Abstract
Iron deficiency (ID) is a major public health problem worldwide among children aged 0–12 months. Several factors seem to contribute to the iron-deficient state in infancy, including insufficient antenatal and neonatal iron supplementation, exclusive breastfeeding, and early umbilical cord clamping after birth. The most concerning complications of ID, except for anemia, are related to altered long-term neurodevelopment. Clinical studies have shown a negative impact of ID anemia on fetal and neonatal behavior including impairments of motor maturity, autonomic response, memory/learning, and mood. ID-induced defects during infancy seem to persist later in life, even after ID treatment. The underlying mechanisms involve dysfunctional myelination, neurotransmission alterations, and altered synaptogenesis and/or dendritogenesis. The purpose of the present review is to summarize these mechanisms and to provide recommendations for future clinical research in the field.
References
Alfimova, M.V., Lezheiko, T.V., Gritsenko, I.K., and Golimbet, V.E. (2012). Association of the insulin-like growth factor II (IGF2) gene with human cognitive functions. Genetika 48, 993–998.Search in Google Scholar
Algarin, C., Peirano, P., Garrido, M., Pizarro, F., and Lozoff, B. (2003). Iron deficiency anemia in infancy: long-lasting effects on auditory and visual system functioning. Pediatr. Res. 53, 217–223.10.1203/01.PDR.0000047657.23156.55Search in Google Scholar
Algarin, C., Nelson, C.A., Peirano, P., Westerlund, A., Reyes, S., and Lozoff, B. (2013). Iron-deficiency anemia in infancy and poorer cognitive inhibitory control at age 10 years. Dev. Med. Child Neurol. 55, 453–458.10.1111/dmcn.12118Search in Google Scholar
Allen, L.H. (2000). Anemia and iron deficiency: effects on pregnancy outcome. Am. J. Clin. Nutr. 71, 1280S–1284S.10.1093/ajcn/71.5.1280sSearch in Google Scholar
Allen, R.P., Auerbach, S., Bahrain, H., Auerbach, M., and Earley, C.J. (2013). The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am. J. Hematol. 88, 261–264.10.1002/ajh.23397Search in Google Scholar
Anderson, J.G., Fordahl, S.C., Cooney, P.T., Weaver, T.L., Colyer, C.L., and Erikson, K.M. (2009). Extracellular norepinephrine, norepinephrine receptor and transporter protein and mRNA levels are differentially altered in the developing rat brain due to dietary iron deficiency and manganese exposure. Brain Res. 1281, 1–14.10.1016/j.brainres.2009.05.050Search in Google Scholar
Andersson, O., Hellstrom-Westas, L., Andersson, D., and Domellof, M. (2011). Effect of delayed versus early umbilical cord clamping on neonatal outcomes and iron status at 4 months: a randomised controlled trial. Br. Med. J. 343, d7157.10.1136/bmj.d7157Search in Google Scholar
Andersson, O., Domellof, M., Andersson, D., and Hellstrom-Westas, L. (2014). Effect of delayed vs. early umbilical cord clamping on iron status and neurodevelopment at age 12 months: a randomized clinical trial. J. Am. Med. Assoc. Pediatr. 168, 547–554.10.1001/jamapediatrics.2013.4639Search in Google Scholar
Angulo-Barroso, R.M., Schapiro, L., Liang, W., Rodrigues, O., Shafir, T., Kaciroti, N., Jacobson, S.W., and Lozoff, B. (2011). Motor development in 9-month-old infants in relation to cultural differences and iron status. Dev. Psychobiol. 53, 196–210.10.1002/dev.20512Search in Google Scholar
Angulo-Kinzler, R.M., Peirano, P., Lin, E., Garrido, M., and Lozoff, B. (2002). Spontaneous motor activity in human infants with iron-deficiency anemia. Early Hum. Dev. 66, 67–79.10.1016/S0378-3782(01)00238-9Search in Google Scholar
Badaracco, M.E., Ortiz, E.H., Soto, E.F., Connor, J., and Pasquini, J.M. (2008). Effect of transferrin on hypomyelination induced by iron deficiency. J. Neurosci. Res. 86, 2663–2673.10.1002/jnr.21709Search in Google Scholar PubMed
Baker, R.D. and Greer, F.R. (2010). Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0–3 years of age). Pediatrics 126, 1040–1050.10.1542/peds.2010-2576Search in Google Scholar
