Long-Term Reduction of Hippocampal Brain-Derived Neurotrophic Factor Activity After Fetal-Neonatal Iron Deficiency in Adult Rats

Abstract

Fetal-neonatal iron deficiency acutely alters hippocampal biochemistry, morphology, neurotransmission and electrophysiology resulting in short-term behavioral impairments. It also down-regulates brain-derived neurotrophic factor (BDNF) expression accompanied by the upregulation of nerve growth factor (NGF), epidermal growth factor (EGF), glial-derived neurotrophic factor (GDNF), and p75 neurotrophic receptor. However, the etiology of long-term hippocampal neural transmission abnormalities and learning impairments remains unclear. Since BDNF modulates learning and memory, we assessed its expression in formerly iron deficient (FID) adult rats that had been iron deficient during the fetal and neonatal periods. BDNF was down-regulated in FID rats, whereas NGF, EGF and GDNF levels were similar to the always iron sufficient control group. Consistent with attenuated BDNF activity, we found lower expression of transcriptional targets of BDNF signaling in FID rats, including activity-dependent immediate early genes (e.g., c-fos, earlygrowth response gene-1 and -2) and the rate-limiting enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl coenzyme A reductase. Our findings show that fetal-neonatal iron deficiency lowers BDNF function beyond the period of iron deficiency in the hippocampus. The lower adult hippocampal BDNF activity may underlie the persistence of learning deficits seen after early-life iron deficiency.

Diagnosis and Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children (0–3 Years of Age)

“…3,[23][24][25][26][27][28][29][30][31] Results of a preponderance of studies have demonstrated an association between IDA in infancy and later cognitive deficits. Lozoff et al 3,25 have reported detecting cognitive deficits 1 to 2 decades after the irondeficient insult during infancy.…”

“…These observations would explain the behavioral findings in human infants that have been associated with ID. [29][30][31] Therefore, taking into account that iron is the world's most common single-nutrient deficiency, it is important to minimize IDA and ID among infants and toddlers, even if an unequivocal relationship between IDA and ID and neurodevelopmental outcomes has yet to be established.…”

Perinatal Iron and Copper Deficiencies Alter Neonatal Rat Circulating and Brain Thyroid Hormone Concentrations

“…Relative mRNA levels were calculated relative to an internal standard cDNA sample. Quantitative RT-PCR for brain-derived neurotropic factor isoform IV (Bdnf IV) and early growth response factor 1 (Egr1) was performed on cDNA equivalent to 20 ng of total RNA, as previously described (29).…”

Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus

“…Moreover, iron-deficient (ID) rat pups have decreased energy metabolism, abnormal neuronal morphology and neurotransmission, and reduced expression of genes critical for neural plasticity in the hippocampus, particularly during the period of peak hippocampal dendritogenesis, synaptogenesis, and myelination (10,16,21,34,35,48,51,60). These abnormalities in gene expression and neuronal morphology can persist beyond the period of early iron deficiency into adulthood (10,61).…”