Abstract
Fetal–neonatal iron deficiency anemia (IDA) causes long-lasting deficits in cognitive development and learning ability. Although certain neurological abnormalities can be corrected with iron treatment, neurotransmission and learning impairments continue to persist inspite of complete iron repletion. The etiologies of the acute and persistent effects of early-life IDA remain largely unknown. To explore the potential molecular bases of these abnormalities, we investigated the effects of early-life IDA on the expression of neurotrophic factors that mediate proliferation, differentiation, and plasticity of hippocampal neurons. We compared hippocampal expression of neurotrophic factors in male rats made iron-deficient (ID) from gestational day 2 to postnatal day (P) 7 to always iron-sufficient controls at P7, 15 and 30 with quantitative RT-PCR, Western analysis, and immunohistology. Iron deficiency up-regulated hippocampal nerve growth factor (NGF), epidermal growth factor (EGF), and glial-derived neurotrophic factor (GDNF), accompanied by an increase in p75NTR receptor expression. In contrast, iron deficiency downregulated brain-derived neurotrophic factor (BDNF) and expression of early-growth response gene-1 and -2 (Egr1 and Egr2), the downstream transcriptional targets of BDNF signaling. Doublecortin expression, a marker of differentiating neurons, was reduced during the period of peak iron deficiency, suggesting impaired neuronal differentiation in the ID hippocampus. In 65 day old formerly iron-deficient (FID) male rats that had been iron deficient during the fetal–neonatal period and treated with iron since P7, expression of BDNF remained downregulated, whereas other neurotrophic factors normalized to the always iron-sufficient control rats. Expression of BDNF activity-dependent targets 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and immediate early genes c-fos, Egr1, and Egr2) were reduced proportionately in FID rats. In turn, hippocampal expression of direct targets of Egr1 and Egr2, including hypoxia-inducible factor 1 (Hif1a), dual-specificity phosphatase 4 (Dusp4), insulin-like growth factor 2 (Igf2), and myelin basic protein (Mbp), were also diminished in FID rats. Collectively, fetal–neonatal iron deficiency impairs neuronal differentiation in the hippocampus and lowers hippocampal BDNF activity beyond the period of iron deficiency. The reduced BDNF activity and its downstream molecular cascade modulating neuronal differentiation and plasticity may underlie the acute effects and the persistent learning deficits of fetal–neonatal iron deficiency.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- BDNF:
-
Brain-Derived Neurotrophic Factor
- CNTF:
-
Ciliary Neurotrophic Factor
- Dcx:
-
Doublecortin
- Dusp4:
-
Dual Specificity Phosphatase 4
- Egr1 and 2:
-
Early-Growth-Response-Gene 1 and 2
- EGF:
-
Epidermal Growth Factor
- ERK1 and 2:
-
Extracellular-Signal Regulated Kinase 1 and 2
- FID:
-
Formerly Iron-Deficient
- GDNF:
-
Glial-Derived Neurotrophic Factor
- Hif1α:
-
Hypoxia Inducible Factor 1α
- HMGCR:
-
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase
- ID:
-
Iron-Deficient
- IS:
-
Iron-Sufficient
- LTP:
-
Long-Term Potentiation
- Mbp:
-
Myelin Basic Protein
- mTOR:
-
Mammalian Target of Rapamycin
- NGF:
-
Nerve Growth Factor
- p75NTR :
-
Neurotrophic Receptor p75
- P:
-
Postnatal Day
- PARV:
-
Parvalbumin
- qPCR:
-
Quantitative RT-PCR
- TrkB:
-
Tyrosine-Receptor Kinase B
- TUNEL:
-
TdT-Mediated biotin-dUTP Nick End Labeling
References
Alder J, Thakker-Varia S, Bangasser DA, Kuroiwa M, Plummer MR, Shors TJ, Black IB. J Neurosci. 2003;23:10800–8.
Beard JL, Wiesinger JA, Connor JR. Dev Neurosci. 2003;25:308–15.
Berasi SP, Huard C, Li D, Shih HH, Sun Y, Zhong W, Paulsen JE, Brown EL, Gimeno RE, Martinez RV. J Biol Chem. 2006;281:27167–77.
Branchi I, Francia N, Alleva E. Behav Pharmacol. 2004;15:353–62.
Bui NT, Konig HG, Culmsee C, Bauerbach E, Poppe M, Krieglstein J, Prehn JH. J Neurochem. 2002;81:594–605.
Calella AM, Nerlov C, Lopez RG, Sciarretta C, von Bohlen und Halbach O, Bereshchenko O, Minichiello L. Neural Dev. 2007;2:4.
Carlson ES, Stead JD, Neal CR, Petryk A, Georgieff MK. Hippocampus. 2007;17:679–91.
Carlson ES, Magid R, Petryk A, Georgieff MK. Brain Res. 2008;1237C:75–83.
Chao MV. Nat Rev Neurosci. 2003;4:299–309.
Chen Y, Ai Y, Slevin JR, Maley BE, Gash DM. Exp Neurol. 2005;196:87–95.