Barkey, R.J., Ben-Shachar, D., Amit, T., and Youdim, M.B. (1985). Increased hepatic and reduced prostatic prolactin (PRL) binding in iron deficiency and during neuroleptic treatment: correlation with changes in serum PRL and testosterone. Eur. J. Pharmacol. 109, 193–200.10.1016/0014-2999(85)90420-0Search in Google Scholar
Barkey, R.J., Amit, T., Ben-Shachar, D., and Youdim, M.B. (1986). Characterization of the hepatic prolactin receptors induced by chronic iron deficiency and neuroleptics. Eur. J. Pharmacol. 122, 259–267.10.1016/0014-2999(86)90111-1Search in Google Scholar
Bartlett, W.P., Li, X.S., and Connor, J.R. (1991). Expression of transferrin mRNA in the CNS of normal and jimpy mice. J. Neurochem. 57, 318–322.10.1111/j.1471-4159.1991.tb02130.xSearch in Google Scholar PubMed
Beard, J.L. and Connor, J.R. (2003). Iron status and neural functioning. Annu. Rev. Nutr. 23, 41–58.10.1146/annurev.nutr.23.020102.075739Search in Google Scholar PubMed
Beard, J.L., Wiesinger, J.A., and Connor, J.R. (2003). Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats. Dev. Neurosci. 25, 308–315.10.1159/000073507Search in Google Scholar PubMed
Beard, J.L., Wiesinger, J.A., and Jones, B.C. (2006). Cellular iron concentrations directly affect the expression levels of norepinephrine transporter in PC12 cells and rat brain tissue. Brain Res. 1092, 47–58.10.1016/j.brainres.2006.03.071Search in Google Scholar PubMed
Ben-Jonathan, N. and Hnasko, R. (2001). Dopamine as a prolactin (PRL) inhibitor. Endocr. Rev. 22, 724–763.10.1210/edrv.22.6.0451Search in Google Scholar PubMed
Berglund, S. and Domellof, M. (2014). Meeting iron needs for infants and children. Curr. Opin. Clin. Nutr. Metab. Care 17, 267–272.10.1097/MCO.0000000000000043Search in Google Scholar PubMed
Biagioli, M., Pinto, M., Cesselli, D., Zaninello, M., Lazarevic, D., Roncaglia, P., Simone, R., Vlachouli, C., Plessy, C., Bertin, N., et al. (2009). Unexpected expression of α- and β-globin in mesencephalic dopaminergic neurons and glial cells. Proc. Natl. Acad. Sci. USA 106, 15454–15459.10.1073/pnas.0813216106Search in Google Scholar PubMed PubMed Central
Blanton, C. (2014). Improvements in iron status and cognitive function in young women consuming beef or non-beef lunches. Nutrients 6, 90–110.10.3390/nu6010090Search in Google Scholar PubMed PubMed Central
Breymann, C., Bian, X.M., Blanco-Capito, L.R., Chong, C., Mahmud, G., and Rehman, R. (2011). Expert recommendations for the diagnosis and treatment of iron-deficiency anemia during pregnancy and the postpartum period in the Asia-Pacific region. J. Perinat. Med. 39, 113–121.10.1515/jpm.2010.132Search in Google Scholar PubMed
Brunette, K.E., Tran, P.V., Wobken, J.D., Carlson, E.S., and Georgieff, M.K. (2010). Gestational and neonatal iron deficiency alters apical dendrite structure of CA1 pyramidal neurons in adult rat hippocampus. Dev. Neurosci. 32, 238–248.10.1159/000314341Search in Google Scholar PubMed PubMed Central
Bulens, C., Meerwaldt, J.D., Van der Wildt, G.J., and Van Deursen, J.B. (1987). Effect of levodopa treatment on contrast sensitivity in Parkinson’s disease. Ann. Neurol. 22, 365–369.10.1002/ana.410220313Search in Google Scholar PubMed
Burhans, M.S., Dailey, C., Beard, Z., Wiesinger, J., Murray-Kolb, L., Jones, B.C., and Beard, J.L. (2005). Iron deficiency: differential effects on monoamine transporters. Nutr. Neurosci. 8, 31–38.10.1080/10284150500047070Search in Google Scholar PubMed
Butte, N.F., Fox, M.K., Briefel, R.R., Siega-Riz, A.M., Dwyer, J.T., Deming, D.M., and Reidy, K.C. (2010). Nutrient intakes of US infants, toddlers, and preschoolers meet or exceed dietary reference intakes. J. Am. Diet. Assoc. 110, S27–S37.10.1016/j.jada.2010.09.004Search in Google Scholar PubMed
Cameron, B.M. and Neufeld, L.M. (2011). Estimating the prevalence of iron deficiency in the first two years of life: technical and measurement issues. Nutr. Rev. 69, S49–S56.10.1111/j.1753-4887.2011.00433.xSearch in Google Scholar PubMed
Carlson, E.S., Stead, J.D., Neal, C.R., Petryk, A., and Georgieff, M.K. (2007). Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus. Hippocampus 17, 679–691.10.1002/hipo.20307Search in Google Scholar PubMed
