The adenosine generating enzymes CD39/CD73 control microglial processes ramification in the mouse brain.

Area of Science:

• Neuroscience
• Cell Biology
• Immunology

Background:

• Microglia, the brain's immune cells, develop a complex, branched structure postnatally.
• These cells utilize purinergic signaling, involving enzymes like CD39 and CD73 that break down ATP into adenosine.
• The role of these enzymes in microglial morphology and function remains incompletely understood.

Purpose of the Study:

• To investigate the impact of CD39 and CD73 deletion on microglial morphology and behavior.
• To elucidate the role of extracellular adenosine in regulating microglial ramification.

Main Methods:

• Utilized knockout mouse models lacking CD39, CD73, or both.
• Performed in vitro studies on isolated microglial cells.
• Analyzed microglial morphology and process extension in acute brain slices and cell cultures.
• Manipulated extracellular adenosine levels using pharmacological inhibitors and enzymatic degradation.

Main Results:

• Mice lacking CD39 and/or CD73 exhibited impaired microglial ramification, with reduced process length and complexity.
• In vitro, CD39/CD73-deficient microglia failed to ramify in response to ATP.
• CD39 deficiency exacerbated microglial process retraction in brain slices and impaired directed process extension.
• Elevating extracellular adenosine levels rescued the ramification defects in CD39/CD73-deficient microglia.

Conclusions:

• CD39 and CD73 nucleotidases are essential regulators of microglial process ramification.
• Extracellular adenosine, controlled by CD39/CD73 and ENT1, dictates microglial morphology.
• These findings highlight a novel mechanism controlling microglial structure and potentially function in the brain.