Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear.

Area of Science:

• Neuroscience
• Immunology
• Psychiatry

Background:

• Carbon dioxide (CO2) inhalation triggers fear and panic attacks in panic disorder.
• The specific molecular and anatomical pathways for CO2-induced fear are not fully understood.
• Microglial cells and their acid-sensing capabilities are implicated in these responses.

Purpose of the Study:

• To investigate the role of microglial acid sensor T cell death-associated gene-8 (TDAG8) in CO2-evoked fear.
• To explore the involvement of microglial proinflammatory responses in CO2-induced behavioral and physiological reactions.
• To elucidate the neural circuits translating CO2 sensing to fear.

Main Methods:

• Assessed CO2-evoked freezing, autonomic, and respiratory responses in TDAG8-deficient and wild-type mice.
• Utilized minocycline (microglial blocker) and IL-1RA (IL-1β antagonist) to investigate microglial and cytokine involvement.
• Measured CO2-chemosensitive neuronal firing using single-cell patch clamping in the subfornical organ.

Main Results:

• TDAG8 expression was found in microglia within sensory circumventricular organs.
• TDAG8-deficient mice showed reduced CO2-evoked freezing and sympathetic responses.
• Inhibition of microglial activation and IL-1β signaling attenuated CO2-evoked freezing.
• Neuronal firing in the subfornical organ in response to CO2 depended on TDAG8 and IL-1β.

Conclusions:

• Microglial acid sensing via TDAG8 acts as a unique chemosensor for hypercapnia.
• This pathway translates CO2 detection into fear-associated behavioral and physiological responses.
• Identified a novel mechanism for homeostatic threat detection relevant to panic disorder.