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.

Iron is a necessary substrate for neuronal function throughout the lifespan, but particularly during development. Early life iron deficiency (ID) in humans (late gestation through 2–3 years) results in persistent cognitive and behavioral abnormalities despite iron repletion. Animal models of early life ID generated using maternal dietary iron restriction also demonstrate persistent learning and memory deficits, suggesting a critical requirement for iron during hippocampal development. Precise definition of the temporal window for this requirement has been elusive due to anemia and total body and brain ID inherent to previous dietary restriction models. To circumvent these confounds, we developed transgenic mice that express tetracycline transactivator regulated, dominant negative transferrin receptor (DNTfR1) in hippocampal neurons, disrupting TfR1 mediated iron uptake specifically in CA1 pyramidal neurons. Normal iron status was restored by doxycycline administration. We manipulated the duration of ID using this inducible model to examine long-term effects of early ID on Morris water maze learning, CA1 apical dendrite structure, and defining factors of critical periods including parvalbmin (PV) expression, perineuronal nets (PNN), and brain derived neurotrophic factor (BDNF) expression. Ongoing ID impaired spatial memory and resulted in disorganized apical dendrite structure accompanied by altered PV and PNN expression and reduced BDNF levels. Iron repletion at P21, near the end of hippocampal dendritogenesis, restored spatial memory, dendrite structure, and critical period markers in adult mice. However, mice that remained hippocampally iron deficient until P42 continued to have spatial memory deficits, impaired CA1 apical dendrite structure, and persistent alterations in PV and PNN expression and reduced BDNF despite iron repletion. Together, these findings demonstrate that hippocampal iron availability is necessary between P21 and P42 for development of normal spatial learning and memory, and that these effects may reflect disruption of critical period closure by early life ID.

Fetal-neonatal iron deficiency acutely alters hippocampal biochemistry, morphology, neurotransmission and electrophysiology resulting in short-term behavioral impairments. It also down-regulates brain-derived neurotrophic factor (BDNF) expression accompanied by the upregulation of nerve growth factor (NGF), epidermal growth factor (EGF), glial-derived neurotrophic factor (GDNF), and p75 neurotrophic receptor. However, the etiology of long-term hippocampal neural transmission abnormalities and learning impairments remains unclear. Since BDNF modulates learning and memory, we assessed its expression in formerly iron deficient (FID) adult rats that had been iron deficient during the fetal and neonatal periods. BDNF was down-regulated in FID rats, whereas NGF, EGF and GDNF levels were similar to the always iron sufficient control group. Consistent with attenuated BDNF activity, we found lower expression of transcriptional targets of BDNF signaling in FID rats, including activity-dependent immediate early genes (e.g., c-fos, earlygrowth response gene-1 and -2) and the rate-limiting enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl coenzyme A reductase. Our findings show that fetal-neonatal iron deficiency lowers BDNF function beyond the period of iron deficiency in the hippocampus. The lower adult hippocampal BDNF activity may underlie the persistence of learning deficits seen after early-life iron deficiency.

Metals can have a number of detrimental or beneficial effects in the cell, but first they must get in. Organisms have evolved transport mechanisms to get metals that are required, or essential into the cell. Nonessential metals often enter the cell through use of the machinery provided for essential metals. Much work has been done to advance our understanding of how these metals are transported across the plasma and organelle membranes. This review provides an overview of these metal transport processes.

Fetal-neonatal iron deficiency alters hippocampal neuronal morphology, reduces its volume, and is associated with acute and long-term learning impairments. However, neither the effects of early-life iron deficiency anemia on growth, differentiation, and survival of hippocampal neurons nor regulation of the neurotrophic factors that mediate these processes has been investigated. We compared hippocampal expression of neurotrophic factors in male rats made iron deficient (ID) from gestational d 2 to postnatal d (P) 7 to iron-sufficient controls at P7, 15, and 30 with quantitative RT-PCR, Western analysis, and immunohistology. Iron deficiency downregulated brain-derived neurotrophic factor (BDNF) expression in the hippocampus without compensatory upregulation of its specific receptor, tyrosine-receptor kinase B. Consistent with low overall BDNF activity, we found lower expression of early-growth response gene-1 and -2, transcriptional targets of BDNF signaling. Doublecortin expression, a marker of differentiating neurons, was reduced during peak iron deficiency, suggesting impaired neuronal differentiation in the ID hippocampus. In contrast, iron deficiency upregulated hippocampal nerve growth factor, epidermal growth factor, and glial-derived neurotrophic factor accompanied by an increase in neurotrophic receptor p75 expression. Our findings suggest that fetal-neonatal iron deficiency lowers BDNF function and impairs neuronal differentiation in the hippocampus.

