Fetal iron deficiency disrupts the maturation of synaptic function and efficacy in area CA1 of the developing rat hippocampus

Abstract

Late fetal and early postnatal iron deficiency (ID) is a common condition that causes learning and memory impairments in humans while they are iron deficient and following iron repletion. Rodent models of fetal ID demonstrate significant short- and long-term hippocampal structural and biochemical abnormalities that may predispose hippocampal area CA1 to abnormal electrophysiology. Rat pups made iron deficient during the fetal and early postnatal period were assessed for basal synaptic transmission, paired-pulse facilitation (PPF), and long-term potentiation (LTP) in CA1 at postnatal days (P)15 and P30 while iron deficient and at P65 following iron repletion. Our results showed no differences in basal synaptic transmission between iron sufficient and iron deficient pups at P15 or P30, but the ID group did fail to demonstrate the expected developmental increase in synaptic strength by P65 (P < 0.05). Similarly, PPF ratios from iron deficient slices also failed to demonstrate the characteristic developmental changes seen in the iron sufficient group (P < 0.001). Iron deficient slices retained a developmentally immature P15 pattern of LTP expression at P30 and after iron repletion, and LTP expression was lower (P < 0.05) in the iron deficient group at P65. Thus, ID in the fetal and early postnatal period delays or abolishes the developmental maturation of electrophysiological components of synaptic efficacy and plasticity, resulting in abnormalities beyond the period of deficiency. These findings provide a functional corroboration to previous structural and biochemical abnormalities found in the iron deficient rat hippocampus and provide a potential model for learning and memory deficits seen in humans exposed to fetal and early postnatal ID.

Iron Mediates N-Methyl-d-aspartate Receptor-dependent Stimulation of Calcium-induced Pathways and Hippocampal Synaptic Plasticity

“…Only a few studies have addressed the role of iron on LTP (4,6,10). Pursuing this earlier work, we report here that iron chelation depressed basal synaptic transmission in hippocampal slices but did not affect paired pulse facilitation, suggesting a postsynaptic target for iron.…”

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

“…Gestational-neonatal iron deficiency was induced by dietary manipulation as previously described with the dietary modifications achieving a 40% loss of total brain iron at P10 (34,52), a degree of brain iron deficiency equivalent to that seen in term newborn humans (46). For the ID group, pregnant dams were maintained on a purified ID diet (4 ppm Fe, TD 80396; Harlan Teklad, Madison, WI) from gestational day 2 to P15.…”

“…In humans, early life iron deficiency leads to long-term cognitive deficits and behavioral abnormalities (39), which have been phenotypically reproduced in preclinical rodent models (13,23,39). 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).…”

Iron Deficiency Anemia: A Public Health Problem of Global Proportions

“…Experiments employing animal models have demonstrated a key role for iron in brain development and function (Beard et al, 2006;Dallman et al, 1975;Felt & Lozoff, 1996;Jorgenson et al, 2005;Nelson et al, 2002). Iron-containing enzymes and hemoproteins are necessary in many important development processes such as myelination, dendritogenesis, synaptogenesis, and neurotransmission.…”