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Vol. 25, No. 6, 2003
Issue release date: November–December (February 2004)
Dev Neurosci 2003;25:412–420

Perinatal Iron Deficiency Alters Apical Dendritic Growth in Hippocampal CA1 Pyramidal Neurons

Jorgenson L.A. · Wobken J.D. · Georgieff M.K.
Departments of Pediatrics, Child Psychology, and Neuroscience, Center for Neurobehavioral Development, University of Minnesota, Minneapolis, Minn., USA

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Iron deficiency early in life is associated with cognitive disturbances that persist beyond the period of iron deficiency. Within cognitive processing circuitry, the hippocampus is particularly susceptible to insults during the perinatal period. During the hippocampal growth spurt, which is predominantly postnatal in rodents, iron transport proteins and their messenger RNA stabilizing proteins are upregulated, suggesting an increased demand for iron import during this developmental period. Rat pups deprived of iron during the perinatal period show a 30–40% decrease in hippocampal metabolic activity during postnatal hippocampal development. We hypothesized that this reduced hippocampal neuronal metabolism impedes developmental processes such as neurite outgrowth. The goals of the current study were to investigate the effects of perinatal iron deficiency on apical dendritic segment growth in the postnatal day (P) 15 hippocampus and to determine if structural abnormalities persist into adulthood (P65) following iron treatment. Qualitative and quantitative immunohistochemical analyses of dendritic structure and growth using microtubule-associated protein-2 as an index showed that iron-deficient P15 pups have truncated apical dendritic morphology in CA1 and a persistence of an immature apical dendritic pattern at P65. These results demonstrate that perinatal iron deficiency disrupts developmental processes in the hippocampal subarea CA1 and that these changes persist despite iron repletion. These structural abnormalities may contribute to the learning and memory deficits that occur during and following early iron deficiency.

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  1. Agarwal KN (2001): Iron and the brain: Neurotransmitter receptors and magnetic resonance spectroscopy. Br J Nutr 85(suppl 2):147–150.
  2. Alcantara O, Obeid L, Hannun Y, Ponka P, Boldt DH (1994): Regulation of protein kinase C (PKC) expression by iron: Effect of different iron compounds on PKC-β and PKC-α gene expression and role of the 5-flanking region of the PKC-β gene in the response to ferric transferrin. Blood 84:3510–3517.
  3. Avila J, Domínguez J, Díaz-Nido J (1994): Regulation of microtubule dynamics by microtubule-associated protein expression and phosphorylation during neuronal development. Int J Dev Biol 38:13–25.
  4. Barks JDE, Sun R, Malinak C, Silverstein FS (1995): Gp 120, an HIV-1 protein, increases susceptibility to hypoglycemic and ischemic brain injury in perinatal rats. Exp Neurol 132:123–133.
  5. Beggs JM, Brown TH, Byrne JH, Crow T, LeDoux JE, LeBar K, Thompson RF (1999): Learning and memory: Basic mechanisms; in Zigmond MJ, Bloom FE, Landis SC, Roberts JL, Squire LR (eds): Fundamental Neuroscience. San Diego, Academic Press, pp 1411–1454.
  6. Cordero ME, Valenzuela CY, Rodriquez A, Aboitiz F (2003): Dendritic morphology and orientation of pyramidal cells of the neocortex in two groups of early postnatal undernourished-rehabilitated rats. Dev Brain Res 142:37–45.
  7. Cotter D, Wilson S, Roberts E, Kerwin R, Everall IP (2000): Increased dendritic MAP-2 expression in the hippocampus in schizophrenia. Schizophr Res 41:313–323.
  8. Dallman PR, Siimes MA, Manies EC (1975): Brain iron: Persistent deficiency following short-term iron deprivation in the young rat. Br J Haematol 31:209–215.
  9. deRegnier RA, Nelson CA, Thomas K, Wewerka S, Georgieff MK (2000): Neurophysiologic evaluation of auditory recognition memory in healthy newborn infants and infants of diabetic mothers. J Pediatr 137:777–784.
  10. DeUngria M, Rao R, Wobken JD, Luciana M, Nelson CA, Georgieff MK (2000): Perinatal iron deficiency decreases cytochrome c oxidase (cytox) activity in selected regions of neonatal rat brain. Pediatr Res 48:169–176.
  11. Dieni S, Rees S (2003): Dendritic morphology is altered in hippocampal neurons following prenatal compromise. J Neurobiol 55:41–52.
  12. Dobbing J, Sands J (1979): Comparative aspects of the brain growth spurt. Early Hum Dev 13:79–83.

