Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior

• Published in: Molecular psychiatry Vol. 26; no. 7; pp. 2740 - 2752
• Main Authors: Yasumoto, Yuki, Stoiljkovic, Milan, Kim, Jung Dae, Sestan-Pesa, Matija, Gao, Xiao-Bing, Diano, Sabrina, Horvath, Tamas L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2021; Nature Publishing Group
• Subjects: 14/28; 631/378; 631/80; 64/60; 9/74; Animal cognition; Animals; Antibodies; Anxiety; Behavior; Behavioral Sciences; Biological Psychology; Brain; Care and treatment; Diagnosis; Electrophysiology; Female; Gene expression; Health aspects; Hippocampus; Immediate Communication; Laboratory animals; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Microglia; Microscopy; Mitochondria; Mitochondrial uncoupling protein 2; Neural Pathways; Neurons; Neurosciences; Parahippocampal region; Phagocytes; Phagocytosis; Pharmacotherapy; Physiological aspects; Psychiatry; Reactive oxygen species; Synapses; Uncoupling Protein 2 - genetics; United States
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-021-01105-1

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.