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Graduate Program in Nutrition, The Pennsylvania State University, University Park, PA 16802
3 To whom correspondence should be addressed. E-mail: its{at}psu.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • iron deficiency • brain development • behavior • rats • humans • neurotransmitters
Iron deficiency is reported to be the most prevalent nutritional problem in the world today with an estimated 2.5–5 billion people so afflicted (1, 2). Among the numerous biological effects of iron, there is considerable evidence that iron is also important for neurological functioning and development (3– 7). This biological basis of the behavioral and cognitive developmental delays observed in iron-deficient infants is not completely understood but possibilities include: i) abnormalities in neurotransmitter metabolism (3, 6, 8, 9); ii) decreased myelin formation (10); and iii) alterations in brain energy metabolism (11). Although the most recent evidence from human studies using auditory-evoked potential changes in iron-deficient infants does not distinguish between these three biological possibilities, it does point toward slowed central neural processing as a key component in neural dysfunction in iron deficiency (5, 12).
This article will focus on distinct bodies of evidence regarding the role of iron in neural functioning and its relationship to cognition and behavior.
How does the brain get iron and where does it go?
Within the brain, there is a system for the acquisition of iron from the plasma pool (transferrin (Tf) receptor), a mechanism for the dispersal or mobilization of iron (Tf)4, a mechanism for cell-specific iron storage (H and L isoforms of ferritin) and a functional pool of iron within each cell (3, 13, 14). The blood-brain barrier provides an effective regulatory point for iron movement from the plasma pool to the cerebral spinal fluid whereas the choroids plexus is also a likely source of iron movement into and out of the brain. Not all brain regions contain the same amount of iron with the basal ganglia, substantia nigra and deep cerebellar nuclei particularly rich in iron (14, 15). Magnetic resonance imaging (MRI) has recently been used to map iron distribution in the brains of children and adolescents (15, 16). The highest concentrations are found in globus pallidus, caudate nucleus, putamen and substantia nigra. As noted in Figure 1, there is nearly a threefold variation in iron concentrations within rat brain as well as a heterogeneous response to dietary iron deprivation, or iron loading. Areas of the brain that are iron rich in adult rat brains are not iron rich for the first 60 d of life (17). Interestingly, the same is true in humans, where the substantia nigra does not become rich in iron until the age of 12–15 y (16). The concentration of iron is highest in the brain at birth, decreases through weaning, and then begins to increase coincident with the onset of myelination and an increased expression of Tf mRNA (5, 17, 18).
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The previously mentioned studies in human infants of nerve conduction provide some evidence that the effects of iron deficiency on biological neural functioning are irreversible (5, 12). The issue of timing of iron deficiency, therefore, is of great importance. These biological measurements are the first data that directly support the contention that human toddlers with iron deficiency anemia suffer developmental delays due to biological abnormalities. Given the fact that nearly all of the published clinical intervention trials in human infants also fail to show a complete normalization in functioning despite a normalization of iron status, investigators are forced to consider the question of "critical periods" of development that absolutely require adequate iron nutriture for "normal" development. A number of animal studies have been conducted in an attempt to mimic and model the human condition and the timing of nutrient deficiency to coincide with the timing of peak risk of human infant iron deficiency (28). As autopsy data of human infants suffering solely from iron deficiency is nonexistent, we have relied on animal models and imaging methods to argue for the existence of "a critical period". Although the course of development in the rat is more compressed than in humans, in both species there is the same sequence of cell migration, significant myelination, cellular differentiation, and increased expression of neuropeptides. What appears to occur from 3–16 mo postnatal in humans occurs from 7–25 d postnatal in rats (28). Iron deficiency during lactation in the rat results in significant loss of regional brain iron that is distinct from those regions that lose iron with dietary restrictions later in life (22) (Fig. 4). Importantly, the restoration of brain iron with later aggressive dietary iron repletion also resulted in incomplete restoration of abnormalities in dopamine (DA) metabolism and in behaviors related to DA (22, 29, 30); i.e. , the sensitivity of a brain region to loss of iron during development is likely to be related to the regional development requirements for iron during that period. In contrast to the perception that brain iron is "resistant" to iron depletion, these experiments demonstrate quite clearly that in the rodent, dietary treatments can decrease brain iron within 10 d and replete iron within 14 d. Comparative data in human infants or primate models are lacking, thus there remains uncertainty regarding the completeness of brain iron recovery in humans despite full restoration of hematological indices of iron status (5, 12).