    External Resources

  13. Felt BT, Lozoff B (1996): Brain iron and behavior of rats are not normalized by treatment of iron deficiency anemia during development. J Nutr 126:693–701.
  14. Findlay E, Ng KT, Reid RL, Armstrong SM (1981): The effect of iron deficiency during development on passive avoidance learning in the adult rat. Physiol Behav 27:1089–1096.
  15. Folkerts MM, Berman RF, Muizelaar JP, Rafols JA (1998): Disruption of MAP-2 immunostaining in rat hippocampus after traumatic brain injury. J Neurotrauma 15:349–363.
  16. Georgieff MK, Schmidt RL, Radmer WJ, Mills MM, Widness JA (1992): Fetal iron and cytochrome c status after intrauterine hypoxemia and erythropoietin administration. Am J Physiol 262:R485–R491.
  17. González-Burgos I, Pérez-Vega MI, Beas-Zárate C (2001): Neonatal exposure to monosodium glutamate induces cell death and dendritic hypotrophy in rat prefrontocortical pyramidal neurons. Neurosci Lett 297:69–72.
  18. Grantham-McGregor S, Ani C (2001): A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr 131:649S–668S.
  19. Hoshi M, Akiyama T, Shinohara Y, Miyata Y, Ogawara H, Nishida E, Sakai H (1988): Protein-kinase-C-catalyzed phosphorylation of the microtubule-binding domain of microtubule-associated protein 2 inhibits its ability to induce tubulin polymerization. Eur J Biochem 174:225–230.
  20. Kuvibidila SR, Kitchens D, Baliga BS (1999): In vivo and in vitro iron deficiency reduces protein kinase C activity and translocation in murine splenic and purified T cells. J Cell Biochem 74:468–478.
  21. Kwik-Uribe CL, Golub MS, Keen CL (2000): Chronic marginal iron intakes during early development in mice alter brain iron concentration and behavior despite postnatal iron supplementation. J Nutr 130:2040–2048.
  22. Larkin EC, Rao GA (1990): Importance of fetal and neonatal iron: Adequacy for normal development of central nervous system; in Dobbing J (ed): Brain, Behavior and Iron in the Infant Diet. London, Springer, pp 43–62.
  23. Lewis RM, James LA, Zhang J, Byrne CD, Hales CN (2001): Effects of maternal iron restriction in the rat on hypoxia-induced gene expression and fetal metabolite levels. Br J Nutr 85:193–201.
  24. Lozoff B, Jimenez E, Hagen J, Mollen E, Wolf AW (2000): Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics 105:852–858.

    External Resources

  25. McAllister AK (2000): Cellular and molecular mechanisms of dendrite growth. Cereb Cortex 10:963–973.
  26. Nelson C, Erikson K, Piñero J, Beard JL (1997): In vivo dopamine metabolism is altered in iron-deficient anemic rats. J Nutr 127:2282–2288.
  27. Nelson C, Silverstein FS (1994): Acute disruption of cytochrome oxidase activity in brain in a perinatal rat stroke model. Pediatr Res 36:12–19.
  28. Petry CD, Eaton MA, Wobken JD, Mills MM, Johnson DE, Georgieff MK (1992): Iron deficiency of liver, heart, and brain in newborn infants of diabetic mothers. J Pediatr 121:109–114.
  29. Pokorny J, Yamamoto T (1981): Postnatal ontogenesis of hippocampal CA1 area in rats. 1. Development of dendritic arborisation in pyramidal neurons. Brain Res Bull 7:113–120.
  30. Ramakers GJA (2002): Rho proteins, mental retardation and the cellular basis of cognition. Trends Neurosci 25:191–199.

