Biological psychiatry (1969), 2016-10, Vol.80 (7), p.541-551
2016
Details
- Autor(en) / Beteiligte
- Titel
- Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear
- Ist Teil von
- Biological psychiatry (1969), 2016-10, Vol.80 (7), p.541-551
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0006-3223eISSN: 1873-2402DOI: 10.1016/j.biopsych.2016.04.022Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5014599
- Format
- –
- Schlagworte
- Acid sensing, Action Potentials - physiology, Animals, Carbon dioxide, Carbon Dioxide - pharmacology, Chemoreceptor Cells - physiology, Fear, Fear - drug effects, Hydrogen-Ion Concentration, Immobility Response, Tonic - drug effects, Immobility Response, Tonic - physiology, Interleukin 1 Receptor Antagonist Protein, Interleukin-1beta - antagonists & inhibitors, Interleukin-1beta - metabolism, Male, Mice, Mice, Knockout, Microglia, Microglia - drug effects, Microglia - metabolism, Microglia - physiology, Microinjections, Minocycline - administration & dosage, Minocycline - pharmacology, Neurons - physiology, Panic, Psychiatry, Receptors, G-Protein-Coupled - biosynthesis, Receptors, G-Protein-Coupled - genetics, Receptors, G-Protein-Coupled - physiology, Subfornical Organ - metabolism, TDAG8