The Chemosensitive Response of Neurons from the Locus Coeruleus (LC) to Hypercapnic Acidosis with Clamped Intracellular pH

Currently, a change in pH _i is believed to be the major signal in the chemosensitive (CS) response of brainstem neurons to hypercapnia; however, multiple factors ( e.g ., Ca ²⁺ , CO ₂ , pH _i , and pHo) have been suggested to contribute to this increase in firing rate. While there is evidence for a significant role of pH _i in the CS response, we hypothesize that hypercapnic acidosis (HA) can increase firing rate even with no change in pH _i . We tested several methods to clamp pH _i , including high intracellular buffer and the use of rapid diffusion of weak bases or weak acids through the cell membrane. We were able to clamp pH _i during hypercapnic exposure using weak acids. We observed a CS response to HA, with pH _i clamped, indicating that intracellular acidification, while sufficient to increase firing rate, is not required for the response of CS neurons. The CS response to HA without a change in pH _i is most likely due to extracellular acidification and/or increased CO ² and strongly supports the multiple factors model of chemosensitive signaling.