Microglia are the immune cells of the brain and become activated during any type of brain injury. In the middle cerebral artery occlusion (MCAo) model, a mouse model for ischemic stroke, we have previously shown that microglia and invaded monocytes upregulate the expression of the muscarinic acetylcholine receptor 3 (M3R) in the ischemic lesion. Here we tested whether this upregulation has an impact on the pathogenesis of MCAo. We depleted the m3R receptor in microglia, but not in circulating monocytes by giving tamoxifen to CX3CR1-CreERT+/+M3Rflox/flox (M3RKOmi) animals 3 weeks prior to MCAo. We found that M3RKOmi male mice had bigger lesions, more pronounced motor deficits after one week and cognitive deficits after about one month compared to control males. The density of Iba1+ cells was lower in the lesions of M3RKO male mice in the early, but not in the late disease phase. In females, these differences were not significant. By giving tamoxifen 1 week prior to MCAo, we depleted m3R in microglia and in circulating monocytes (M3RKOmi/mo). Male M3RKOmi/mo did not differ in lesion size, but had a lower survival rate, showed motor deficits and a reduced accumulation of Iba1+ positive cells into the lesion site. In conclusion, our data suggest that the upregulation of m3R in microglia and monocytes in stroke has a beneficial effect on the clinical outcome in male mice.

中文翻译：

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小胶质细胞中毒蕈碱乙酰胆碱受体 3 的缺失影响脑缺血性损伤

小胶质细胞是大脑的免疫细胞，在任何类型的脑损伤期间都会被激活。在大脑中动脉闭塞 (MCAo) 模型（一种缺血性中风的小鼠模型）中，我们之前已经证明小胶质细胞和侵入的单核细胞上调了缺血性病变中毒蕈碱乙酰胆碱受体 3 (M3R) 的表达。在这里，我们测试了这种上调是否对 MCAo 的发病机制有影响。我们通过在 MCAo 前 3 周向 CX3CR1-CreERT+/+M3Rflox/flox (M3RKOmi) 动物给予他莫昔芬，耗尽了小胶质细胞中的 m3R 受体，但没有耗尽循环单核细胞中的 m3R 受体。我们发现，与对照雄性小鼠相比，M3RKOmi 雄性小鼠的病变更大，一周后运动障碍更明显，一个月后认知障碍更明显。M3RKO雄性小鼠早期病灶中Iba1+细胞密度较低，但不是在疾病晚期。在女性中，这些差异并不显着。通过在 MCAo 前 1 周给予他莫昔芬，我们耗尽了小胶质细胞和循环单核细胞中的 m3R (M3RKOmi/mo)。男性 M3RKOmi/mo 的病变大小没有差异，但存活率较低，表现出运动缺陷和 Iba1+ 阳性细胞在病变部位的积累减少。总之，我们的数据表明，中风中小胶质细胞和单核细胞中 m3R 的上调对雄性小鼠的临床结果具有有益的影响。显示运动缺陷和 Iba1+ 阳性细胞在病变部位的积累减少。总之，我们的数据表明，中风中小胶质细胞和单核细胞中 m3R 的上调对雄性小鼠的临床结果具有有益的影响。显示运动缺陷和 Iba1+ 阳性细胞在病变部位的积累减少。总之，我们的数据表明，中风中小胶质细胞和单核细胞中 m3R 的上调对雄性小鼠的临床结果具有有益的影响。