Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear

• Autor(a) principal: Vollmer, Lauren Larke
• Data de Publicação: 2016
• Outros Autores: Ghosal, Sriparna, McGuire, Jennifer L., Ahlbrand, Rebecca L., Li, Ke-Yong, Santin, Joseph M., Ratliff-Rang, Christine A., Patrone, Luis G. A. [UNESP], Rush, Jennifer, Lewkowich, Ian P., Herman, James P., Putnam, Robert W., Sah, Renu
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNESP
• Texto Completo: http://dx.doi.org/10.1016/j.biopsych.2016.04.022; http://hdl.handle.net/11449/161997
• topic: Acid sensing; Carbon dioxide; Fear; Microglia; Panic; TDAG8

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 (1/1) mice. Involvement of TDAG8-dependent microglial activation and proinflammatory cytokine interleukin (IL)-1 beta with CO2-evoked responses was investigated using microglial blocker, minocycline, and IL-1 beta 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-1 beta within the subfornical organ. Central infusion of microglial activation blocker minocycline and IL-1 beta 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-1 beta. 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.