Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear
Document Type
Article
Publication Date
10-1-2016
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Repository Citation
Vollmer, L. L.,
Ghosal, S.,
McGuire, J. L.,
Ahlbrand, R. L.,
Li, K.,
Santin, J. M.,
Ratliff-Rang, C. A.,
Patrone, L. G.,
Rush, J.,
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.
https://corescholar.libraries.wright.edu/ncbp/1109
DOI
10.1016/j.biopsych.2016.04.022