Chassagne, P., Bahri, O., and Roca, F. (2014). Iron deficiency in elderly people. Clinical presentation and management. Geriatr. Psychol. Neuropsychiatr. Vieil. 12, 11–15.Search in Google Scholar
Chen, M.H., Su, T.P., Chen, Y.S., Hsu, J.W., Huang, K.L., Chang, W.H., Chen, T.J., and Bai, Y.M. (2013). Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study. BMC Psychiatry 13, 161.10.1186/1471-244X-13-161Search in Google Scholar PubMed PubMed Central
Coleman, R., Tanne, Z., Nahir, M., Shomrat, D., Miller-Lotan, R., and Youdim, M.B. (1995). Ultrastructural changes in mitochondria of the adrenal cortex of iron-deficient rats. Acta Anat. (Basel) 152, 33–40.10.1159/000147681Search in Google Scholar PubMed
Collard, K.J. (2009). Iron homeostasis in the neonate. Pediatrics 123, 1208–1216.10.1542/peds.2008-1047Search in Google Scholar
Connor, J.R. and Menzies, S.L. (1990). Altered cellular distribution of iron in the central nervous system of myelin deficient rats. Neuroscience 34, 265–271.10.1016/0306-4522(90)90320-4Search in Google Scholar
Connor, J.R. and Menzies, S.L. (1996). Relationship of iron to oligodendrocytes and myelination. Glia 17, 83–93.10.1002/(SICI)1098-1136(199606)17:2<83::AID-GLIA1>3.0.CO;2-7Search in Google Scholar
Connor, J.R., Phillips, T.M., Lakshman, M.R., Barron, K.D., Fine, R.E., and Csiza, C.K. (1987). Regional variation in the levels of transferrin in the CNS of normal and myelin-deficient rats. J. Neurochem. 49, 1523–1529.10.1111/j.1471-4159.1987.tb01023.xSearch in Google Scholar
Cunningham, J.T., Rodgers, J.T., Arlow, D.H., Vazquez, F., Mootha, V.K., and Puigserver, P. (2007). mTOR controls mitochondrial oxidative function through a YY1-PGC-1α transcriptional complex. Nature 450, 736–740.10.1038/nature06322Search in Google Scholar
Domellof, M., Lonnerdal, B., Abrams, S.A., and Hernell, O. (2002). Iron absorption in breast-fed infants: effects of age, iron status, iron supplements, and complementary foods. Am. J. Clin. Nutr. 76, 198–204.10.1093/ajcn/76.1.198Search in Google Scholar
Eden, A.N. (2005). Iron deficiency and impaired cognition in toddlers: an underestimated and undertreated problem. Paediatr. Drugs 7, 347–352.10.2165/00148581-200507060-00003Search in Google Scholar
Erikson, K.M., Jones, B.C., and Beard, J.L. (2000). Iron deficiency alters dopamine transporter functioning in rat striatum. J. Nutr. 130, 2831–2837.10.1093/jn/130.11.2831Search in Google Scholar
Erikson, K.M., Jones, B.C., Hess, E.J., Zhang, Q., and Beard, J.L. (2001). Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol. Biochem. Behav. 69, 409–418.10.1016/S0091-3057(01)00563-9Search in Google Scholar
Escobar Cabrera, O.E., Zakin, M.M., Soto, E.F., and Pasquini, J.M. (1997). Single intracranial injection of apotransferrin in young rats increases the expression of specific myelin protein mRNA. J. Neurosci. Res. 47, 603–608.10.1002/(SICI)1097-4547(19970315)47:6<603::AID-JNR5>3.0.CO;2-HSearch in Google Scholar
Estrada, J.A., Contreras, I., Pliego-Rivero, F.B., and Otero, G.A. (2014). Molecular mechanisms of cognitive impairment in iron deficiency: alterations in brain-derived neurotrophic factor and insulin-like growth factor expression and function in the central nervous system. Nutr. Neurosci. 17, 193–206.10.1179/1476830513Y.0000000084Search in Google Scholar PubMed
Felt, B.T., Beard, J.L., Schallert, T., Shao, J., Aldridge, J.W., Connor, J.R., Georgieff, M.K., and Lozoff, B. (2006). Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats. Behav. Brain Res. 171, 261–270.10.1016/j.bbr.2006.04.001Search in Google Scholar PubMed PubMed Central
Felt, B.T., Peirano, P., Algarin, C., Chamorro, R., Sir, T., Kaciroti, N., and Lozoff, B. (2012). Long-term neuroendocrine effects of iron-deficiency anemia in infancy. Pediatr. Res. 71, 707–712.10.1038/pr.2012.22Search in Google Scholar PubMed PubMed Central
Ferri, C., Procianoy, R.S., and Silveira, R.C. (2014). Prevalence and risk factors for iron-deficiency anemia in very-low-birth-weight preterm infants at 1 year of corrected age. J. Trop. Pediatr. 60, 53–60.10.1093/tropej/fmt077Search in Google Scholar PubMed