Chockalingam UM, Murphy E, Ophoven JC, Weisdorf SA, Georgieff MK. J Pediatr. 1987;111:283–6.
Clardy SL, Wang X, Zhao W, Liu W, Chase GA, Beard JL, True Felt B, Connor JR. J Neural Transm Suppl. 2006;173–96.
Culmsee C, Gerling N, Lehmann M, Nikolova-Karakashian M, Prehn JH, Mattson MP, Krieglstein J. Neuroscience. 2002;115:1089–108.
Dieni S, Rees S. Exp Neurol. 2005;192:265–73.
Dong M, Wu Y, Fan Y, Xu M, Zhang J. Neurosci Lett. 2006;400:177–80.
Eide FF, Vining ER, Eide BL, Zang K, Wang XY, Reichardt LF. J Neurosci. 1996;16:3123–9.
Erickson JT, Brosenitsch TA, Katz DM. J Neurosci. 2001;21:581–9.
Felt BT, Beard JL, Schallert T, Shao J, Aldridge JW, Connor JR, Georgieff MK, Lozoff B. Behav Brain Res. 2006;171:261–70.
Francis F, Koulakoff A, Boucher D, Chafey P, Schaar B, Vinet MC, Friocourt G, McDonnell N, Reiner O, Kahn A, McConnell SK, Berwald-Netter Y, Denoulet P, Chelly J. Neuron. 1999;23:247–56.
Friedman WJ. J Neurosci. 2000;20:6340–6.
Gillian AL, Svaren J. J Biol Chem. 2004;279:9056–63.
Gluckman PD, Hanson MA, Cooper C, Thornburg KL. N Engl J Med. 2008;359:61–73.
Golub MS, Hogrefe CE, Germann SL, Capitanio JP, Lozoff B. Neurotoxicol Teratol. 2006;28:3–17.
Grosse G, Djalali S, Deng DR, Holtje M, Hinz B, Schwartzkopff K, Cygon M, Rothe T, Stroh T, Hellweg R, Ahnert-Hilger G, Hortnag H. Brain Res Dev Brain Res. 2005;156:111–26.
Guan KL, Butch E. J Biol Chem. 1995;270:7197–203.
Guenette S, Chang Y, Hiesberger T, Richardson JA, Eckman CB, Eckman EA, Hammer RE, Herz J. EMBO J. 2006;25:420–31.
Heldt SA, Stanek L, Chhatwal JP, Ressler KJ. Mol Psychiatry. 2007;12:656–70.
Hennigan A, O’Callaghan RM, Kelly AM. Biochem Soc Trans. 2007;35:424–7.
Ikin AF, Sabo SL, Lanier LM, Buxbaum JD. Mol Cell Neurosci. 2007;35:57–63.
Jang SW, LeBlanc SE, Roopra A, Wrabetz L, Svaren J. J Neurochem. 2006;98:1678–87.
Jiang B, Kitamura A, Yasuda H, Sohya K, Maruyama A, Yanagawa Y, Obata K, Tsumoto T. Eur J Neurosci. 2004;20:709–18.
Jorgenson LA, Wobken JD, Georgieff MK. Dev Neurosci. 2003;25:412–20.
Jorgenson LA, Sun M, O’Connor M, Georgieff MK. Hippocampus. 2005;15:1094–102.
Kelly A, Laroche S, Davis S. J Neurosci. 2003;23:5354–60.
Klein R, Conway D, Parada LF, Barbacid M. Cell. 1990;61:647–56.
Klein RS, Rubin JB. Trends Immunol. 2004;25:306–14.
Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Proc Natl Acad Sci U S A. 1995;92:8856–60.
Lee R, Kermani P, Teng KK, Hempstead BL. Science. 2001;294:1945–8.
Lozoff B, Georgieff MK. Semin Pediatr Neurol. 2006;13:158–65.
Lozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T. Nutr Rev. 2006;64:S34–S91.
Malenka RC. Nat Rev Neurosci. 2003;4:923–6.
Marty S, Carroll P, Cellerino A, Castren E, Staiger V, Thoenen H, Lindholm D. J Neurosci. 1996;16:675–87.
McAllister AK, Katz LC, Lo DC. Annu Rev Neurosci. 1999;22:295–318.
Minichiello L, Calella AM, Medina DL, Bonhoeffer T, Klein R, Korte M. Neuron. 2002;36:121–37.
Miyamoto E. J Pharmacol Sci. 2006;100:433–42.
Nelson CA, Wewerka S, Thomas KM, Tribby-Walbridge S, deRegnier R, Georgieff M. Behav Neurosci. 2000;114:950–6.
Patterson SL, Grover LM, Schwartzkroin PA, Bothwell M. Neuron. 1992;9:1081–8.
Petry CD, Eaton MA, Wobken JD, Mills MM, Johnson DE, Georgieff MK. J Pediatr. 1992;121:109–14.
Pham TM, Winblad B, Granholm AC, Mohammed AH. Pharmacol Biochem Behav. 2002;73:167–75.
Pillai A, Mahadik SP. Schizophr Res. 2008;100:325–33.
