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., Ca²⁺, CO₂, 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 CO² and strongly supports the multiple factors model of chemosensitive signaling.