Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Hippocampus. 2012 Aug;22(8):1691-702. doi: 10.1002/hipo.22004. Epub 2012 Feb 27.
Iron 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.
铁是神经元功能所必需的底物，贯穿整个生命周期，尤其是在发育过程中。人类生命早期（妊娠后期至 2-3 岁）铁缺乏会导致持续的认知和行为异常，尽管已经进行了铁补充。使用母体饮食铁限制产生的动物模型也显示出持续的学习和记忆缺陷，这表明铁在海马体发育过程中具有关键需求。由于先前饮食限制模型中存在贫血和全身及脑铁缺乏，因此一直难以明确界定这种需求的时间窗口。为了规避这些混杂因素，我们开发了一种转基因小鼠，其在海马神经元中表达四环素反式激活剂调节的显性负性转铁蛋白受体（DNTfR1），特异性地破坏 TfR1 介导的铁摄取。通过给予强力霉素可恢复正常的铁状态。我们使用这种诱导模型来操纵铁缺乏的持续时间，以检查早期铁缺乏对 Morris 水迷宫学习、CA1 椎体神经元顶树突结构的长期影响，以及包括 parvalbmin（PV）表达、神经元周围网络（PNN）和脑源性神经营养因子（BDNF）表达在内的关键期定义因素。持续的铁缺乏会损害空间记忆，并导致顶树突结构紊乱，伴随着 PV 和 PNN 表达的改变以及 BDNF 水平的降低。在海马体树突生成结束的 P21 时进行铁补充，可恢复成年小鼠的空间记忆、树突结构和关键期标志物。然而，直到 P42 时仍存在海马体铁缺乏的小鼠，尽管进行了铁补充，但仍持续存在空间记忆缺陷、CA1 顶树突结构受损以及 PV 和 PNN 表达改变和 BDNF 降低。总之，这些发现表明，在 P21 和 P42 之间，海马体铁的可利用性对于正常空间学习和记忆的发展是必需的，并且这些影响可能反映了早期铁缺乏对关键期关闭的破坏。
