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.
Nerve Growth Factor Neurotrophic Factor Iron Deficiency Iron Deficiency Anemia BDNF Level
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Brain-Derived Neurotrophic Factor
Ciliary Neurotrophic Factor
Dual Specificity Phosphatase 4
Egr1 and 2
Early-Growth-Response-Gene 1 and 2
Epidermal Growth Factor
ERK1 and 2
Extracellular-Signal Regulated Kinase 1 and 2
Glial-Derived Neurotrophic Factor
Hypoxia Inducible Factor 1α
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase
Myelin Basic Protein
Mammalian Target of Rapamycin
Nerve Growth Factor
Neurotrophic Receptor p75
Tyrosine-Receptor Kinase B
TdT-Mediated biotin-dUTP Nick End Labeling
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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.
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