Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA 94143, USA.
Weill Institute for Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA.
Sci Adv. 2022 May 6;8(18):eabm2545. doi: 10.1126/sciadv.abm2545.
Parvalbumin-positive (PV) interneurons play a critical role in maintaining circuit rhythm in the brain, and their reduction is implicated in autism spectrum disorders. Animal studies demonstrate that maternal immune activation (MIA) leads to reduced PV interneurons in the somatosensory cortex and autism-like behaviors. However, the underlying molecular mechanisms remain largely unknown. Here, we show that MIA down-regulates microglial expression in fetal brains in an interleukin-17a-dependent manner and that conditional deletion of microglial [ conditional knockout (cKO)] mimics MIA-induced PV interneuron defects and autism-like behaviors in offspring. We further demonstrate that elevated microglial tumor necrosis factor-α expression is the underlying mechanism by which MIA and cKO impair interneuron generation. Genetically restoring expression in microglia ameliorates PV interneuron deficits and autism-like behaviors in MIA offspring. Together, our study demonstrates that microglial GPR56 plays an important role in PV interneuron development and serves as a salient target of MIA-induced neurodevelopmental disorders.
钙结合蛋白阳性（PV）中间神经元在维持大脑回路节律方面发挥着关键作用，其减少与自闭症谱系障碍有关。动物研究表明，母体免疫激活（MIA）导致感觉皮层中的 PV 中间神经元减少，并出现类似自闭症的行为。然而，其潜在的分子机制在很大程度上尚不清楚。在这里，我们表明 MIA 以白细胞介素-17a 依赖的方式下调胎儿大脑中的小胶质细胞表达，并且小胶质细胞特异性敲除（cKO）模拟了 MIA 诱导的 PV 中间神经元缺陷和后代的自闭症样行为。我们进一步证明，小胶质细胞肿瘤坏死因子-α表达升高是 MIA 和 cKO 损害中间神经元发生的潜在机制。在小胶质细胞中遗传恢复表达可改善 MIA 后代的 PV 中间神经元缺陷和自闭症样行为。总之，我们的研究表明小胶质细胞 GPR56 在 PV 中间神经元发育中起着重要作用，是 MIA 诱导的神经发育障碍的一个显著靶点。
