School of Medical Sciences (Neuroscience theme), Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
Glia. 2024 Jul;72(7):1217-1235. doi: 10.1002/glia.24522. Epub 2024 Mar 21.
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.
大脑功能的正常运作依赖于正确的回路组装。小胶质细胞在免疫防御和神经可塑性方面起着重要作用，但其是否也能介导经验诱导的错误连接回路的纠正尚不清楚。Ten-m3 敲除（KO）小鼠在其视觉丘脑中表现出明显且刻板的同侧视网膜输入的视拓扑错位，为探测回路纠正机制提供了一个有用的模型。环境丰富（EE）从出生开始进行，但不是在生命后期进行，可以驱动 Ten-m3 KO 小鼠中最错位的视网膜输入的部分纠正。在这里，我们评估了丰富是否可以解锁小胶质细胞选择性吞噬和去除错误连接的能力，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、空间受限的变化，这种变化在出生后第 18 天（P18）尚未开始，在 P21 时明显，在 P25 时更明显，在 P30 时已经停止。这种变化仅在纠正性修剪部位观察到，在对照部位不存在。在 P25 小鼠的纠正性修剪部位进行的吞噬实验显示，EE 驱动了小胶质细胞对错位轴突末端的吞噬。这种情况具有时间和空间特异性，因为在 P18 KO 小鼠或对照部位没有观察到 EE 驱动的小胶质细胞吞噬。从解剖学上确定的 EE 驱动的纠正性修剪的时间进程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，经验可以在有限的出生后窗口内驱动错误连接的神经回路的靶向小胶质细胞吞噬。这对于涉及异常神经连接的神经发育状况可能具有重要的治疗意义。
