Extracellular pH regulates excitability of vomeronasal sensory neurons

The mouse vomeronasal organ (VNO) plays a critical role in semiochemical detection and social communication. Vomeronasal stimuli are typically secreted in various body fluids. Following direct contact with urine deposits or other secretions, a peristaltic vascular pump mediates fluid entry into the recipient’s VNO. Therefore, while vomeronasal sensory neurons (VSNs) sample various stimulatory semio-chemicals dissolved in the intraluminal mucus, they might also be affected by the general physicochemical properties of the “solvent.” Here, we report cycle stage-correlated variations in urinary pH among female mice. Estrus-specific pH decline is observed exclusively in urine samples from sexually experienced females. Moreover, patch-clamp recordings in acute VNO slices reveal that mouse VSNs reliably detect extracellular acidosis. Acid-evoked responses share the biophysical and pharmacological hallmarks of the hyperpolarization-activated current I_h. Mechanistically, VSN acid sensitivity depends on a pH-induced shift in the voltage-dependence of I_h activation that causes the opening of HCN channels at rest, thereby increasing VSN excitability. Together, our results identify extracellular acidification as apotent activator of vomeronasal I_h and suggest HCN channel-dependent vomeronasal gain control of social chemosignaling. Our data thus reveal a potential mechanistic basis for stimulus pH detection in rodent chemosensory communication.