Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
Institute of Human Nutrition and Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
Mol Psychiatry. 2021 Jul;26(7):2740-2752. doi: 10.1038/s41380-021-01105-1. Epub 2021 Apr 20.
Microglia have been implicated in synapse remodeling by phagocytosis of synaptic elements in the adult brain, but the mechanisms involved in the regulation of this process are ill-defined. By examining microglia-neuronal interaction in the ventral hippocampus, we found a significant reduction in spine synapse number during the light phase of the light/dark cycle accompanied by increased microglia-synapse contacts and an elevated amount of microglial phagocytic inclusions. This was followed by a transient rise in microglial production of reactive oxygen species (ROS) and a concurrent increase in expression of uncoupling protein 2 (Ucp2), a regulator of mitochondrial ROS generation. Conditional ablation of Ucp2 from microglia hindered phasic elimination of spine synapses with consequent accumulations of ROS and lysosome-lipid droplet complexes, which resulted in hippocampal neuronal circuit dysfunctions assessed by electrophysiology, and altered anxiety-like behavior. These observations unmasked a novel and chronotypical interaction between microglia and neurons involved in the control of brain functions.
小胶质细胞通过吞噬成年大脑中的突触成分参与突触重塑，但调节这一过程的机制尚不清楚。通过研究腹侧海马体中的小胶质细胞-神经元相互作用，我们发现在光/暗循环的光相期间，突触棘的数量显著减少，伴随着小胶质细胞-突触接触的增加和小胶质细胞吞噬内含物的增加。随后，小胶质细胞产生的活性氧 (ROS) 短暂上升，同时解偶联蛋白 2 (Ucp2) 的表达增加，Ucp2 是线粒体 ROS 产生的调节剂。从小胶质细胞中条件性敲除 Ucp2 会阻碍棘突触的阶段性消除，从而导致 ROS 和溶酶体-脂滴复合物的积累，这会导致通过电生理学评估的海马神经元回路功能障碍，并改变焦虑样行为。这些观察结果揭示了小胶质细胞和神经元之间一种新型的、具有时间特征的相互作用，参与了大脑功能的控制。
