CO2-evoked freezing, autonomic, and respiratory responses were assessed in TDAG8-deficient (–/–) and wild-type (+/+) mice. Involvement of TDAG8-dependent microglial activation and proinflammatory cytokine interleukin (IL)-1β with CO2-evoked responses was investigated using microglial blocker, minocycline, and IL-1β antagonist IL-1RA. CO2-chemosensitive firing responses using single-cell patch clamping were measured in TDAG8–/– and TDAG8+/+ mice to gain functional insights.
TDAG8 expression was localized in microglia enriched within the sensory circumventricular organs. TDAG8–/– mice displayed attenuated CO2-evoked freezing and sympathetic responses. TDAG8 deficiency was associated with reduced microglial activation and proinflammatory cytokine IL-1β within the subfornical organ. Central infusion of microglial activation blocker minocycline and IL-1β antagonist IL-1RA attenuated CO2-evoked freezing. Finally, CO2-evoked neuronal firing in patch-clamped subfornical organ neurons was dependent on acid sensor TDAG8 and IL-1β.
Our data identify TDAG8-dependent microglial acid sensing as a unique chemosensor for detecting and translating hypercapnia to fear-associated behavioral and physiological responses, providing a novel mechanism for homeostatic threat detection of relevance to psychiatric conditions such as panic disorder.