Institut de Biologie de l'École Normale Supérieure (IBENS), Département de Biologie, École Normale Supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France.
Neurophysiologie et Nouvelles Microscopies, INSERM U1128, Université Paris Descartes, 75006 Paris, France.
Cell Rep. 2019 Jul 30;28(5):1119-1126.e4. doi: 10.1016/j.celrep.2019.06.086.
The etiology of neurodevelopmental disorders is linked to defects in parvalbumin (PV)-expressing cortical interneurons and to prenatal immune challenges. Mouse models of maternal immune activation (MIA) and microglia deficits increase the postnatal density of PV interneurons, raising the question of their functional integration. Here, we show that MIA and embryonic depletion of macrophages including microglia have a two-step impact on PV interneurons wiring onto their excitatory target neurons in the barrel cortex. In adults, both challenges reduced the inhibitory drive from PV interneurons, as reported in neurodevelopmental disorders. In juveniles, however, we found an increased density of PV neurons, an enhanced strength of unitary connections onto excitatory cells, and an aberrant horizontal inhibition with a reduced lateral propagation of sensory inputs in vivo. Our results provide a comprehensive framework for understanding the impact of prenatal immune challenges onto the developmental trajectory of inhibitory circuits that leads to pathological brain wiring.
神经发育障碍的病因与表达 parvalbumin（PV）的皮质中间神经元的缺陷和产前免疫挑战有关。母体免疫激活（MIA）和小胶质细胞缺陷的小鼠模型增加了 PV 中间神经元的出生后密度，这引发了它们功能整合的问题。在这里，我们表明 MIA 和胚胎巨噬细胞（包括小胶质细胞）耗竭对桶状皮层中 PV 中间神经元与兴奋性靶神经元的连接布线有两步影响。在成年人中，两种挑战都降低了 PV 中间神经元的抑制作用，这与神经发育障碍的报告一致。然而，在青少年中，我们发现 PV 神经元的密度增加，单位连接到兴奋性细胞的强度增强，以及异常的水平抑制，导致感觉输入的横向传播减少。我们的研究结果为理解产前免疫挑战对导致病理性大脑连接的抑制回路发育轨迹的影响提供了一个全面的框架。
