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Ingestive Behavior and Neurosciences

Iron Is Essential for Neuron Development and Memory Function in Mouse Hippocampus^1,2,3

⁴ Medical Scientist Training Program, Minneapolis, MN 55455 ⁵ Graduate Program in Neuroscience, Minneapolis, MN 55455 ⁶ Pediatrics, Minneapolis, MN 55455 ⁷ Center for Neurobehavioral Development, Minneapolis, MN 55455 ⁸ Center for Magnetic Resonance Research, Minneapolis, MN 55455 ⁹ Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN 55455 ¹⁰ Howard Hughes Medical Institute, Chevy Chase, MD 20815 ¹¹ Duke University School of Medicine, Durham, NC 27710 ¹² Institute for Neuroscience, University of Texas, Austin, TX 78712 ¹³ Department of Psychology, University of Texas, Austin, TX 78712 ¹⁴ Department of Nutrition, University of Massachusetts, Amherst, MA 01003

Iron deficiency (ID) is the most prevalent micronutrient deficiency in the world and it affects neurobehavioral outcome. It is unclear whether the effect of dietary ID on the brain is due to the lack of neuronal iron or from other processes occurring in conjunction with ID (e.g. hypoxia due to anemia). We delineated the role of murine Slc11a2 [divalent metal ion transporter-1 (DMT-1)] in hippocampal neuronal iron uptake during development and memory formation. Camk2a gene promoter-driven creatine recombinase (Cre) transgene (Camk2a-Cre) mice were mated with Slc11a2 flox/flox mice to obtain nonanemic Slc11a2^hipp/hipp (double mutant, hippocampal neuron-specific knockout of Slc11a2_hipp/hipp) mice, the first conditionally targeted model of iron uptake in the brain. Slc11a2^hipp/hipp mice had lower hippocampal iron content; altered developmental expression of genes involved in iron homeostasis, energy metabolism, and dendrite morphogenesis; reductions in markers for energy metabolism and glutamatergic neurotransmission on magnetic resonance spectroscopy; and altered pyramidal neuron dendrite morphology in area 1 of Ammon's Horn in the hippocampus. Slc11a2^hipp/hipp mice did not reach the criterion on a difficult spatial navigation test but were able to learn a spatial navigation task on an easier version of the Morris water maze (MWM). Learning of the visual cued task did not differ between the Slc11a2^WT/WT and Slc11a2^hipp/hipp mice. Slc11a2^WT/WT mice had upregulation of genes involved in iron uptake and metabolism in response to MWM training, and Slc11a2^hipp/hipp mice had differential expression of these genes compared with Slc11a2^WT/WT mice. Neuronal iron uptake by DMT-1 is essential for normal hippocampal neuronal development and Slc11a2 expression is induced by spatial memory training. Deletion of Slc11a2 disrupts hippocampal neuronal development and spatial memory behavior.

^* To whom correspondence should be addressed. E-mail: georg001{at}umn.edu.

Manuscript received 26 August 2008. Initial review completed 21 October 2008. Revision accepted 13 January 2009.