Iron is essential for neuron development and memory function in mouse hippocampus 1-3

Erik S. Carlson, Ivan Tkac, Rhamy Magid, Michael B. O'Connor, Nancy C. Andrews, Timothy Schallert, Hiromi Gunshin, Michael K.Georgieff, Anna Petryk

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

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 cre 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.

Original languageEnglish (US)
Pages (from-to)672-679
Number of pages8
JournalJournal of Nutrition
Volume139
Issue number4
DOIs
StatePublished - Apr 1 2009

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