Pokorny J, Yamamoto T. Brain Res Bull. 1981;7:113–20.
Rao R, Tkac I, Townsend EL, Gruetter R, Georgieff MK. J Nutr. 2003;133:3215–21.
Rao R, Tkac I, Townsend EL, Ennis K, Gruetter R, Georgieff MK. J Cereb Blood Flow Metab. 2007;27:729–40.
Riggins T, Miller NC, Bauer PJ, Georgieff MK, Nelson CA. Dev Sci. 2009;12:209–19.
Rossler OG, Thiel G. Am J Physiol Cell Physiol. 2004;286:C1118–29.
Roth TL, Lubin FD, Funk AJ, Sweatt JD. Biol Psychiatry. 2009;65:760–9.
Rotwein P, Burgess SK, Milbrandt JD, Krause JE. Proc Natl Acad Sci U S A. 1988;85:265–9.
Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW. Neuroscience. 2000;101:305–12.
Schmidt AT, Waldow KJ, Grove WM, Salinas JA, Georgieff MK. Behav Neurosci. 2007;121:475–82.
Schratt GM, Nigh EA, Chen WG, Hu L, Greenberg ME. J Neurosci. 2004;24:7366–77.
Schiavo G, Stenbeck G, Rothman JE, Sollner TH. Proc Natl Acad Sci USA. 1997;94:997–1001.
Siddappa AJ, Rao RB, Wobken JD, Leibold EA, Connor JR, Georgieff MK. J Neurosci Res. 2002;68:761–75.
Siddappa AM, Georgieff MK, Wewerka S, Worwa C, Nelson CA, Deregnier RA. Pediatr Res. 2004;55:1034–41.
Siegel GJ, Chauhan NB. Brain Res Rev. 2000;33:199–227.
Silhol M, Arancibia S, Perrin D, Maurice T, Alliot J, Tapia-Arancibia L. Rejuvenation Res. 2008;11:1031–40.
Sperandio S, Fortin J, Sasik R, Robitaille L, Corbeil J, de Belle I. Mol Carcinog. 2009;48:38–44.
Steward O, Falk PM. J Comp Neurol. 1991;314:545–57.
Suzuki S, Kiyosue K, Hazama S, Ogura A, Kashihara M, Hara T, Koshimizu H, Kojima M. J Neurosci. 2007;27:6417–27.
Sweet DG, Savage G, Tubman TR, Lappin TR, Halliday HL. Arch Dis Child Fetal Neonatal Ed. 2001;84:F40–3.
Tamura T, Goldenberg RL, Hou J, Johnston KE, Cliver SP, Ramey SL, Nelson KG. J Pediatr. 2002;140:165–70.
Tang SJ, Reis G, Kang H, Gingras AC, Sonenberg N, Schuman EM. Proc Natl Acad Sci U S A. 2002;99:467–72.
Timmusk T, Palm K, Metsis M, Reintam T, Paalme V, Saarma M, Persson H. Neuron. 1993;10:475–89.
Tran PV, Carlson ES, Fretham SJB, Georgieff MK. J Nutr. 2008;138:2495–501.
Tran PV, Fretham SJ, Carlson ES, Georgieff MK. Pediatr Res. 2009;65:493–8.
Tsuji Y, Moran E, Torti SV, Torti FM. J Biol Chem. 1999;274:7501–7.
WHO. Micronutrient deficiencies. 2008. http://www.who.int/nutrition/topics/ida/en/index.html
Wong K, Sharma A, Awasthi S, Matlock EF, Rogers L, Van Lint C, Skiest DJ, Burns DK, Harrod R. J Biol Chem. 2005;280:9390–9.
Wong RW, Guillaud L. Cytokine Growth Factor Rev. 2004;15:147–56.
Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B. Nat Neurosci. 2005;8:1069–77.
Yamada M, Ikeuchi T, Hatanaka H. Prog Neurobiol. 1997;51:19–37.
Ye P, Li L, Richards RG, DiAugustine RP, D’Ercole AJ. J Neurosci. 2002;22:6041–51.
Zagrebelsky M, Holz A, Dechant G, Barde YA, Bonhoeffer T, Korte M. J Neurosci. 2005;25:9989–99.
Acknowledgments
We apologize that we were unable to cite all relevant works in this article to due space constraint. We thank Heather McLaughlin for editorial assistance. This work is supported by NICHD RO1 HD29421 to MKG and NIMH Training grant T32MH073129 to PVT.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Georgieff, M.K., Tran, P.V. (2011). Fetal–Neonatal Iron Deficiency Affects Neurotrophic Factor Expression, Neural Differentiation, and Neuroplasticity in the Rat Hippocampus. In: Preedy, V., Watson, R., Martin, C. (eds) Handbook of Behavior, Food and Nutrition. Springer, New York, NY. https://doi.org/10.1007/978-0-387-92271-3_151
Download citation
DOI: https://doi.org/10.1007/978-0-387-92271-3_151
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-92270-6
Online ISBN: 978-0-387-92271-3
eBook Packages: MedicineMedicine (R0)