Brain function is critically dependent on correct circuit assembly. Microglia are well‐known for their important roles in immunological defense and neural plasticity, but whether they can also mediate experience‐induced correction of miswired circuitry is unclear. Ten‐m3 knockout (KO) mice display a pronounced and stereotyped visuotopic mismapping of ipsilateral retinal inputs in their visual thalamus, providing a useful model to probe circuit correction mechanisms. Environmental enrichment (EE) commenced around birth, but not later in life, can drive a partial correction of the most mismapped retinal inputs in Ten‐m3 KO mice. Here, we assess whether enrichment unlocks the capacity for microglia to selectively engulf and remove miswired circuitry, and the timing of this effect. Expression of the microglial‐associated lysosomal protein CD68 showed a clear enrichment‐driven, spatially restricted change which had not commenced at postnatal day (P)18, was evident at P21, more robust at P25, and had ceased by P30. This was observed specifically at the corrective pruning site and was absent at a control site. An engulfment assay at the corrective pruning site in P25 mice showed EE‐driven microglial‐uptake of the mismapped axon terminals. This was temporally and spatially specific, as no enrichment‐driven microglial engulfment was seen in P18 KO mice, nor the control locus. The timecourse of the EE‐driven corrective pruning as determined anatomically, aligned with this pattern of microglia reactivity and engulfment. Collectively, these findings show experience can drive targeted microglial engulfment of miswired neural circuitry during a restricted postnatal window. This may have important therapeutic implications for neurodevelopmental conditions involving aberrant neural connectivity.

中文翻译：

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在有限的产后时期，早期丰富的经验会驱动小胶质细胞有针对性地吞噬错误的神经回路

大脑功能很大程度上取决于正确的电路组装。小胶质细胞因其在免疫防御和神经可塑性中的重要作用而闻名，但它们是否也能介导经验诱导的错误电路的纠正尚不清楚。 10-m3 基因敲除 (KO) 小鼠的视觉丘脑同侧视网膜输入显示出明显且刻板的视觉定位错误映射，为探测电路校正机制提供了一个有用的模型。环境富集（EE）在出生前后开始，但不是在生命后期，可以部分纠正 Ten-m3 KO 小鼠最错误的视网膜输入。在这里，我们评估富集是否释放了小胶质细胞选择性吞噬和去除错误接线电路的能力，以及这种效应的时间。小胶质细胞相关溶酶体蛋白 CD68 的表达显示出明显的富集驱动的、空间受限的变化，这种变化在出生后 (P)18 天尚未开始，在 P21 时明显，在 P25 时更为强烈，并在 P30 时停止。这是在矫正修剪部位特别观察到的，而在对照部位则不存在。 P25 小鼠纠正性修剪部位的吞噬试验显示，EE 驱动的小胶质细胞摄取了错误映射的轴突末端。这是时间和空间特异性的，因为在 P18 KO 小鼠和对照基因座中没有看到富集驱动的小胶质细胞吞噬。 EE 驱动的校正修剪的时间进程是在解剖学上确定的，与小胶质细胞反应和吞噬的这种模式一致。总的来说，这些发现表明，在有限的产后窗口期间，经验可以驱动小胶质细胞有针对性地吞噬错误的神经回路。这可能对涉及异常神经连接的神经发育状况具有重要的治疗意义。