Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear
Carbon dioxide (CO2) inhalation, a biological challenge and pathologic marker in panic disorder, evokes intense fear and panic attacks in susceptible individuals. The molecular identity and anatomic location of CO2-sensing systems that translate CO2-evoked fear remain unclear. We investigated contributions of microglial acid sensor T cell death–associated gene-8 (TDAG8) and microglial proinflammatory responses in CO2-evoked behavioral and physiological responses.
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.
Vollmer, L. L.,
McGuire, J. L.,
Ahlbrand, R. L.,
Santin, J. M.,
Ratliff-Rang, C. A.,
Patrone, L. G.,
Lewkowich, I. P.,
Herman, J. P.,
Putnam, R. W.,
& Sah, R.
(2016). Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear. Biological Psychiatry, 80 (7), 541-551.