AbstractAcids can disturb the ecosystem of wild animals through altering their olfaction and olfaction-related survival behaviors. It is known that the main olfactory epithelia (MOE) of mammals rely on odorant receptors and type III adenylyl cyclase (AC3) to detect general odorants. However, it is unknown how the olfactory system sense protons or acidic odorants. Here we show that the mouse MOE responded to acidic volatile stimuli in the presence and the absence of AC3. Acetic acid-induced electro-olfactogram (EOG) responses in wild type (WT) MOE can be dissected into two components: one dependent on the AC3-mediated cAMP pathway and the other not. MOE of AC3 knockout (KO) mice retained an acid-evoked EOG response but failed to respond to an odor mix. The acid-evoked responses of the AC3 KO could be blocked by diminazene, an inhibitor of acid-sensing ion channels (ASICs), but not by forskolin/IBMX, which desensitize the cAMP pathway. AC3 KO mice lost their sensitivity to detect pungent odorants but maintained sniffing behavior to acetic acid. Immunofluorescence staining demonstrated that ASIC1 proteins were highly expressed in olfactory sensory neurons (OSNs), mostly enriched in the knobs, dendrites, and somata, but not in olfactory cilia. Moreover, mice exhibited reduced preference to attractive objects when placed in an environment with acidic volatiles. Together, we conclude that the mouse olfactory system has a non-conventional, ASICs-mediated mechanism for acid-sensing. Acid stimulation of ASICs may unselectively depolarize different OSNs and interfere with the anatomical logic for odor perception.
