Complement component 3 (C3) expression is increased in the cerebellum of aging mice that demonstrate locomotor impairments and increased excitatory synapse density. However, C3 regulation of locomotion, as well as C3 roles in excitatory synapse function, remains poorly understood. Here, we demonstrate that constitutive loss of C3 function in mice evokes a locomotor phenotype characterized by decreased speed, increased active state locomotor probability, and gait ataxia. C3 loss does not alter metabolism or body mass composition. No evidence of significant muscle weakness or degenerative arthritis was found in C3 knockout mice to explain decreased gait speeds. In an enriched primary cerebellar granule cell culture model, loss of C3 protein results in increased excitatory synaptic density and increased response to KCl depolarization. Our analysis of excitatory synaptic density in the cerebellar internal granule cell and molecular layers did not demonstrate increased synaptic density in vivo, suggesting the presence of compensatory mechanisms regulating synaptic development. Functional deficits in C3 knockout mice are therefore more likely to result from altered synaptic function and/or connectivity than gross synaptic deficits. Our data demonstrate a novel role for complement proteins in cerebellar regulation of locomotor output and control.

衰老小鼠小脑中的补体成分 3 (C3) 表达增加，表现出运动障碍和兴奋性突触密度增加。然而，C3 对运动的调节以及 C3 在兴奋性突触功能中的作用仍然知之甚少。在这里，我们证明了小鼠 C3 功能的组成性丧失引起了以速度降低、活动状态运动概率增加和步态共济失调为特征的运动表型。C3 损失不会改变新陈代谢或体重组成。在 C3 基因敲除小鼠中没有发现明显的肌肉无力或退行性关节炎的证据来解释步态速度降低。在丰富的原代小脑颗粒细胞培养模型中，C3 蛋白的丢失导致兴奋性突触密度增加和对 KCl 去极化的反应增加。我们对小脑内部颗粒细胞和分子层中兴奋性突触密度的分析并未证明体内突触密度增加，这表明存在调节突触发育的补偿机制。因此，C3 敲除小鼠的功能缺陷更可能是由于突触功能和/或连接性改变而不是总突触缺陷造成的。我们的数据证明了补体蛋白在小脑调节运动输出和控制中的新作用。因此，C3 敲除小鼠的功能缺陷更可能是由于突触功能和/或连接性改变而不是总突触缺陷造成的。我们的数据证明了补体蛋白在小脑调节运动输出和控制中的新作用。因此，C3 敲除小鼠的功能缺陷更可能是由于突触功能和/或连接性改变而不是总突触缺陷造成的。我们的数据证明了补体蛋白在小脑调节运动输出和控制中的新作用。