| Iron deficiency (ID) is the most prevalent micronutrient deficiency in the world, affecting infants in both industrialized and developing countries. Children are at risk for ID during toddlerhood, and infants are at risk for ID during late gestation and early infancy due to severe maternal ID and pregnancies complicated by intrauterine growth restriction or diabetes mellitus. In both of these populations, there is evidence for both acute (during the period of ID) and long-term (after iron repletion) cognitive abnormalities. Animal models of early ID also show cognitive abnormalities, with iron deficient rat pups performing worse on spatial and recognition memory tasks. One caveat of these models is that dietary ID in the rat brain is liable to affect multiple brain systems and it is difficult to parse out the specific contribution of ID to the abnormal development seen in infants and rats. Furthermore, it is unclear whether the effect on the hippocampus is due to the lack of iron or from other processes occurring in conjunction with ID (e.g. maternal stress, hypoxia, anemia). Additionally, the effects of ID during gestation appear to target recognition memory circuitry, as opposed to other brain structures. In other words, dietary models of iron deficiency are not entirely congruent with the human disease being modeled.;For this dissertation I have 3 objectives: (1) To quantitate differences due to dietary ID in mRNAs and proteins salient to hippocampal development and function during ID, and after iron repletion in rat. (2) To delineate the role of the murine Slc11a2 (divalent metal ion transporter-1) in neuronal iron uptake during hippocampal development, to determine the molecular, neurometabolomic, and behavioral alterations occurring due to hippocampal-specific ID during development. (3) To determine the effects of a timed reduction of hippocampal iron uptake on iron metabolism and function by characterizing a mouse carrying a hippocampus-specific tet--responsive transgene of a dominant negative TfR-1 (transferrin receptor-1).;Thus, the specific aims focus on the role of iron in the developing hippocampus and ultimately to determine the contribution of hippocampal dysfunction to the overall clinical spectrum of abnormal cognitive behavior seen with early ID. |
