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Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior
Yuki Yasumoto1, Milan Stoiljkovic1, Jung Dae Kim2
1Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
Abstract:
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.
Insights
Microglia regulate daily synapse elimination in the brain. Disrupting this process via uncoupling protein 2 (Ucp2) impairs neuronal circuits and behavior.
Area of Science:
- Neuroscience
- Cellular Biology
- Chronobiology
Background:
- Microglia, the brain's immune cells, are known to remodel synapses via phagocytosis.
- The precise regulatory mechanisms governing this microglial function in adult brains remain unclear.
Purpose of the Study:
- To investigate the mechanisms regulating microglia-mediated synapse remodeling in the adult hippocampus.
- To explore the role of reactive oxygen species (ROS) and uncoupling protein 2 (Ucp2) in this process.
Main Methods:
- Analysis of microglia-neuronal interactions in the ventral hippocampus across the light/dark cycle.
- Assessment of spine synapse numbers, microglia-synapse contacts, and microglial phagocytic inclusions.
- Conditional ablation of Ucp2 in microglia.
- Electrophysiological recordings and behavioral tests to assess neuronal circuit function and anxiety-like behavior.
Main Results:
- A daily reduction in spine synapse number was observed during the light phase, correlating with increased microglia-synapse contacts and phagocytic activity.
- Microglial reactive oxygen species (ROS) production and uncoupling protein 2 (Ucp2) expression increased concurrently with synapse elimination.
- Conditional ablation of Ucp2 in microglia disrupted daily synapse elimination, leading to ROS accumulation, lysosome-lipid droplet complex buildup, and subsequent hippocampal circuit dysfunction and altered anxiety-like behavior.
Conclusions:
- Microglia engage in a novel, chronotypical interaction with neurons to control synapse remodeling.
- Uncoupling protein 2 (Ucp2) in microglia is critical for regulating ROS levels and facilitating daily synapse elimination, thereby maintaining neuronal circuit function and normal behavior.
