German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany; Institut für Biochemie und Zellbiologie, Otto-von-Guericke-University, Medical Faculty, Magdeburg, Germany; ESF International Graduate School on Analysis, Imaging and Modelling of Neuronal and Inflammatory Processes, Magdeburg, Germany.
German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
Brain Behav Immun. 2023 May;110:245-259. doi: 10.1016/j.bbi.2023.02.023. Epub 2023 Mar 9.
Remodeling of synapses by microglia is essential for synaptic plasticity in the brain. However, during neuroinflammation and neurodegenerative diseases, microglia can induce excessive synaptic loss, although the precise underlying mechanisms are unknown. To directly observe microglia-synapse interactions under inflammatory conditions, we performed in vivo two-photon time-lapse imaging of microglia-synapse interactions after bacterial lipopolysaccharide administration to model systemic inflammation, or after inoculation of Alzheimer's disease (AD) brain extracts to model disease-associated neuroinflammatory microglial response. Both treatments prolonged microglia-neuron contacts, decreased basal surveillance of synapses and promoted synaptic remodeling in response to synaptic stress induced by focal single-synapse photodamage. Spine elimination correlated with the expression of microglial complement system/phagocytic proteins and the occurrence of synaptic filopodia. Microglia were observed contacting spines, then stretching and phagocytosing spine head filopodia. Thus, in response to inflammatory stimuli microglia exacerbated spine remodeling through prolonged microglial contact and elimination of spines 'tagged' by synaptic filopodia.
小胶质细胞对突触的重塑对于大脑中的突触可塑性至关重要。然而，在神经炎症和神经退行性疾病期间，小胶质细胞可引起过度的突触损失，尽管确切的潜在机制尚不清楚。为了在炎症条件下直接观察小胶质细胞-突触相互作用，我们在给予细菌脂多糖以模拟全身性炎症后，或在接种阿尔茨海默病 (AD) 脑提取物以模拟与疾病相关的神经炎症性小胶质细胞反应后，对活体小胶质细胞-突触相互作用进行了双光子时程成像。这两种处理都延长了小胶质细胞-神经元的接触，减少了突触的基础监测，并促进了对焦点单突触光损伤诱导的突触应激的突触重塑。棘突的消除与小胶质细胞补体系统/吞噬蛋白的表达和突触丝状伪足的发生相关。观察到小胶质细胞接触棘突，然后拉伸并吞噬棘突头部丝状伪足。因此，小胶质细胞通过延长与被突触丝状伪足“标记”的棘突的接触并消除这些棘突来加剧炎症刺激后的棘突重塑。