    External Resources

  31. Rao R, Tkac I, Townsend E, Gruetter R, Georgieff MK (2003): Perinatal iron deficiency alters the neurochemical profile of the developing rat hippocampus. J Nutr 133:3215–3221.
  32. Rao R, Georgieff MK (2002): Perinatal aspects of iron metabolism. Acta Paediatrica Suppl 438:124–129.
  33. Rao R, deUngria M, Sullivan D, Wu P, Wobken JD, Nelson CA, Georgieff MK (1999): Perinatal brain iron deficiency increases the vulnerability of rat hippocampus to hypoxic ischemic insult. J Nutr 129:199–206.
  34. Rice D, Barone S Jr (2000): Critical periods of vulnerability for the developing nervous system: Evidence from human and animal models. Environ Health Perspect 198:511–533.
  35. Rihn LL, Claiborne BJ (1990): Dendritic growth and regression in rat dentate granule cells during late postnatal development. Brain Res Dev Brain Res 54:115–124.
  36. Roy TS, Sabherwal U (1998): Effects of gestational nicotine exposure on hippocampal morphology. Neurotoxicol Teratol 20:465–473.
  37. Sánchez C, Díaz-Nido J, Avila J (2000): Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function. Prog Neurobiol 61:133–168.
  38. Sherwood NM, Timiras PS (1970): A Stereotaxic Atlas of the Developing Rat Brain. Berkley, University of California Press.
  39. Schrenk K, Kapfhammer JP, Metzger F (2002): Altered dendritic development of cerebellar purkinje cells in slice cultures from protein kinase Cγ-deficient mice. Neuroscience 110:675–689.
  40. Siddappa AJM, Rao RB, Wobken JD, Casperson K, Leibold EA, Connor JR, Georgieff MK (2003): Iron deficiency alters iron regulatory protein and iron transport protein expression in the perinatal rat brain. Pediatr Res 53:800–807.
  41. Siddappa AJM, Rao RB, Wobken JD, Leibold EA, Connor JR, Georgieff MK (2002): Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain. J Neurosci Res 68:761–775.
  42. Tamura T, Goldenberg RL, Hou J, Johnston KE, Cliver SP, Ramey SL, Nelson KG (2002): Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age. J Pediatr 2:165–170.

    External Resources

  43. Tanaka M, Kariya F, Kaihatsu K, Nakamura K, Asakura T, Kuroda Y, Ohira Y (1995): Effects of chronic iron deficiency anemia on brain metabolism. Jpn J Physiol 45:257–263.
  44. Whitford KJ, Dijkhuizen P, Polleux F, Ghosh A (2002): Molecular control of cortical dendrite development. Annu Rev Neurosci 25:127–149.
  45. Wilson MT, Keith CH (1998): Glutamate modulation of dendrite outgrowth: Alterations in the distribution of dendritic microtubules. J Neurosci Res 52:599–611.
  46. Woolf NJ, Zinnerman MD, Johnson GVW (1999): Hippocampal microtubule-associated protein-2 alterations with contextual memory. Brain Res 821:241–249.
  47. Yanni PA, Lindsley TA (2000): Ethanol inhibits development of dendrites and synapses in rat hippocampal pyramidal neuron cultures. Brain Res Dev Brain Res 120:233–243.
  48. Yehuda S, Youdim MEH, Mostofsky DI (1986): Brain iron deficiency causes reduced learning capacity in rats. Pharmacol Biochem Behav 25:141–144.
  49. Youdim MBH, Green AR, Bloomfield MR, Mitchell BD, Heal DJ, Grahame-Smith DG (1980): The effects of iron deficiency on brain biogenic monoamine biochemistry and function in rats. Neuropharmacology 19:259–267.
  50. Youdim MBH, Yehuda S (2000): The neurochemical basis of cognitive deficits induced by brain iron deficiency: Involvement of dopamine-opiate system. Cell Mol Biol 46:491–500.
  51. Yu GSM, Steinkirchner TM, Rao GA, Larkin EC (1986): Effect of prenatal iron deficiency on myelination in rat pups. Am J Pathol 125:620–624.

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