Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear

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Data

2016-10-01

Autores

Vollmer, Lauren Larke
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.

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Editor

Elsevier B.V.

Resumo

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.

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Palavras-chave

Acid sensing, Carbon dioxide, Fear, Microglia, Panic, TDAG8

Como citar

Biological Psychiatry. New York: Elsevier Science Inc, v. 80, n. 7, p. 541-551, 2016.