Stephanie J.B. Fretham1,2,3,4, Erik S. Carlson1,2,3,5,4, J. D. Wobken2, Philippe Tran1,2, Anna Petryk6,2, M.K. Georgieff1,2,3
1Center for Neurobehavioral Development, University of Minnesota Medical School, Minneapolis, Minnesota
2Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
3Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota
4S.J.B.F. and E.S.C. contributed equally to this study.
5Medical Scientist Training Program, University of Minnesota Medical School, Minneapolis, Minnesota
6Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, Minnesota
Tóm tắt
AbstractIron is a necessary substrate for neuronal function throughout the lifespan, but particularly during development. Early life iron deficiency (ID) in humans (late gestation through 2–3 yr) results in persistent cognitive and behavioral abnormalities despite iron repletion. Animal models of early life ID generated using maternal dietary iron restriction also demonstrate persistent learning and memory deficits, suggesting a critical requirement for iron during hippocampal development. Precise definition of the temporal window for this requirement has been elusive due to anemia and total body and brain ID inherent to previous dietary restriction models. To circumvent these confounds, we developed transgenic mice that express tetracycline transactivator regulated, dominant negative transferrin receptor (DNTfR1) in hippocampal neurons, disrupting TfR1 mediated iron uptake specifically in CA1 pyramidal neurons. Normal iron status was restored by doxycycline administration. We manipulated the duration of ID using this inducible model to examine long‐term effects of early ID on Morris water maze learning, CA1 apical dendrite structure, and defining factors of critical periods including parvalbmin (PV) expression, perineuronal nets (PNN), and brain‐derived neurotrophic factor (BDNF) expression. Ongoing ID impaired spatial memory and resulted in disorganized apical dendrite structure accompanied by altered PV and PNN expression and reduced BDNF levels. Iron repletion at P21, near the end of hippocampal dendritogenesis, restored spatial memory, dendrite structure, and critical period markers in adult mice. However, mice that remained hippocampally iron deficient until P42 continued to have spatial memory deficits, impaired CA1 apical dendrite structure, and persistent alterations in PV and PNN expression and reduced BDNF despite iron repletion. Together, these findings demonstrate that hippocampal iron availability is necessary between P21 and P42 for development of normal spatial learning and memory, and that these effects may reflect disruption of critical period closure by early life ID. © 2012 Wiley Periodicals, Inc.
