Abstract
While nutritional and neurobehavioral problems are associated with both iron deficiency during growth and overload in the elderly, the effect of iron loading in growing ages on neurobehavioral performance has not been fully explored. To characterize the role of dietary iron loading in memory function in the young, weanling rats were fed iron-loading diet (10,000 mg iron/kg diet) or iron-adequate control diet (50 mg/kg) for one month, during which a battery of behavioral tests were conducted. Iron-loaded rats displayed elevated non-heme iron levels in serum and liver, indicating a condition of systemic iron overload. In the brain, non-heme iron was elevated in the prefrontal cortex of iron-loaded rats compared with controls, whereas there was no difference in iron content in other brain regions between the two diet groups. While iron loading did not alter motor coordination or anxiety-like behavior, iron-loaded rats exhibited a better recognition memory, as represented by an increased novel object recognition index (22% increase from the reference value) than control rats (12% increase; P=0.047). Western blot analysis showed an up-regulation of dopamine receptor 1 in the prefrontal cortex from iron-loaded rats (142% increase; P=0.002). Furthermore, levels of glutamate receptors (both NMDA and AMPA) and nicotinic acetylcholine receptor (nAChR) were significantly elevated in the prefrontal cortex of iron-loaded rats (62% increase in NR1; 70% increase in Glu1A; 115% increase in nAChR). Dietary iron loading also increased the expression of NMDA receptors and nAChR in the hippocampus. These results support the idea that iron is essential for learning and memory and further reveal that iron supplementation during developmental and rapidly growing periods of life improves memory performance. Our investigation also demonstrates that both cholinergic and glutamatergic neurotransmission pathways are regulated by dietary iron and provides a molecular basis for the role of iron loading in improved memory.
Highlights
A strong relationship exists between iron status and neurobehavioral functions [1,2,3,4,5,6,7,8]
Since intact blood-brain barrier (BBB) prevents brain from iron loading even at increased iron levels in the circulation [19,55], disruption of the BBB has been proposed as a potential mechanism of elevated brain iron and iron-mediated neurotoxicity
Traumatic brain injury has been shown to be in line with increased brain iron and reduced learning capacity, which was attenuated by iron chelator deferoxamine [56,57]
Summary
A strong relationship exists between iron status and neurobehavioral functions [1,2,3,4,5,6,7,8]. Iron is essential for the development and proper function of the brain, including myelination [9], monoamine metabolism [10] and regulation of nitric oxide synthase [11]. Iron and Memory cofactor for tyrosine hydroxylase and tryptophan hydroxylase, which are enzymes for dopamine and serotonin synthesis, respectively. A recent investigation has demonstrated that iron supplementation enhances brain synaptic plasticity by activation of N-methyl-D-aspartate (NMDA) receptor, a receptor associated with memory function [13], suggesting that altered iron status in the brain significantly modulates neurotransmission pathways and neural activities
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