Yu Alfred, Fang Camille, Tan Li Xuan, Lakkaraju Aparna, Della Santina Luca, Ou Yvonne
Department of Ophthalmology, UCSF School of Medicine, San Francisco, CA, USA.
School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, China.
iScience. 2025 Mar 11;28(4):112201. doi: 10.1016/j.isci.2025.112201. eCollection 2025 Apr 18.
During development, microglia prune excess synapses to refine neuronal circuits. In neurodegeneration, understanding the role of microglia-mediated synaptic pruning in circuit remodeling and dysfunction is important for developing therapies aimed at modulating microglial function. Here, we analyzed microglia-mediated synapse disassembly of degenerating postsynaptic neurons in the inner retina. After inducing transient intraocular pressure elevation to injure retinal ganglion cells, microglia increase in number, shift to hyper-ramified morphology, and exhibit greater process movement. Furthermore, due to the greater number of microglia, there is increased colocalization of microglia with synaptic components throughout the inner plexiform layer and with excitatory synaptic sites along individual ganglion cell dendrites. Microglia depletion partially protects ganglion cell function, suggesting that microglia activation may be neurotoxic in early neurodegeneration. Our results demonstrate the important role of microglia in synapse disassembly in degenerating circuits, highlighting that microgliosis is the primary mechanism for increased synapse colocalization early after neuronal injury.
在发育过程中，小胶质细胞会修剪多余的突触以优化神经回路。在神经退行性变中，了解小胶质细胞介导的突触修剪在回路重塑和功能障碍中的作用，对于开发旨在调节小胶质细胞功能的治疗方法至关重要。在此，我们分析了内视网膜中退化的突触后神经元的小胶质细胞介导的突触解体。在诱导短暂的眼内压升高以损伤视网膜神经节细胞后，小胶质细胞数量增加，转变为高度分支的形态，并表现出更大的突起运动。此外，由于小胶质细胞数量的增加，在内网状层中，小胶质细胞与突触成分的共定位增加，并且在单个神经节细胞树突上与兴奋性突触位点的共定位也增加。小胶质细胞的清除部分保护了神经节细胞的功能，这表明小胶质细胞的激活在早期神经退行性变中可能具有神经毒性。我们的结果证明了小胶质细胞在退化回路中的突触解体中的重要作用，突出了小胶质细胞增生是神经元损伤后早期突触共定位增加的主要机制。
