Stanford University, Institute for Stem Cell Biology and Regenerative Medicine, Stanford, California 94305-5454.
J Neurosci. 2013 Oct 23;33(43):16874-88. doi: 10.1523/JNEUROSCI.4654-12.2013.
We have previously shown in mice that cytokine-mediated damage to the placenta can temporarily limit the flow of nutrients and oxygen to the fetus. The placental vulnerability is pronounced before embryonic day 11, when even mild immune challenge results in fetal loss. As gestation progresses, the placenta becomes increasingly resilient to maternal inflammation, but there is a narrow window in gestation when the placenta is still vulnerable to immune challenge yet resistant enough to allow for fetal survival. This gestational window correlates with early cortical neurogenesis in the fetal brain. Here, we show that maternal illness during this period selectively alters the abundance and laminar positioning of neuronal subtypes influenced by the Tbr1, Satb2, and Ctip2/Fezf2 patterning axis. The disturbances also lead to a laminar imbalance in the proportions of projection neurons and interneurons in the adult and are sufficient to cause changes in social behavior and cognition. These data illustrate how the timing of an illness-related placental vulnerability causes developmental alterations in neuroanatomical systems and behaviors that are relevant to autism spectrum disorders.
我们之前在小鼠中表明，细胞因子介导的胎盘损伤会暂时限制营养物质和氧气流向胎儿。胎盘在胚胎第 11 天之前非常脆弱，即使是轻微的免疫挑战也会导致胎儿流产。随着妊娠的进展，胎盘对母体炎症的抵抗力逐渐增强，但在妊娠期间仍有一个狭窄的窗口，胎盘仍然容易受到免疫挑战，但足以允许胎儿存活。这个妊娠窗口与胎儿大脑的早期皮质神经发生有关。在这里，我们表明，在此期间母亲患病会选择性地改变受 Tbr1、Satb2 和 Ctip2/Fezf2 模式轴影响的神经元亚型的丰度和层定位。这些干扰还导致成年人大脑中投射神经元和中间神经元的层不平衡，并足以导致社会行为和认知的变化。这些数据说明了与疾病相关的胎盘脆弱性的时间如何导致与自闭症谱系障碍相关的神经解剖系统和行为的发育变化。
