Long-term reduction of hippocampal brain-derived neurotrophic factor activity after fetal-neonatal iron deficiency in adult rats.
Fetal-neonatal iron deficiency acutely alters hippocampal biochemistry, neural morphology, and electrophysiology accompanied by a downregulation of brain-derived neurotrophic factor (BDNF). These changes provide a cellular and molecular basis for observed short-term learning and memory impairments. However, the etiology of residual, long-term hippocampal neurotransmission abnormalities and learning impairments after treatment remain unclear. Because BDNF modulates learning and memory, we assessed its expression in 65-d-old formerly iron deficient (FID) male rats that had been iron deficient during the fetal-neonatal period and treated with iron since postnatal day 7. BDNF-III and -IV mRNAs and BDNF protein expression remained down-regulated in FID rats when compared with the always iron-sufficient rats. Expressions of BDNF activity-dependent downstream targets (3-hydroxy-3-methylglutaryl CoA reductase and immediate early genes c-fos, early growth response gene 1 and 2) were reduced in FID rats. In turn, hippocampal expressions of direct targets of early-growth response genes, including hypoxia-inducible factor 1, dual-specificity phosphatase 4, IGF 2, and myelin basic protein were also diminished in FID rats. Collectively, fetal-neonatal iron deficiency lowers hippocampal BDNF expression and function beyond the period of iron deficiency. These findings may underlie the persistence of learning deficits seen after fetal-neonatal iron deficiency.
Tran
Phu V
PV
Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Fretham
Stephanie J B
SJ
Carlson
Erik S
ES
Georgieff
Michael K
MK
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D006624:Hippocampus / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D000090463:Iron Deficiencies; D019266:Iron, Dietary / Q000008:administration & dosage; D008297:Male; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D051766:Early Growth Response Protein 1; D051767:Early Growth Response Protein 2; C486110:Egr1 protein, rat; C497328:Egr2 protein, rat; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019266:Iron, Dietary; D004676:Myelin Basic Protein; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D007335:Insulin-Like Growth Factor II; D006903:Hydroxymethylglutaryl CoA Reductases; D020813:Receptor, trkB; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; C094132:Dusp4 protein, rat