganglia, in a way that improves the RLS symptoms. But reduced folates or folic acid might also have no effect on iron utilization by cells in the brain and no consistent effects on RLS symptoms. The folic acid might have just influenced the firing rates of dopaminergic neurons by some complicated mechanism, independently of any effect on iron utilization.

This is a really recent article that's interesting and shows that folate depletion increases amygdalar brain-derived neurotrophic factor (BDNF) (an effect that the authors say is associated with increased anxiety) and somewhat selectively damages dopaminergic neurons in mice lacking a repair enzyme for misincorporated uracil in DNA:

http://www.ncbi.nlm.nih.gov/pubmed/18614692

I'm getting off-topic with this, but this is a really good article. That's sort of like amplifying the effect of folate depletion (to use folate depletion in mice lacking uracil-DNA glycosylase activity) and is similar to the type of thing you'd expect to occur in response to the combination of folate depletion and ischemia. That article is interesting, too, because it shows that folate depletion in normal mice reduces the turnover of serotonin and increases amygdalar and hippocampal noradrenaline. That (along with the increase in amygdalar BDNF levels, according to the authors) could explain some of the effects of methylfolate in psychiatric conditions, and the authors mention that. Increases in the steady-state noradrenaline levels in those parts of the brain could be sort of loosely consistent with the activation of the stress response, producing anxiety in association with folate depletion. The noradrenergic neurons in the locus ceruleus that project to those areas increase their firing rates in response to stressors and anticipatory stress. Folate depletion, in that above article, also decreased neurogenesis in one part of the hippocampus (the dentate gyrus) (http://stemcells.alphamedpress.org/cgi/content/abstract/stemcells.2008-0732v1) that retains the capacity for neurogenesis into adulthood, and that decrease in cell proliferation was accompanied by hippocampal degeneration and decrease in BDNF levels. The folate depletion also interfered with spatial learning and produced "despair-like" behaviors.