Iron deficiency (ID) during early life causes long-lasting detrimental cognitive sequelae, many of which are linked to alterations in hippocampus function, dopamine synthesis, and the modulation of dopaminergic circuitry by the hippocampus. These same features have been implicated in the origins of schizophrenia, a neuropsychiatric disorder with significant cognitive impairments. Deficits in sensorimotor gating represent a reliable endophenotype of schizophrenia that can be measured by prepulse inhibition (PPI) of the acoustic startle reflex. Using two rodent model systems, we investigated the influence of early-life ID on PPI in adulthood. To isolate the role of hippocampal iron in PPI, our mouse model utilized a timed (embryonic day 18.5), hippocampus-specific knockout of Slc11a2, a gene coding an important regulator of cellular iron uptake, the divalent metal transport type 1 protein (DMT-1). Our second model used a classic rat dietary-based global ID during gestation, a condition that closely mimics human gestational ID anemia (IDA). Both models exhibited impaired PPI in adulthood. Furthermore, our DMT-1 knockout model displayed reduced long-term potentiation (LTP) and elevated paired pulse facilitation (PPF), electrophysiological results consistent with previous findings in the IDA rat model. These results, in combination with previous findings demonstrating impaired hippocampus functioning and altered dopaminergic and glutamatergic neurotransmission, suggest that iron availability within the hippocampus is critical for the neurodevelopmental processes underlying sensorimotor gating. Ultimately, evidence of reduced PPI in both of our models may offer insights into the roles of fetal ID and the hippocampus in the pathophysiology of schizophrenia.

Iron deficiency (ID) is the most common gestational micronutrient deficiency in the world, targets the fetal hippocampus and striatum and results in long-term behavioral abnormalities. These structures primarily mediate spatial and procedural memory, respectively, in the rodent but have interconnections that result in competition or cooperation during cognitive tasks. We determined whether ID-induced impairment of one alters the function of the other by genetically inducing a 40% reduction of hippocampus iron content in late fetal life in mice and measuring dorsal striatal gene expression and metabolism and the behavioral balance between the two memory systems in adulthood. Slc11a2hipp/hipp mice had similar striatum iron content, but 18% lower glucose and 44% lower lactate levels, a 30% higher phosphocreatine:creatine ratio, and reduced iron transporter gene expression compared to wild type (WT) littermates, implying reduced striatal metabolic function. Slc11a2hipp/hipp mice had longer mean escape times on a cued task paradigm implying impaired procedural memory. Nevertheless, when hippocampal and striatal memory systems were placed in competition using a Morris Water Maze task that alternates spatial navigation and visual cued responses during training, and forces a choice between hippocampal and striatal strategies during probe trials, Slc11a2hipp/hipp mice used the hippocampus-dependent response less often (25%) and the visual cued response more often (75%) compared to WT littermates that used both strategies approximately equally. Hippocampal ID not only reduces spatial recognition memory performance but also affects systems that support procedural memory, suggesting an altered balance between memory systems.Electronic supplementary materialThe online version of this article (doi:10.1007/s11689-010-9049-0) contains supplementary material, which is available to authorized users.

Tran PV, Fretham SJ, Wobken J, Miller BS, Georgieff MK. Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus. Am J Physiol Endocrinol Metab 302: E316 -E324, 2012. First published November 8, 2011; doi:10.1152/ajpendo.00369.2011.-Gestationalneonatal iron deficiency, a common micronutrient deficiency affecting the offspring of more than 30% of pregnancies worldwide, leads to long-term cognitive and behavioral abnormalities. Preclinical models of gestational-neonatal iron deficiency result in reduced energy metabolism and expression of genes critical for neuronal plasticity and cognitive function, which are associated with a smaller hippocampal volume and abnormal neuronal dendrite growth. Because insulin-like growth factor (IGF) modulates early postnatal cellular growth, differentiation, and survival, we used a dietary-induced rat model to assess the effects of gestational iron deficiency on activity of the IGF system. We hypothesized that gestational iron deficiency attenuates postnatal hippocampal IGF signaling and results in downstream effects that contribute to hippocampal anatomic and functional deficits. At postnatal day (P) 15 untreated gestational-neonatal iron deficiency markedly suppressed hippocampal IGF activation and protein kinase B signaling, and reduced neurogenesis, while elevating extracellular signal-regulated kinase 1/2 signaling and hypoxia-inducible factor-1␣ expression. Iron treatment beginning at P7 restored IGF signaling, increased neurogenesis, and normalized all parameters by the end of rapid hippocampal differentiation (P30). Expression of the neuronspecific synaptogenesis marker, disc-large homolog 4 (PSD95), increased more rapidly than the glia-specific myelination marker, myelin basic protein, following iron treatment, suggesting a more robust response to iron therapy in IGF-I-dependent neurons than IGF-IIdependent glia. Collectively, our findings suggest that IGF dysfunction is in part responsible for hippocampal abnormalities in untreated iron deficiency. Early postnatal iron treatment of gestational iron deficiency reactivates the IGF system and promotes neurogenesis and differentiation in the hippocampus during a critical developmental period. hippocampal development; micronutrient deficiency; insulin receptor; insulin-like growth factor I receptor; neurogenesis; extracellular signal-regulated kinase; protein kinase B IRON DEFICIENCY IS THE MOST COMMON nutrient deficiency, affecting approximately two billion people and 30 -50% of pregnancies and their fetuses worldwide (49). Common clinical conditions during pregnancy such as severe maternal iron deficiency anemia, intrauterine insufficiency due to maternal hypertension (i.e., intrauterine growth restriction), and maternal diabetes mellitus as well as nonclinical conditions such as cigarette smoking result in fetal iron deficiency (15,28, 46,57). In humans, early life iron deficiency leads to long-term cognitive deficits and behavioral abnormalities (39), which...