A mathematical model of the regulation of OHC basolateral permeability and transducer operating point

Abstract

The cochlea presumably possesses a number of regulatory mechanisms to maintain cochlear sensitivity in the face of disturbances to its function. Evidence for such mechanisms can be found in the time-course of the recovery of CAP thresholds during experimental manipulations, and in observations of slow oscillations in cochlear micromechanics following exposure to LF tones (the 'bounce phenomenon') and other perturbations. To increase our understanding of the regulatory processes within the cochlea, and OHCs in particular, we have developed a mathematical model of the OHC that takes into account its known electrical properties, and includes the effect of fast and slow-motility of the cell body on transducer operating point and apical conductance. Central to the operation of the model is a putative intracellular 2nd-messenger system based on cytosolic Ca2+ concentration. Cytosolic Ca2+ is involved in regulation of i) the operating point of OHC MET channels via slow motility and axial stiffness; ii) the permeability of the basolateral wall to potassium via Ca2+-sensitive potassium channels; and iii) the cytosolic concentration of Ca2+ itself, via extrusion from the OHC (via the Ca2+-ATPases in the plasma membrane) and Ca2+-induced Ca2+-release (CICR) from intracellular Ca2+ storage organelles. The permeability of the OHC basolateral wall determines the standing current through the OHCs (and therefore a component of EP regulation), and in the presence of sound, affects the magnitude of the AC receptor potential that drives the prestin-mediated somatic electromotility and active gain. The mathematical model we have developed provides a physiologically-plausible and internally-consistent explanation for the time-courses of the cochlear changes observed during a number of different perturbations. We show how much of the oscillatory behaviour can be attributed to oscillations in cytosolic calcium concentration, and present results from the model for a number of simulations, including DC current injection into scala media, perilymphatic perfusions, and exposure to LF tones, and compare the results of these simulations to experimental data recorded from the guinea pig.