Fitsanakis, V.A., Thompson, K.N., Deery, S.E., Milatovic, D., Shihabi, Z.K., Erikson, K.M., Brown, R.W., and Aschner, M. (2009). A chronic iron-deficient/high-manganese diet in rodents results in increased brain oxidative stress and behavioral deficits in the Morris water maze. Neurotox. Res. 15, 167–178.10.1007/s12640-009-9017-1Search in Google Scholar PubMed PubMed Central
Fretham, S.J., Carlson, E.S., and Georgieff, M.K. (2011). The role of iron in learning and memory. Adv. Nutr. 2, 112–121.10.3945/an.110.000190Search in Google Scholar PubMed PubMed Central
Fretham, S.J., Carlson, E.S., and Georgieff, M.K. (2013). Neuronal-specific iron deficiency dysregulates mammalian target of rapamycin signaling during hippocampal development in non-anemic genetic mouse models. J. Nutr. 143, 260–266.10.3945/jn.112.168617Search in Google Scholar PubMed PubMed Central
Galvez, T., Teruel, M.N., Heo, W.D., Jones, J.T., Kim, M.L., Liou, J., Myers, J.W., and Meyer, T. (2007). siRNA screen of the human signaling proteome identifies the PtdIns(3,4,5)P3-mTOR signaling pathway as a primary regulator of transferrin uptake. Genome Biol. 8, R142.10.1186/gb-2007-8-7-r142Search in Google Scholar PubMed PubMed Central
Ganou, V., Pagida, M.A., Konstantinidou, A.E., Malidelis, Y.I., Kontostavlaki, D.P., Tsekoura, E., Patsouris, E., and Panayotacopoulou, M.T. (2010). Increased expression of tyrosine hydroxylase in the supraoptic nucleus of the human neonate under hypoxic conditions: a potential neuropathological marker for prolonged perinatal hypoxia. J. Neuropathol. Exp. Neurol. 69, 1008–1016.10.1097/NEN.0b013e3181f12ca2Search in Google Scholar PubMed
Garcia, S.J., Gellein, K., Syversen, T., and Aschner, M. (2007). Iron deficient and manganese supplemented diets alter metals and transporters in the developing rat brain. Toxicol. Sci. 95, 205–214.10.1093/toxsci/kfl139Search in Google Scholar PubMed
Gunnar, M.R. and Vazquez, D.M. (2001). Low cortisol and a flattening of expected daytime rhythm: potential indices of risk in human development. Dev. Psychopathol. 13, 515–538.10.1017/S0954579401003066Search in Google Scholar
Han, J., Day, J.R., Connor, J.R., and Beard, J.L. (2003). Gene expression of transferrin and transferrin receptor in brains of control vs. iron-deficient rats. Nutr. Neurosci. 6, 1–10.Search in Google Scholar
Herguner, S., Kelesoglu, F.M., Tanidir, C., and Copur, M. (2012). Ferritin and iron levels in children with autistic disorder. Eur. J. Pediatr. 171, 143–146.10.1007/s00431-011-1506-6Search in Google Scholar PubMed
Hoehn, M.M., Crowley, T.J., and Rutledge, C.O. (1977). The Parkinsonian syndrome and its dopamine correlates. Adv. Exp. Med. Biol. 90, 243–254.10.1007/978-1-4684-2511-6_15Search in Google Scholar PubMed
Ikenoue, T., Inoki, K., Yang, Q., Zhou, X., and Guan, K.L. (2008). Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 27, 1919–1931.10.1038/emboj.2008.119Search in Google Scholar PubMed PubMed Central
Jaime-Perez, J.C., Herrera-Garza, J.L., and Gomez-Almaguer, D. (2005). Sub-optimal fetal iron acquisition under a maternal environment. Arch. Med. Res. 36, 598–602.10.1016/j.arcmed.2005.03.023Search in Google Scholar PubMed
Jellen, L.C., Lu, L., Wang, X., Unger, E.L., Earley, C.J., Allen, R.P., Williams, R.W., and Jones, B.C. (2013). Iron deficiency alters expression of dopamine-related genes in the ventral midbrain in mice. Neuroscience 252, 13–23.10.1016/j.neuroscience.2013.07.058Search in Google Scholar PubMed PubMed Central
Jenner, P., Sheehy, M., and Marsden, C.D. (1983). Noradrenaline and 5-hydroxytryptamine modulation of brain dopamine function: implications for the treatment of Parkinson’s disease. Br. J. Clin. Pharmacol. 15, 277S–289S.10.1111/j.1365-2125.1983.tb05876.xSearch in Google Scholar PubMed PubMed Central
Johnstone, D. and Milward, E.A. (2010). Molecular genetic approaches to understanding the roles and regulation of iron in brain health and disease. J. Neurochem. 113, 1387–1402.10.1111/j.1471-4159.2010.06697.xSearch in Google Scholar PubMed
