We and others have established behavioral and cognitive deficits associated with fetal-neonatal iron deficiency anemia, many of which persist beyond the period of iron deficiency (1
). In particular, fetal-neonatal iron deficiency affects the hippocampal-dependent learning and memory formation in adult FID rats (29
). This study demonstrates that fetal-neonatal iron deficiency results in long-term decreased BDNF activity without a compensatory increase in TrkB expression in the rat hippocampus. It also suggests a potential role of iron homeostasis in long-term programming of hippocampal BDNF expression. Given the central role of BDNF in modulating learning and memory function, the findings provide a possible new molecular basis for the persistent long-term cognitive deficits observed in fetal-neonatal iron deficiency.
Our previous study revealed lower mRNA and protein levels of calmodulin regulated kinase-IIα (CamKIIα) and post-synaptic density 95 (PSD95), critical factors for synaptic structure and plasticity in the hippocampus of FID P65 rats (32
). We speculate that decreased BDNF contributes to the reduced expression of CamKIIα and PSD95, ultimately leading to the documented impairment of synaptic plasticity in the FID rat (14
). The translation of these proteins at the synapse is known to depend on BDNF and the mTOR intracellular signaling pathway (38
), both of which are compromised during iron deficiency (16
). mTOR integrates stimuli including growth factors and nutrient and energy availability to regulate protein translation and cellular growth (40
C-fos, Egr-1, and Egr-2 are activity-dependent immediate early transcription factors that are regulated by BDNF administration (41
), N-methyl-D-aspartate (NMDA) receptor activation (42
), or exposure to an enriched environment (43
). These manipulations increase synaptic plasticity and LTP in the hippocampus. Thus, lower expression of c-fos, Egr-1 and Egr-2 suggests a loss of plasticity in the hippocampus of FID adult rats. This less plastic hippocampus could be realized at the structural level by altered dendritic morphology (11
) accompanied by altered expression of molecules involved in guiding and mediating structural changes in response to experience (i.e., synaptic input from CA3) including PSD95, CamKIIα and chemokine-(C-X-C motif)-ligand-12 (32
). Furthermore, HMGCR and synaptobrevin I (Vamp1) are important factors for the formation and release of synaptic vesicles and contribute to the fluidity of synaptic efficacy in response to experience (35
). Lower HMGCR and Vamp1 (32
) expression in FID hippocampus further support a reduction of synaptic plasticity, and are consistent with reductions in paired-pulse facilitation, a measure of presynaptic plasticity, reported in this model (14
). Although HMGCR is expressed in both neurons and astrocytes (35
), BDNF regulates HMGCR expression specifically in neurons (35
). We speculate that the association of reduced expression of BDNF and HMGCR in FID P65 hippocampus found in this study provides evidence that the long-term HMGCR effects are neuronal in origin and thus may be responsible for pyramidal cell dysfunction.
The long-term down-regulation of BDNF without compensatory TrkB expression suggests an effect of early-life iron deficiency on the dampening of this neurotrophic system potentially throughout the life span. Fundamentally, long-term abnormalities in hippocampal function following the abatement of iron deficiency can be ascribed to permanent changes in structure induced by the lack of iron during critical periods of development or to long-term dysregulation of genes important for optimal function. These are not mutually exclusive conditions. We have previously demonstrated the former possibility as evidenced by persistently abnormal dendritic structure at P65 in this model (12
). The current study provides evidence of the latter possibility and is intriguing because this dysregulation exists in spite of re-establishment of nutritional adequacy. The mechanism of the effect is unknown but may relate to those involved in the developmental origins of health and disease (46
), including epigenetic modifications (e.g., methylation and acetylation) of genes. The finding emphasizes the concept that provision of nutrients alone is not adequate to maintain optimal brain function, but that regulation by growth factors that ensure proper utilization of those nutrients is essential. Long-term dysregulation of these growth factors may thus account for persistent abnormal function in spite of nutrient repletion. These findings may also be an important part of understanding the early antecedents of adult neurological disorders characterized by reduced hippocampal function or early hippocampal degeneration, including Alzheimer and Parkinson diseases. Both are characterized by reduction of BDNF levels without compensatory increases in TrkB expression (19
). The altered expression of genes involved in the pathogenesis of Alzheimer disease (29
) supports this possibility.
In summary, previous studies demonstrate the persistence of cognitive deficits in perinatal iron deficient children lasting beyond the period of iron treatment. Such deficits also occur in the rat model of perinatal iron deficiency. This animal model allowed the investigation into the molecular basis underlying these long-term deficits in the hippocampus, an area of the brain that subserves recognition memory. Our findings here corroborate the lower LTP expression and provide the basis for lower expression of factors (CamKIIα and PSD95) critical for synaptic plasticity in FID rats. Moreover, the current study suggests that interventions that enhance BDNF activity such as exercise or selective serotonin reuptake inhibitors (48
) may be useful as therapeutic approaches to treat long-term effects of fetal-neonatal iron deficiency.