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