Loss of divalent metal transporter 1 function promotes brain copper accumulation and increases impulsivity

Abstract

The divalent metal transporter 1 (DMT1) is a major iron transporter required for iron absorption and erythropoiesis. Loss of DMT1 function results in microcytic anemia. While iron plays an important role in neural function, the behavioral consequences of DMT1 deficiency are largely unexplored. The goal of this study was to define the neurobehavioral and neurochemical phenotypes of homozygous Belgrade (b/b) rats that carry DMT1 mutation and explore potential mechanisms of these phenotypes. The b/b rats (11–12 wk old) and their healthy littermate heterozygous (+/b) Belgrade rats used as controls, were subject to elevated plus maze tasks. The b/b rats spent more time in open arms, entered open arms more frequently and traveled more distance in the maze than +/b controls, suggesting increased impulsivity. Impaired emotional behavior was associated with down-regulation of GABA in the hippocampus in b/b rats. Also, b/b rats showed increased GABAA receptor α1 and GABA transporter, indicating altered GABAergic function. Furthermore, metal analysis revealed that b/b rats have decreased total iron, but normal non-heme iron, in the brain. Interestingly, b/b rats exhibited unusually high copper levels in most brain regions, including striatum and hippocampus. Quantitative PCR analysis showed that both copper importer Ctr1 and exporter Atp7a were up-regulated in the hippocampus from b/b rats. Finally, b/b rats exhibited increased 8-isoprostane levels and decreased GSH/GSSG ratio in the hippocampus, reflecting elevated oxidative stress. Combined, our results suggest that copper loading in DMT1 deficiency could induce oxidative stress and impair GABA metabolism, which promote impulsivity-like behavior.

Influence of iron metabolism on manganese transport and toxicity

“…Functional studies using the duodenum from b/b rats revealed a ~70% reduction in Mn transport activity 45, 46 . Consistently, basal Mn levels are lower in the liver and blood of b/b rats compared with control rats 45, 47 . However, Shawki et al recently reported that specific-knockout of intestinal DMT1 does not affect the absorption or tissue distribution (including spleen, heart, kidney and liver) of Mn in mice 48 .…”

“…However, the contribution of DMT1 to Mn distribution appears to be limited to the uptake process, and steady-state levels of Mn in the tissue could be more dependent on the export process. For example, b/b rats has lower or unchanged basal Mn levels in the liver compared with control rats 45, 47 , whereas the distribution of intravenously injected 54 Mn into the liver is greater in b/b rats 45 . Since the liver transfers Mn into the bile for excretion 92 , it is possible that Mn excretion is enhanced in b/b rats.…”

“…Crossgrove et al demonstrated that dysfunction of DMT1 does not affect the transport of free 54 Mn 2+ in serum or Tf- 54 Mn into the brain, as assessed by both in vivo and in situ brain perfusion experiments 96 , which is different from 59 Fe transport 97 . Han et al revealed that b/b rats have normal levels of Mn in the brain 47 . These studies suggest that DMT1 is not a primary transporter responsible for Mn uptake into the brain.…”

Oral nucleic acid therapy using multicompartmental delivery systems

“…DMT1 can be validated by using DMT1 mutant rats expressing nonfunctional DMT1. [109][110][111][112]144,145 3. The availability of HFE-deficient mice, a genetic model of iron overload hemochromatosis in humans, 113,114,[146][147][148] will allow investigators to explore the therapeutic efficacy of DMT1 siRNA against iron overload.…”

Neuroprotective effect of dietary black seed flour on key enzymes linked with neuronal signaling molecules in rats exposed to mixture of environmental metals

“…A few of investigations reported both sub‐acute and sub‐chronic toxic effect of metal mixture on hypothalamus, anterior pituitary as well as cerebrum using animal models (Bo & Yanli, ; Han, Chang, & Kim, ; Menon, Chang, & Kim, ). Also, from our laboratory, metabolic alterations involving antagonistic and competitive interactions were speculated as the major mechanism by which mixed‐metals elicit their toxic manifestations in brain tissues (Akintunde & Oboh, ).…”