A Prediction for the Role of Gap Junction Mutations from a 3D Model of Ionic Circulation in the Cochlea

February 14-19, 2009 Baltimore, Maryland, USA We have recently developed a computational model of the 3D electrical current flow within the cochlea (Mistrik & Ashmore, J. R Soc Interface, 2008). The model splits the cochlea longitudinally into 300 cross-sections and divides each section into 6 compartments: scala media, inner and outer hair cells (IHC, OHC), extracellular space near the IHCs, and extracellular space near the OHCs and stria vascularis. The electrical properties of these compartments are represented in the model by standard elements (resistors, capacitors and batteries). The transducer conductances are driven by a basilar membrane displacement generated by a physiologically realistic model of cochlear mechanics. This approach allows us to analyse how the resistance of K+ reabsorbing radial pathways within and longitudinal electrical coupling between the cross-sections would affect the frequency selectivity and sensitivity of the OHC transmembrane potentials and therefore cochlear amplification. The electrical resistances are dictated predominantly by gap junction networks in the organ of Corti and would be altered by mutations in the connexion genes. We have also investigated the role of extracellular space and intercellular capacitative coupling. The simulations suggest that reduced conductivity of gap junctions would result in decreased OHC receptor potentials with a roll-off of 6dB/octave. The effect is therefore most significant at high frequencies. The result argues for a compromised ionic recirculation within the cochlea, rather than decreased metabolic signalling between cells, as a possible mechanism for the high frequency hearing loss observed in patients carrying pathogenic mutations in GJB2. Supported by EuroHear LSHG-CT-20054-512063.