The role of iron in learning and memory

Abstract

Iron deficiency (ID) is the most common nutrient deficiency, affecting 2 billion people and 30% of pregnant women and their offspring. Early life ID affects at least 3 major neurobehavioral domains, including speed of processing, affect, and learning and memory, the latter being particularly prominent. The learning and memory deficits occur while the infants are iron deficient and persist despite iron repletion. The neural mechanisms underlying the short- and long-term deficits are being elucidated. Early ID alters the transcriptome, metabolome, structure, intracellular signaling pathways, and electrophysiology of the developing hippocampus, the brain region responsible for recognition learning and memory. Until recently, it was unclear whether these effects are directly due to a lack of iron interacting with important transcriptional, translational, or post-translational processes or to indirect effects such as hypoxia due to anemia or stress. Nonanemic genetic mouse models generated by conditionally altering expression of iron transport proteins specifically in hippocampal neurons in late gestation have led to a greater understanding of iron's role in learning and memory. The learning deficits in adulthood likely result from interactions between direct and indirect effects that contribute to abnormal hippocampal structure and plasticity.

Figure 1

Classic mechanism of neuronal iron uptake. Mono- or di-ferric Tf is bound to its transmembrane receptor, TfR-1. The Tf:TfR-1 complex is endocytosed into the neuronal cytoplasm. After endosomal acidification and reduction of ferric iron, ferrous iron is transported by DMT-1 across the endosome membrane for utilization in hemoproteins and iron cluster proteins or for storage in ferritin. The residual apo-Tf and TfR-1 are recycled to the extracellular space to reinitiate the cycle.

Figure 2

Coincidental events during hippocampal neuronal differentiation in the rodent. The waveforms represent relative amounts of activity of a given process across the life span. Supporting references in parentheses accompany each waveform. Note that activity peaks for all processes between birth and P25 in the rodent. The corresponding developmentally equivalent time points in the human are shown above the rodent time points.

Figure 3

The role of iron in regulating the mTOR signaling pathway. Note potential entry points where iron can directly and indirectly alter mTOR signaling. Figure adapted with permission from Wullschleger et al. (80). Citations supporting the evidence for iron regulation are noted in parentheses.

Figure 4

Conceptualization of early life ID effects on neuronal processes mediating short- and long-term learning and memory.