Center for Neurobehavioral Development, University of Minnesota, Minneapolis MN, USA.
Am J Physiol Endocrinol Metab. 2012 Feb 1;302(3):E316-24. doi: 10.1152/ajpendo.00369.2011. Epub 2011 Nov 16.
Gestational-neonatal iron deficiency, a common micronutrient deficiency affecting the offspring of more than 30% of pregnancies worldwide, leads to long-term cognitive and behavioral abnormalities. Preclinical models of gestational-neonatal iron deficiency result in reduced energy metabolism and expression of genes critical for neuronal plasticity and cognitive function, which are associated with a smaller hippocampal volume and abnormal neuronal dendrite growth. Because insulin-like growth factor (IGF) modulates early postnatal cellular growth, differentiation, and survival, we used a dietary-induced rat model to assess the effects of gestational iron deficiency on activity of the IGF system. We hypothesized that gestational iron deficiency attenuates postnatal hippocampal IGF signaling and results in downstream effects that contribute to hippocampal anatomic and functional deficits. At postnatal day (P) 15 untreated gestational-neonatal iron deficiency markedly suppressed hippocampal IGF activation and protein kinase B signaling, and reduced neurogenesis, while elevating extracellular signal-regulated kinase 1/2 signaling and hypoxia-inducible factor-1α expression. Iron treatment beginning at P7 restored IGF signaling, increased neurogenesis, and normalized all parameters by the end of rapid hippocampal differentiation (P30). Expression of the neuron-specific synaptogenesis marker, disc-large homolog 4 (PSD95), increased more rapidly than the glia-specific myelination marker, myelin basic protein, following iron treatment, suggesting a more robust response to iron therapy in IGF-I-dependent neurons than IGF-II-dependent glia. Collectively, our findings suggest that IGF dysfunction is in part responsible for hippocampal abnormalities in untreated iron deficiency. Early postnatal iron treatment of gestational iron deficiency reactivates the IGF system and promotes neurogenesis and differentiation in the hippocampus during a critical developmental period.
妊娠期-新生儿铁缺乏症是一种常见的微量营养素缺乏症，影响着全球超过 30%妊娠的后代，导致长期的认知和行为异常。妊娠期-新生儿铁缺乏症的临床前模型导致能量代谢减少和神经元可塑性及认知功能关键基因的表达减少，这与海马体体积较小和神经元树突生长异常有关。由于胰岛素样生长因子 (IGF) 调节出生后早期细胞的生长、分化和存活，我们使用饮食诱导的大鼠模型来评估妊娠期铁缺乏对 IGF 系统活性的影响。我们假设妊娠期铁缺乏会减弱产后海马 IGF 信号转导，并导致下游效应，从而导致海马体解剖和功能缺陷。在未治疗的妊娠期-新生儿铁缺乏症的大鼠中，在出生后第 15 天，海马 IGF 激活和蛋白激酶 B 信号明显受到抑制，神经发生减少，而细胞外信号调节激酶 1/2 信号和缺氧诱导因子-1α 的表达增加。从第 7 天开始的铁治疗恢复了 IGF 信号转导，增加了神经发生，并在快速海马分化（第 30 天）结束时使所有参数正常化。神经元特异性突触发生标记物，Disc-large 同源物 4 (PSD95) 的表达比胶质特异性髓鞘形成标记物，髓鞘碱性蛋白 (myelin basic protein) 更快地增加，这表明在 IGF-I 依赖性神经元中，对铁治疗的反应比 IGF-II 依赖性胶质更为强烈。总的来说，我们的发现表明 IGF 功能障碍是未经治疗的铁缺乏症中海马体异常的部分原因。妊娠期铁缺乏症的早期产后铁治疗可使 IGF 系统重新激活，并在关键发育期间促进海马体的神经发生和分化。
