PKD2L1 CHANNELS SEGREGATED TO THE APICAL COMPARTMENT ARE THE EXCLUSIVE DUAL-MODE PH SENSOR IN CEREBROSPINAL FLUID-CONTACTING NEURONS

Cerebrospinal fluid-contacting neurons (CSFcNs) are GABAergic neurons of the spinal cord. They are characterized by a soma that is located sub-ependymally, around the central canal (CC) and a specialized dendrite that ends as a bulbous structure, the apical process (ApPr), located within the canal lumen and therefore in contact with the cerebrospinal fluid (CSF). Although the ApPr is known to sense CSF composition, the pH sensitivity of the ApPr -a subcellular domain exposed to an extracellular milieu distinct from the soma-, and how this relates to the role of CSFcNs as multimodal sensors remain unexplored.
CSFcNs display prominent spontaneous electrical activity mediated by PKD2L1 channels, non-selective cation channels modulated by protons and mechanical forces. In this study we investigate PKD2L1 subcellular distribution, its pH sensitivity and its effects on CSFcNs excitability. We show that spontaneous activation of PKD2L1 channels mediates not only phasic inward currents, but also a tonic inward current. Both components are bidirectionally modulated by pH, with high sensitivity around physiological values. We further assess the distribution of PKD2L1 channels using electrophysiological approaches (direct recordings from intact and isolated ApPrs) and optical methods (laser photolysis of protons), and demonstrate that they are functionally restricted to the ApPr. The spatial segregation, high single-channel conductance (» 200 pS) and pH sensitivity of the channels, together with the ApPr’s high input resistance, render CSFcNs extremely sensitive to PKD2L1 modulation. Altogether, our findings illustrate how the properties of ApPrs are finely tuned to support its sensory role.