Minocycline Alleviates Abnormal Phagocytosis of Synapses by Microglia in a Mouse Model of Depression

Background Depression is an affective disorder characterized by low mood and loss of interest. So far, the mechanism of antidepressants commonly used in clinical practice has proved problematic, thus it is urgent to gain an updated understanding of the pathogenesis of depression and find potential therapeutic targets. As both functional brain imaging studies and autopsy reports indicated that there is indeed a loss of synapses in depressed patients, it is necessary to explore the mechanism of this process. Methods We firstly investigated the effect of CSDS (a mouse model of depression) on behaviors, synapses, microglia, and phagocytosis of synapses by microglia in mice. Then, to confirm the role of microglia in depression, we used minocycline, a microglial activation inhibitor, to study its effect on behaviors and phagocytosis of synapses in stressed mice. Results Our results show that the expression levels of PSD-95 in the hippocampus of CSDS-induced depression mice are significantly reduced, while the microglia are significantly activated. We co-labeled the synaptic protein PSD-95 with the microglia marker Iba-1, and found that the microglia in the hippocampus of stressed mice contained significantly more PSD-95 engulfed puncta, which revealed that microglia in stressed mice abnormally phagocytized synapses. Moreover, our results indicated that minocycline treatment dampened microglial activation, reduced synaptic loss, alleviated behavioral impairment, and reduced abnormal phagocytosis of synapses by microglia in stressed mice. Conclusions Under depressive pathological conditions, the activated microglia may abnormally engulf neuronal synapses causing synaptic loss. Our findings are important for the discovery of novel drugs for the treatment of depression.