Jorgenson, L.A., Wobken, J.D., and Georgieff, M.K. (2003). Perinatal iron deficiency alters apical dendritic growth in hippocampal CA1 pyramidal neurons. Dev. Neurosci. 25, 412–420.10.1159/000075667Search in Google Scholar PubMed
Kim, J., Li, Y., Buckett, P.D., Bohlke, M., Thompson, K.J., Takahashi, M., Maher, T.J., and Wessling-Resnick, M. (2012). Iron-responsive olfactory uptake of manganese improves motor function deficits associated with iron deficiency. PLoS One 7, e33533.10.1371/journal.pone.0033533Search in Google Scholar PubMed PubMed Central
Krebs, N.F., Sherlock, L.G., Westcott, J., Culbertson, D., Hambidge, K.M., Feazel, L.M., Robertson, C.E., and Frank, D.N. (2013). Effects of different complementary feeding regimens on iron status and enteric microbiota in breastfed infants. J. Pediatr. 163, 416–423.10.1016/j.jpeds.2013.01.024Search in Google Scholar
Kwik-Uribe, C.L., Gietzen, D., German, J.B., Golub, M.S., and Keen, C.L. (2000). Chronic marginal iron intakes during early development in mice result in persistent changes in dopamine metabolism and myelin composition. J. Nutr. 130, 2821–2830.10.1093/jn/130.11.2821Search in Google Scholar
Latif, A., Heinz, P., and Cook, R. (2002). Iron deficiency in autism and asperger syndrome. Autism 6, 103–114.10.1177/1362361302006001008Search in Google Scholar
Lavenex, P. and Banta Lavenex, P. (2013). Building hippocampal circuits to learn and remember: insights into the development of human memory. Behav. Brain Res. 254, 8–21.10.1016/j.bbr.2013.02.007Search in Google Scholar
Li, D. (1998). Effects of iron deficiency on iron distribution and γ-aminobutyric acid (GABA) metabolism in young rat brain tissues. Hokkaido Igaku Zasshi 73, 215–225.Search in Google Scholar
Li, Y., Kim, J., Buckett, P.D., Bohlke, M., Maher, T.J., and Wessling-Resnick, M. (2011). Severe postnatal iron deficiency alters emotional behavior and dopamine levels in the prefrontal cortex of young male rats. J. Nutr. 141, 2133–2138.10.3945/jn.111.145946Search in Google Scholar
Lopez, N.L., Vazquez, D.M., and Olson, S.L. (2004). An integrative approach to the neurophysiological substrates of social withdrawal and aggression. Dev. Psychopathol. 16, 69–93.10.1017/S0954579404044414Search in Google Scholar
Lozoff, B. (2011). Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. J. Nutr. 141, 740S–746S.10.3945/jn.110.131169Search in Google Scholar
Lozoff, B., Felt, B.T., Nelson, E.C., Wolf, A.W., Meltzer, H.W., and Jimenez, E. (1995). Serum prolactin levels and behavior in infants. Biol. Psychiatry 37, 4–12.10.1016/0006-3223(94)00148-VSearch in Google Scholar
Lozoff, B., Jimenez, E., Hagen, J., Mollen, E., and Wolf, A.W. (2000). Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics 105, E51.10.1542/peds.105.4.e51Search in Google Scholar PubMed
Lozoff, B., Beard, J., Connor, J., Barbara, F., Georgieff, M., and Schallert, T. (2006). Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr. Rev. 64, S34–S43; discussion S72–S91.Search in Google Scholar
Maguire, J.L., Salehi, L., Birken, C.S., Carsley, S., Mamdani, M., Thorpe, K.E., Lebovic, G., Khovratovich, M., and Parkin, P.C. (2013). Association between total duration of breastfeeding and iron deficiency. Pediatrics 131, e1530–e1537.10.1542/peds.2012-2465Search in Google Scholar PubMed
McAdams, R.M. (2014). Time to implement delayed cord clamping. Obstet. Gynecol. 123, 549–552.10.1097/AOG.0000000000000122Search in Google Scholar PubMed
McEchron, M.D., Goletiani, C.J., and Alexander, D.N. (2010). Perinatal nutritional iron deficiency impairs noradrenergic-mediated synaptic efficacy in the CA1 area of rat hippocampus. J. Nutr. 140, 642–647.10.3945/jn.109.114702Search in Google Scholar PubMed PubMed Central
Menget, A., Mougey, C., Thiriez, G., and Riethmuller, D. (2013). Advantage of delayed umbilical cord clamping in the newborn infant. Arch. Pediatr. 20, 1022–1027.10.1016/j.arcped.2013.06.016Search in Google Scholar PubMed
