Iron Is Essential for Neuron Development and Memory Function in Mouse Hippocampus

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.

A role for iron deficiency in dopaminergic neurodegeneration

“…Low serum ferritin is often seen in infants born to severely anemic mothers (23). Hippocampal iron deficiency induced by tissue-specific knockout of Slc11a2 caused defective hippocampal development and spatial memory (24). Collectively, these studies indicate a critical role for maternal iron status and dietary iron in early neural development.…”

In vivo assessment of myelination by phase imaging at high magnetic field

“…Iron staining was done using a modified Perls iron staining as described previously (Carlson et al, 2009). Briefly, free floating sections of a P30 control brain and the P30 iron extracted brain were simultaneously incubated for 5 min in 10% potassium ferrocyanide (Sigma Aldrich).…”

Diagnosis and Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children (0–3 Years of Age)

“…These observations would explain the behavioral findings in human infants that have been associated with ID. [29][30][31] Therefore, taking into account that iron is the world's most common single-nutrient deficiency, it is important to minimize IDA and ID among infants and toddlers, even if an unequivocal relationship between IDA and ID and neurodevelopmental outcomes has yet to be established.…”

“…3,[23][24][25][26][27][28][29][30][31] Results of a preponderance of studies have demonstrated an association between IDA in infancy and later cognitive deficits. Lozoff et al 3,25 have reported detecting cognitive deficits 1 to 2 decades after the irondeficient insult during infancy.…”