title: 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 weeks old) and their healthy littermate heterozygous (+/b) Belgrade rats 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 copper transporter 1 and exporter copper-transporting ATPase 1 were up-regulated in the hippocampus from b/b rats. Finally, b/b rats exhibited increased 8-isoprostane levels and decreased glutathione/glutathione disulfide 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. Iron-copper model: Mutations in the divalent metal transporter 1 (DMT1) decrease body iron status and up-regulate copper absorption, which leads to copper loading in the brain and consequently increases metal-induced oxidative stress. This event disrupts GABAergic neurotransmission and promotes impulsivity-like behavior. Our model provides better understanding of physiological risks associated with imbalanced metal metabolism in mental function and, more specifically, the interactions with GABA and redox control in the treatment of emotional disorders.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Murui
authors.initials: M
authors.lastname: Han
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA.
authors.forename: JuOae
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA. j.kim@neu.edu.
authors.forename: Jonghan
authors.initials: J
authors.lastname: Kim
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001522:Behavior, Animal; D001923:Brain Chemistry / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D015536:Down-Regulation; D004644:Emotions / Q000502:physiology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007175:Impulsive Behavior; D007501:Iron / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives; D009154:Mutation / Q000235:genetics; D019159:Nonheme Iron Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011963:Receptors, GABA-A / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D000251:Adenosine Triphosphatases; D027682:Cation Transport Proteins; D003300:Copper; D000079923:Copper Transporter 1; D050485:GABA Plasma Membrane Transport Proteins; D007501:Iron; D008715:Methionine; D019159:Nonheme Iron Proteins; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D000099236:Solute Carrier Family 11, Member 2; C108102:2-(2'-(methylthio)ethyl)methionine
keywords: Belgrade rats; GABA; Wilson's disease; elevated plus maze; emotion; oxidative stress