Monga, M., Walia, V., Gandhi, A., Chandra, J., and Sharma, S. (2010). Effect of iron deficiency anemia on visual evoked potential of growing children. Brain Dev. 32, 213–216.10.1016/j.braindev.2009.02.009Search in Google Scholar PubMed
Morales Gonzalez, E., Contreras, I., and Estrada, J.A. (2013). Effect of iron deficiency on the expression of insulin-like growth factor-II and its receptor in neuronal and glial cells. Neurologia. 29, 408–415.10.1016/j.nrl.2013.10.005Search in Google Scholar PubMed
Morath, D.J. and Mayer-Proschel, M. (2001). Iron modulates the differentiation of a distinct population of glial precursor cells into oligodendrocytes. Dev. Biol. 237, 232–243.10.1006/dbio.2001.0352Search in Google Scholar PubMed
Munoz, P. and Humeres, A. (2012). Iron deficiency on neuronal function. Biometals 25, 825–835.10.1007/s10534-012-9550-xSearch in Google Scholar PubMed
Munoz, P., Humeres, A., Elgueta, C., Kirkwood, A., Hidalgo, C., and Nunez, M.T. (2011). Iron mediates N-methyl-d-aspartate receptor-dependent stimulation of calcium-induced pathways and hippocampal synaptic plasticity. J. Biol. Chem. 286, 13382–13392.10.1074/jbc.M110.213785Search in Google Scholar PubMed PubMed Central
Nagpal, J., Sachdev, H.P., Singh, T., and Mallika, V. (2004). A randomized placebo-controlled trial of iron supplementation in breastfed young infants initiated on complementary feeding: effect on haematological status. J. Health Popul. Nutr. 22, 203–211.Search in Google Scholar
Ndong, M., Kazami, M., Suzuki, T., Uehara, M., Katsumata, S., Inoue, H., Kobayashi, K., Tadokoro, T., Suzuki, K., and Yamamoto, Y. (2009). Iron deficiency down-regulates the Akt/TSC1-TSC2/mammalian target of rapamycin signaling pathway in rats and in COS-1 cells. Nutr. Res. 29, 640–647.10.1016/j.nutres.2009.09.007Search in Google Scholar PubMed
Oliveira Fde, C., Assis, K.F., Martins, M.C., Prado, M.R., Ribeiro, A.Q., Sant’Ana, L.F., Priore, S.E., and Franceschini Sdo, C. (2014). Timing of clamping and factors associated with iron stores in full-term newborns. Rev. Saude Publica 48, 10–18.Search in Google Scholar
Ortiz, E., Pasquini, J.M., Thompson, K., Felt, B., Butkus, G., Beard, J., and Connor, J.R. (2004). Effect of manipulation of iron storage, transport, or availability on myelin composition and brain iron content in three different animal models. J. Neurosci. Res. 77, 681–689.10.1002/jnr.20207Search in Google Scholar PubMed
Pagida, M.A., Konstantinidou, A.E., Tsekoura, E., Mangoura, D., Patsouris, E., and Panayotacopoulou, M.T. (2013a). Vulnerability of the mesencephalic dopaminergic neurons of the human neonate to prolonged perinatal hypoxia: an immunohistochemical study of tyrosine hydroxylase expression in autopsy material. J. Neuropathol. Exp. Neurol. 72, 337–350.10.1097/NEN.0b013e31828b48b3Search in Google Scholar
Pagida, M.A., Konstantinidou, A.E., Tsekoura, E., Patsouris, E., and Panayotacopoulou, M.T. (2013b). Immunohistochemical demonstration of urocortin 1 in Edinger-Westphal nucleus of the human neonate: colocalization with tyrosine hydroxylase under acute perinatal hypoxia. Neurosci. Lett. 554, 47–52.10.1016/j.neulet.2013.08.054Search in Google Scholar
Parisi, P., Villa, M.P., Donfrancesco, R., Miano, S., Paolino, M.C., and Cortese, S. (2012). Could treatment of iron deficiency both improve ADHD and reduce cardiovascular risk during treatment with ADHD drugs? Med. Hypotheses 79, 246–249.10.1016/j.mehy.2012.04.049Search in Google Scholar
Park, K., Kersey, M., Geppert, J., Story, M., Cutts, D., and Himes, J.H. (2009). Household food insecurity is a risk factor for iron-deficiency anaemia in a multi-ethnic, low-income sample of infants and toddlers. Public Health Nutr. 12, 2120–2128.10.1017/S1368980009005540Search in Google Scholar
Pavord, S., Myers, B., Robinson, S., Allard, S., Strong, J., and Oppenheimer, C. (2012). UK guidelines on the management of iron deficiency in pregnancy. Br. J. Haematol. 156, 588–600.10.1111/j.1365-2141.2011.09012.xSearch in Google Scholar
