Microglia coordinate activity-dependent protein synthesis in neurons through metabolic coupling

Area of Science:

• Neuroscience
• Immunology
• Metabolism

Background:

• Long-lasting synaptic plasticity and memory formation require new protein synthesis, which is metabolically demanding.
• The specific cell types and mechanisms sensing and responding to this increased metabolic demand in the mammalian brain are not fully understood.

Purpose of the Study:

• To investigate the role of microglia in coordinating metabolic responses to fuel neuronal protein synthesis in the active brain.
• To identify the molecular mechanisms underlying this neuroimmune metabolic coupling.

Main Methods:

• Utilized a motor task in mice to induce increased metabolic demand in the motor cortex.
• Investigated the effects of microglia depletion and CYR61 signaling blockade on neuronal protein synthesis and metabolic fluxes.
• Analyzed changes in glucose transporter expression in brain vasculature.

Main Results:

• Microglia were found to coordinate metabolic coupling between endothelial cells, astrocytes, and neurons.
• Increased motor task demand stimulated microglia to secrete the hypoxia-responsive protein CYR61.
• CYR61 increased glucose transporter expression in brain vasculature, fueling protein synthesis in active neurons.
• Microglia depletion or CYR61 signaling blockade reduced training-induced metabolic fluxes and neuronal protein synthesis.

Conclusions:

• Microglia play a critical role in sensing and responding to metabolic demands associated with learning and memory.
• A neuroimmune metabolic circuit involving microglia and CYR61 is essential for on-demand protein synthesis in active neurons.
• This circuit is crucial for supporting synaptic plasticity and memory formation.