Early-life insults to brain development can have devastating, long-lasting effects on cognitive function. Iron deficiency (ID) during late gestation and the first few years of life is one such insult that commonly results from maternal anemia, gestational diabetes, intrauterine growth restriction and insufficient dietary iron intake. In both humans and animal models, early ID causes alterations in hippocampally-dependent functions including memory. Animal models have provided evidence that early ID affects a broad range of processes crucial for neuronal development including gene expression, protein synthesis, dendritic morphology and electrophysiology. The mechanisms through which ID results in these persistent cognitive effects are unknown, largely because dietary animal models of ID induce total body ID which includes anemia, hypoxia, the activation of reactive oxygen species, and ID in multiple organ systems. These secondary effects of total body ID confound attempts to identify precisely how iron interacts with neuronal development and function. The broad objective of this application is to use a novel genetic mouse model of hippoampal-specific tissue level ID to identify the interaction between iron and pathways central to basic processes necessary for neuronal growth and development, such as mammalian target of rapamycin (mTOR) signaling which monitors cell status (growth factors, oxygen, nutrients, and stress) to regulate cell growth. mTOR does this by regulating protein synthesis, actin organization, and autophagy.
The specific aims of this application are to 1) assess the consequences of tissue-level ID on mTOR activity and 2) examine the downstream consequences of mTOR activity on the regulation of protein synthesis. The results of this proposal will provide basic scientific knowledge about the ways that iron interacts with processes crucial for neuronal development. Understanding the mechanisms through which iron interacts with cellular processes is highly relevant for public health as iron deficiency affects two billion people worldwide and has particularly devastating long-term consequences during fetal growth and the first several years of life.
| Fretham, Stephanie J B; Carlson, Erik S; Georgieff, Michael K (2013) Neuronal-specific iron deficiency dysregulates mammalian target of rapamycin signaling during hippocampal development in nonanemic genetic mouse models. J Nutr 143:260-6 |
| Pisansky, Marc T; Wickham, Robert J; Su, Jianjun et al. (2013) Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex. Hippocampus 23:952-62 |
| Bastian, Thomas W; Anderson, Jeremy A; Fretham, Stephanie J et al. (2012) Fetal and neonatal iron deficiency reduces thyroid hormone-responsive gene mRNA levels in the neonatal rat hippocampus and cerebral cortex. Endocrinology 153:5668-80 |
| Fretham, S J B; Carlson, E S; Wobken, J et al. (2012) Temporal manipulation of transferrin-receptor-1-dependent iron uptake identifies a sensitive period in mouse hippocampal neurodevelopment. Hippocampus 22:1691-702 |
| Fretham, Stephanie J B; Carlson, Erik S; Georgieff, Michael K (2011) The role of iron in learning and memory. Adv Nutr 2:112-21 |