Peirano, P.D., Algarin, C.R., Chamorro, R., Reyes, S., Garrido, M.I., Duran, S., and Lozoff, B. (2009). Sleep and neurofunctions throughout child development: lasting effects of early iron deficiency. J. Pediatr. Gastroenterol. Nutr. 48, S8–S15.10.1097/MPG.0b013e31819773bSearch in Google Scholar
Peirano, P.D., Algarin, C.R., Chamorro, R.A., Reyes, S.C., Duran, S.A., Garrido, M.I., and Lozoff, B. (2010). Sleep alterations and iron deficiency anemia in infancy. Sleep Med. 11, 637–642.10.1016/j.sleep.2010.03.014Search in Google Scholar
Pokorny, J. and Yamamoto, T. (1981a). Postnatal ontogenesis of hippocampal CA1 area in rats. I. Development of dendritic arborisation in pyramidal neurons. Brain Res. Bull. 7, 113–120.10.1016/0361-9230(81)90075-7Search in Google Scholar
Pokorny, J. and Yamamoto, T. (1981b). Postnatal ontogenesis of hippocampal CA1 area in rats. II. Development of ultrastructure in stratum lacunosum and moleculare. Brain Res Bull. 7, 121–130.10.1016/0361-9230(81)90076-9Search in Google Scholar
Qubty, W. and Renaud, D.L. (2014). Cognitive impairment associated with low ferritin responsive to iron supplementation. Pediatr. Neurol. 51, 831–833.10.1016/j.pediatrneurol.2014.08.035Search in Google Scholar PubMed
Rao, R., Tkac, I., Schmidt, A.T., and Georgieff, M.K. (2011). Fetal and neonatal iron deficiency causes volume loss and alters the neurochemical profile of the adult rat hippocampus. Nutr. Neurosci. 14, 59–65.10.1179/1476830511Y.0000000001Search in Google Scholar PubMed PubMed Central
Rosato-Siri, M.V., Badaracco, M.E., Ortiz, E.H., Belforte, N., Clausi, M.G., Soto, E.F., Bernabeu, R., and Pasquini, J.M. (2010). Oligodendrogenesis in iron-deficient rats: effect of apotransferrin. J. Neurosci. Res. 88, 1695–1707.10.1002/jnr.22348Search in Google Scholar PubMed
Rothman, D.L., Behar, K.L., Hyder, F., and Shulman, R.G. (2003). In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function. Annu. Rev. Physiol. 65, 401–427.10.1146/annurev.physiol.65.092101.142131Search in Google Scholar PubMed
Sanghvi, T.G., Harvey, P.W., and Wainwright, E. (2010). Maternal iron-folic acid supplementation programs: evidence of impact and implementation. Food Nutr. Bull. 31, S100–S107.10.1177/15648265100312S202Search in Google Scholar PubMed
Sesack, S.R., Carr, D.B., Omelchenko, N., and Pinto, A. (2003). Anatomical substrates for glutamate-dopamine interactions: evidence for specificity of connections and extrasynaptic actions. Ann. NY Acad. Sci. 1003, 36–52.10.1196/annals.1300.066Search in Google Scholar PubMed
Shafir, T., Angulo-Barroso, R., Su, J., Jacobson, S.W., and Lozoff, B. (2009). Iron deficiency anemia in infancy and reach and grasp development. Infant Behav. Dev. 32, 366–375.10.1016/j.infbeh.2009.06.002Search in Google Scholar PubMed PubMed Central
Shukla, A., Agarwal, K.N., Chansuria, J.P., and Taneja, V. (1989). Effect of latent iron deficiency on 5-hydroxytryptamine metabolism in rat brain. J. Neurochem. 52, 730–735.10.1111/j.1471-4159.1989.tb02515.xSearch in Google Scholar PubMed
Siddappa, A.M., Rao, R., Long, J.D., Widness, J.A., and Georgieff, M.K. (2007). The assessment of newborn iron stores at birth: a review of the literature and standards for ferritin concentrations. Neonatology 92, 73–82.10.1159/000100805Search in Google Scholar PubMed PubMed Central
Stern, S.A., Kohtz, A.S., Pollonini, G., and Alberini, C.M. (2014). Enhancement of memories by systemic administration of insulin-like growth factor II. Neuropsychopharmacology 39, 2179–2190.10.1038/npp.2014.69Search in Google Scholar PubMed PubMed Central
Taneja, V., Mishra, K., and Agarwal, K.N. (1986). Effect of early iron deficiency in rat on the gamma-aminobutyric acid shunt in brain. J. Neurochem. 46, 1670–1674.10.1111/j.1471-4159.1986.tb08483.xSearch in Google Scholar PubMed
Taylor, E.M. and Morgan, E.H. (1990). Developmental changes in transferrin and iron uptake by the brain in the rat. Brain Res. Dev. Brain Res. 55, 35–42.10.1016/0165-3806(90)90103-6Search in Google Scholar
Todorich, B., Pasquini, J.M., Garcia, C.I., Paez, P.M., and Connor, J.R. (2009). Oligodendrocytes and myelination: the role of iron. Glia 57, 467–478.10.1002/glia.20784Search in Google Scholar