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Iron and neurotransmitters
The dopaminergic system develops rapidly during early postnatal life with a rapid increase in the number and density of DA transporters, and receptors in terminal field up to early puberty. Other monoamine transporters and receptors are also being actively expressed in developing neuronal tracts during this time period with continued modification in density up through puberty and into adulthood. These monoamine projections play an important role in the organization of axonal growth and synapse formation during early stages of brain growth but convert to their more traditional role of neurotransmission with aging. The role of iron, or other micronutrients, in this "pruning" of neuronal connections with development is not generally known, nor is there an awareness of the impact of this potential role of iron in brain biology on subsequent developmental achievement.
The potential, or demonstrated, role of iron in neurotransmitter metabolism has been investigated by a number of research groups over the past four decades. As a result, we know that iron is essential for a number of enzymes involved in neurotransmitter synthesis (3, 14) including tryptophan hydroxylase (serotonin) and tyrosine hydroxylase (norepinephrine (NE) and DA). In addition, iron is a cofactor for ribonucleotide reductase, and is essential for the functioning of a number of electron transfer reactions related to both lipid metabolism and brain-energy metabolism (14). Iron is related to the activity of monoamine oxidase, an enzyme critical for proper rates of degradation of these neurotransmitters. Apart from these biochemical roles of iron there are several other fundamental observations: i) iron is colocalized with dopaminergic neurons throughout the brain (6, 14); ii) extracellular DA and NE are elevated in brains of iron-deficient rats, but other neurotransmitters are not (8, 30, 33); iii) as brain iron concentration drops due to dietary iron restriction, there are decreases in density of D2 and D1 receptors and DA transporters in striatum (8, 29, 35); iv) the loss of brain iron with dietary iron deficiency is region specific and leads to a heterogeneous effect on DA neurobiology, i.e., in the regions where iron does not fall, there are no changes in DA biology (8, 9); and v) the effects of iron deficiency on brain DA are not due to anemia, per se, because hemolytic anemia in the absence of iron deficiency does not produce these abnormalities in DA neurobiology (Fig. 4) (6, 8, 35).
Although most of the research activity on brain iron and neurotransmitters has focused on DA, there is evidence that both serotonin and NE metabolism are also altered in brain iron insufficiency. The serotonin transporter density was significantly lower in brains of iron-deficient mice (34) whereas in vivo microdialysis in rats provided evidence for decreased rates of uptake of NE (33). Our own studies of cold tolerance and thermoregulation showed that iron-deficient anemic women and rats had elevated plasma NE levels (36). This is consistent with a more rapid loss of NE from peripheral sympathetic nervous system pools and are suggestive of an effect of iron deficiency on monoamine uptake mechanisms. It is important to recall that serotonin, NE and DA transporters are all members of the same family of Na+ cotransporters and show similar characteristics with respect to regulation and translocation (37). The only other neurotransmitter studied relative to brain iron status has been 
-aminobutyric acid (38).
A direct mechanism of effect of cellular iron status on monoamine metabolism has yet to be demonstrated although recent cell culture experiments from our laboratory support such a concept (39). Experiments with pheochromocytoma (PC12) cells and neuroblastoma cells demonstrated a dose response relationship between iron chelation and expression of the DA and the NE transporter (Fig. 5a, b). These experiments demonstrate for the first time direct evidence for a cellular relationship of iron and monoamine metabolism.
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Iron-deficient animals and human infants have changes in behavior that are resistant to iron therapy (2– 5, 40). We demonstrated, in animal models, that behavioral changes are robustly associated with changes to central DA and iron concentrations (8, 22, 29). Our most recent analysis of behavior, DA and regional brain iron, however, reveals some relevant relationships:
Adult iron deficiency and cognitive functioning
A limited number of studies have been conducted to determine if iron deficiency during nondevelopmental periods of life are associated with changes in behavior, cognition and brain function (31, 43). Studies in adolescents who were iron deficient, but not anemic, revealed alterations in cognitive functioning that could be attributed to iron depletion but not anemia (31). When specific tests of attention are performed, iron-deficient anemic adolescents perform less well than iron-sufficient teens and also respond to iron therapy.
This brief article has highlighted several of the known biologic roles of brain iron on neural metabolism and functioning. Although much of the work has focused on early development as the "critical period", there is not yet certainty that that period has been exactly defined or limited to infants less than 2 y of age. The more recent evidence with adults with RLS, iron deficiency in renal disease and simple postpartum iron deficiency all suggest that neural functioning and behavioral consequences to brain iron deficits are not limited to infants.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 We acknowledge support for our research from National Institutes of Health (grants: R01-NS35088, R01-NS34280, P01-HD39386) and U.S. Department of Agriculture (grant 99-35200-7610).
4 Abbreviations used: DA, dopamine; Tf, transferrin; NE, norepinephrine; RLS, restless legs syndrome.
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LITERATURE CITED |
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