Department of Biomedical Genetics, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Department of Neurology, University of Colorado Denver - Anschutz Medical Campus, 13001 East 17th Place, Aurora, CO 80045, USA.
Development. 2023 Oct 15;150(20). doi: 10.1242/dev.201068. Epub 2023 Mar 3.
Gestational iron deficiency (gID) is highly prevalent and associated with an increased risk of intellectual and developmental disabilities in affected individuals that are often defined by a disrupted balance of excitation and inhibition (E/I) in the brain. Using a nutritional mouse model of gID, we previously demonstrated a shift in the E/I balance towards increased inhibition in the brains of gID offspring that was refractory to postnatal iron supplementation. We thus tested whether gID affects embryonic progenitor cells that are fated towards inhibitory interneurons. We quantified relevant cell populations during embryonic inhibitory neuron specification and found an increase in the proliferation of Nkx2.1+ interneuron progenitors in the embryonic medial ganglionic eminence at E14 that was associated with increased Shh signaling in gID animals at E12. When we quantified the number of mature inhibitory interneurons that are known to originate from the MGE, we found a persistent disruption of differentiated interneuron subtypes in early adulthood. Our data identify a cellular target that links gID with a disruption of cortical interneurons which play a major role in the establishment of the E/I balance.
妊娠期缺铁（gID）非常普遍，与受影响个体的智力和发育障碍风险增加有关，这些个体通常表现为大脑中兴奋和抑制（E/I）平衡失调。我们之前使用营养性 gID 小鼠模型证明，gID 后代的 E/I 平衡向抑制性增强转变，而这种转变对产后补铁具有抗性。因此，我们测试了 gID 是否会影响注定成为抑制性中间神经元的胚胎祖细胞。我们在胚胎抑制性神经元特化过程中对相关细胞群进行了定量分析，发现在 E14 时 E12 的 gID 动物中 Nkx2.1+ 抑制性神经元祖细胞的增殖增加，与 Shh 信号转导增加有关。当我们对已知起源于 MGE 的成熟抑制性中间神经元的数量进行定量分析时，我们发现早期成年时分化的中间神经元亚型持续受到破坏。我们的数据确定了一个细胞靶标，将 gID 与皮质中间神经元的破坏联系起来，而皮质中间神经元在 E/I 平衡的建立中起着重要作用。