Tran, P.V., Carlson, E.S., Fretham, S.J., and Georgieff, M.K. (2008). Early-life iron deficiency anemia alters neurotrophic factor expression and hippocampal neuron differentiation in male rats. J. Nutr. 138, 2495–2501.10.3945/jn.108.091553Search in Google Scholar
Tran, P.V., Fretham, S.J., Carlson, E.S., and Georgieff, M.K. (2009). Long-term reduction of hippocampal brain-derived neurotrophic factor activity after fetal-neonatal iron deficiency in adult rats. Pediatr. Res. 65, 493–498.10.1203/PDR.0b013e31819d90a1Search in Google Scholar
Tran, T.D., Tran, T., Simpson, J.A., Tran, H.T., Nguyen, T.T., Hanieh, S., Dwyer, T., Biggs, B.A., and Fisher, J. (2014). Infant motor development in rural Vietnam and intrauterine exposures to anaemia, iron deficiency and common mental disorders: a prospective community-based study. BMC Pregnancy Childbirth 14, 8.10.1186/1471-2393-14-8Search in Google Scholar
Tussing-Humphreys, L., Pusatcioglu, C., Nemeth, E., and Braunschweig, C. (2012). Rethinking iron regulation and assessment in iron deficiency, anemia of chronic disease, and obesity: introducing hepcidin. J. Acad. Nutr. Diet. 112, 391–400.10.1016/j.jada.2011.08.038Search in Google Scholar
van Rheenen, P. and Brabin, B.J. (2004). Late umbilical cord-clamping as an intervention for reducing iron deficiency anaemia in term infants in developing and industrialised countries: a systematic review. Ann. Trop. Paediatr. 24, 3–16.10.1179/027249304225013286Search in Google Scholar
Wang, X., Wiesinger, J., Beard, J., Felt, B., Menzies, S., Earley, C., Allen, R., and Connor, J. (2004). Thy1 expression in the brain is affected by iron and is decreased in restless legs syndrome. J. Neurol. Sci. 220, 59–66.10.1016/j.jns.2004.02.004Search in Google Scholar
Wang, B., Zhan, S., Gong, T., and Lee, L. (2013). Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia. Cochrane Database Syst. Rev. 6, CD001444.10.1002/14651858.CD001444.pub2Search in Google Scholar
Weinberg, J., Dallman, P.R., and Levine, S. (1980). Iron deficiency during early development in the rat: behavioral and physiological consequences. Pharmacol. Biochem. Behav. 12, 493–502.10.1016/0091-3057(80)90179-3Search in Google Scholar
Whitlock, J.R., Heynen, A.J., Shuler, M.G., and Bear, M.F. (2006). Learning induces long-term potentiation in the hippocampus. Science 313, 1093–1097.10.1126/science.1128134Search in Google Scholar PubMed
Wu, L.L., Zhang, L., Shao, J., Qin, Y.F., Yang, R.W., and Zhao, Z.Y. (2008). Effect of perinatal iron deficiency on myelination and associated behaviors in rat pups. Behav. Brain Res. 188, 263–270.10.1016/j.bbr.2007.11.003Search in Google Scholar PubMed
Wullschleger, S., Loewith, R., and Hall, M.N. (2006). TOR signaling in growth and metabolism. Cell 124, 471–484.10.1016/j.cell.2006.01.016Search in Google Scholar PubMed
Ye, Z. and Connor, J.R. (2000). Identification of iron responsive genes by screening cDNA libraries from suppression subtractive hybridization with antisense probes from three iron conditions. Nucleic Acids Res. 28, 1802–1807.10.1093/nar/28.8.1802Search in Google Scholar PubMed PubMed Central
Yokusoglu, M., Nevruz, O., Baysan, O., Uzun, M., Demirkol, S., Avcu, F., Koz, C., Cetin, T., Hasimi, A., Ural, A.U., et al. (2007). The altered autonomic nervous system activity in iron deficiency anemia. Tohoku J. Exp. Med. 212, 397–402.10.1620/tjem.212.397Search in Google Scholar PubMed
Youdim, M.B. (2008). Brain iron deficiency and excess; cognitive impairment and neurodegeneration with involvement of striatum and hippocampus. Neurotox. Res. 14, 45–56.10.1007/BF03033574Search in Google Scholar PubMed
Youdim, M.B., Ben-Shachar, D., and Yehuda, S. (1989). Putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behavior. Am. J. Clin. Nutr. 50, 607–615; discussion 615–607.10.1093/ajcn/50.3.607Search in Google Scholar PubMed
Yu, G.S., Steinkirchner, T.M., Rao, G.A., and Larkin, E.C. (1986). Effect of prenatal iron deficiency on myelination in rat pups. Am. J. Pathol. 125, 620–624.Search in Google Scholar
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