Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Center for Brain and Spinal Cord Repair, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Glia. 2022 Jul;70(7):1359-1379. doi: 10.1002/glia.24179. Epub 2022 Apr 8.
Microglial control of activity-dependent plasticity and synaptic remodeling in neuronal networks has been the subject of intense research in the past several years. Although microglia-neuron interactions have been extensively studied, less is known about how microglia influence astrocyte-dependent control over neuronal structure and function. Here, we explored a role for microglia in regulating the structure and function of the astrocyte syncytium in mouse hippocampus. After depleting microglia using a CSF1R antagonist (PLX5622, Plexxikon), we observed severe disruption of astrocyte syncytial isopotentiality and dye coupling. A decrease in astrocyte-specific gap junction connexin (Cx) 30 and 43 expression, at least partially accounts for these microglia-dependent changes in astrocytes. Because neuronal function requires intact astrocyte coupling, we also evaluated the effects of microglia depletion on synaptic transmission in the hippocampus. Without microglia, the strength of synaptic transmission was reduced at baseline and after long-term potentiation (LTP). Conversely, priming microglia with systemic injections of lipopolysaccharide enhanced CA3-CA1 synaptic transmission. This microglia-induced scaling of synaptic transmission was associated with increased expression of post-synaptic scaffold proteins (Homer1) in CA1. However, astrocyte network function was not affected by microglia priming, indicating that microglia-dependent effects on astrocytes and neurons vary across functional states. Through manipulation of microglia in the brain, our results reveal the importance of microglia in homeostatic regulation of the astrocyte syncytium and scaling of synaptic transmission. These novel mechanisms uncover a new direction for future studies interrogating microglia function in various physiological and pathological contexts.
过去几年，人们对小胶质细胞控制神经元网络中活性依赖型可塑性和突触重构的机制进行了深入研究。虽然小胶质细胞-神经元相互作用已经得到了广泛的研究，但人们对小胶质细胞如何影响星形胶质细胞依赖性控制神经元结构和功能知之甚少。在这里，我们探索了小胶质细胞在调节小鼠海马体星形胶质细胞合胞体的结构和功能中的作用。使用 CSF1R 拮抗剂（PLX5622，Plexxikon）耗尽小胶质细胞后，我们观察到星形胶质细胞合胞体等电和染料偶联的严重破坏。星形胶质细胞特异性缝隙连接连接蛋白（Cx）30 和 43 的表达减少至少部分解释了这些小胶质细胞依赖性星形胶质细胞变化。由于神经元功能需要完整的星形胶质细胞偶联，我们还评估了小胶质细胞耗竭对海马体突触传递的影响。没有小胶质细胞，基线和长时程增强（LTP）后突触传递的强度降低。相反，用脂多糖全身注射预先刺激小胶质细胞增强 CA3-CA1 突触传递。这种小胶质细胞诱导的突触传递缩放与 CA1 中突触后支架蛋白（Homer1）的表达增加有关。然而，小胶质细胞预刺激对星形胶质细胞网络功能没有影响，表明小胶质细胞对星形胶质细胞和神经元的影响因功能状态而异。通过在大脑中操纵小胶质细胞，我们的结果揭示了小胶质细胞在星形胶质细胞合胞体的稳态调节和突触传递缩放中的重要性。这些新的机制为未来在各种生理和病理背景下研究小胶质细胞功能的研究提供了一个新的方向。
