Acid-sensing ion channels contribute to chemosensitivity of breathing-related neurons of the nucleus of the solitary tract

Key point A subset of neurons of the nucleus of the solitary tract (nucleus tractus solitarius, NTS) show a response to changes in pH within the physiological range (7.4 to 7.0) that is mediated by acid sensing ion channels (ASICs). These responder neurons appear to cluster dorsally in the NTS. ASIC1 and ASIC2 transcripts are expressed in the NTS. NTS neurons projecting to the ventral respiratory column show ASIC-mediated responses to mild pH challenges and may modulate the respiratory response to . Injection of the ASIC inhibitor amiloride into the NTS transiently depresses breathing frequency in hypercapnic anaesthetized rats. Abstract Cellular mechanisms of central pH chemosensitivity remain largely unknown. The nucleus of the solitary tract (NTS) integrates peripheral afferents with central pathways controlling breathing; NTS neurons function as central chemosensors, but only limited information exists concerning the ionic mechanisms involved. Acid-sensing ion channels (ASICs) mediate chemosensitivity in nociceptive terminals, where pH values similar to 6.5 are not uncommon in inflammation, but are also abundantly expressed throughout the brain where pH is tightly regulated and their role is less clear. Here we test the hypothesis that ASICs are expressed in NTS neurons and contribute to intrinsic chemosensitivity and control of breathing. In electrophysiological recordings from acute rat NTS slices, similar to 40% of NTS neurons responded to physiological acidification (pH 7.0) with a transient depolarization. This response was also present in dissociated neurons suggesting an intrinsic mechanism. In voltage clamp recordings in slices, a pH drop from 7.4 to 7.0 induced ASIC-like inward currents (blocked by 100 similar to mu m amiloride) in similar to 40% of NTS neurons, while at pH similar to=similar to 6.5 these currents were detected in all neurons tested; RT-PCR revealed expression of ASIC1 and, less abundantly, ASIC2 in the NTS. Anatomical analysis of dye-filled neurons showed that ASIC-dependent chemosensitive cells (cells responding to pH 7.0) cluster dorsally in the NTS. Using in vivo retrograde labelling from the ventral respiratory column, 90% (9/10) of the labelled neurons showed an ASIC-like response to pH 7.0, suggesting that ASIC currents contribute to control of breathing. Accordingly, amiloride injection into the NTS reduced phrenic nerve activity of anaesthetized rats with an elevated arterial .