Local calcium accumulations promote phagocyte-mediated synapse removal in cortical neuroinflammation

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. Here we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy. Overall design: RNA-seq of sorted cells from brain of Cortical MS mouse treated with vehicle or CSF1R inhibitor

罹患神经炎症性疾病多发性硬化（multiple sclerosis, MS）的患者，其皮质病理改变可引发慢性认知功能损伤。目前对于此类灰质炎症如何影响神经元结构与功能的机制尚未完全阐明。本研究借助皮质型多发性硬化小鼠模型的活体功能与结构成像技术，证实皮质炎症发作会破坏皮质环路活动，同时伴随广泛但一过性的树突棘丢失。即将被清除的树突棘会出现局部钙聚集，随后被浸润的巨噬细胞或活化的小胶质细胞清除。使用新型集落刺激因子1受体（colony-stimulating factor 1 receptor, CSF1R）拮抗剂靶向调控吞噬细胞活化，可阻止皮质突触丢失。综上，本研究证实突触丢失是炎症性灰质病变的关键病理特征，且该病理过程可通过免疫调节治疗进行干预。实验整体设计：对给予溶剂对照或CSF1R抑制剂的皮质型多发性硬化小鼠脑组织中分选得到的细胞开展RNA测序（RNA-seq）。