Traumatic brain injury (TBI) is associated with the development of visual system disorders. Visual deficits can present with delay and worsen over time, and may be associated with an ongoing neuroinflammatory response that is known to occur after TBI. Complement system activation is strongly associated with the neuroinflammatory response after TBI, but whether it contributes to vision loss after TBI is unexplored. Acute and chronic neuroinflammatory changes within the dorsal lateral geniculate nucleus (dLGN) and retina were investigated subsequent to a moderate to severe murine unilateral controlled cortical impact. Neuroinflammatory and histopathological outcomes were interpreted in the context of behavioral and visual function data. To investigate the role of complement, cohorts were treated after TBI with the complement inhibitor, CR2-Crry. At 3 days after TBI, complement component C3 was deposited on retinogeniculate synapses in the dLGN both ipsilateral and contralateral to the lesion, which was reduced in CR2-Crry treated animals. This was associated with microglia morphological changes in both the ipsilateral and contralateral dLGN, with a less ramified phenotype in vehicle compared to CR2-Crry treated animals. Microglia in vehicle treated animals also had a greater internalized VGlut2 + synaptic volume after TBI compared to CR2-Crry treated animals. Microglia morphological changes seen acutely persisted for at least 49 days after injury. Complement inhibition also reduced microglial synaptic internalization in the contralateral dLGN and increased the association between VGLUT2 and PSD95 puncta, indicating preservation of intact synapses. Unexpectedly, there were no changes in the thickness of the inner retina, retinal nerve fiber layer or retinal ganglion layer. Neuropathological changes in the dLGN were accompanied by reduced visual acuity at subacute and chronic time points after TBI, with improvement seen in CR2-Crry treated animals. TBI induces complement activation within the dLGN and promotes microglial activation and synaptic internalization. Complement inhibition after TBI in a clinically relevant paradigm reduces complement activation, maintains a more surveillance-like microglia phenotype, and preserves synaptic density within the dLGN. Together, the data indicate that complement plays a key role in the development of visual deficits after TBI via complement-dependent microglial phagocytosis of synapses within the dLGN.

中文翻译：

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补体在脑外伤后传播视觉系统病理

创伤性脑损伤 (TBI) 与视觉系统疾病的发生有关。视觉缺陷可能会随着时间的推移而延迟出现并恶化，并且可能与已知在 TBI 后发生的持续神经炎症反应有关。补体系统激活与 TBI 后的神经炎症反应密切相关，但其是否会导致 TBI 后视力丧失尚不清楚。在中度至重度的小鼠单侧受控皮质冲击后，研究了背外侧膝状核（dLGN）和视网膜内的急性和慢性神经炎症变化。神经炎症和组织病理学结果是在行为和视觉功能数据的背景下解释的。为了研究补体的作用，在 TBI 后使用补体抑制剂 CR2-Crry 治疗队列。 TBI 后 3 天，补体成分 C3 沉积在病变同侧和对侧 dLGN 的视网膜突触上，在 CR2-Crry 治疗的动物中，补体成分 C3 减少。这与同侧和对侧 dLGN 中的小胶质细胞形态变化有关，与 CR2-Crry 治疗的动物相比，载体中的分支表型较少。与 CR2-Crry 治疗的动物相比，TBI 后，载体治疗的动物中的小胶质细胞也具有更大的内化 VGlut2 + 突触体积。小胶质细胞形态变化在损伤后持续至少 49 天。补体抑制还减少了对侧 dLGN 中小胶质细胞突触的内化，并增加了 VGLUT2 和 PSD95 点之间的关联，表明完整突触的保存。出乎意料的是，视网膜内层、视网膜神经纤维层或视网膜神经节层的厚度没有变化。 dLGN 的神经病理学变化伴随着 TBI 后亚急性和慢性时间点的视力下降，而 CR2-Crry 治疗的动物中观察到视力有所改善。 TBI 诱导 dLGN 内的补体激活，并促进小胶质细胞激活和突触内化。在临床相关范例中，TBI 后的补体抑制可减少补体激活，维持更像监视的小胶质细胞表型，并保留 dLGN 内的突触密度。总之，数据表明，补体通过 dLGN 内突触的补体依赖性小胶质细胞吞噬作用，在 TBI 后视觉缺陷的发展中发挥关键作用。