Region-specific Impact of Iron Deficiency on Postnatal CNS Development

Abstract

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pathology and Laboratory Medicine, 2012.Iron has been identified as an essential nutrient for sustaining life and must be absorbed through our diet. Specifically, iron plays a key role as cofactor for enzymes that are critical for many biological processes. Chronic suboptimal iron availability leads to Iron deficiency (ID) that is associated with systemic changes to cellular physiology such as decreased red blood cell generation (anemia) upon severe iron shortage. ID is the most prevalent nutritional deficiency worldwide, and anemia is the most commonly diagnosed sequela of ID due to definitive cellular and physiological hallmarks. Studies using rodent models of iron deficiency anemia (IDA) revealed long term consequences on central nervous system (CNS) metabolic processes, many of which are likely due to the hypoxic condition that is generated by the anemia. To fully understand the impact of iron deficiency on cellular and molecular components, it is imperative to separate the condition of ID from IDA. In this thesis, we show that iron deficiency without the confounding variables of anemia disrupts both conduction velocity in the auditory nerve, as well as signaling strength in the corpus callosum. In both CNS regions, there is a marked decrease in axon diameter, one of the critical determinants of signal conduction integrity. Interestingly, the severe myelin defects that have been found in iron deficiency anemia that can concomitantly affect signal conduction were not seen. Furthermore, studies in the hippocampus and cortex reveal that ID not only disrupts structural development in axons, but also in the dendrites of neurons. Although iron deficiency is a systemic condition, there apparently exists a region-specific effect intrinsic to the cell type and CNS tissue of interest. Our data reveal novel phenotypes of ID in neurodevelopment, clarifying the neural consequences of iron deficiency compared to anemia. Results from this work provide further insight into the role of iron in the complex dynamic between neurons and glia during development of different CNS regions