Effects of gap junction uncoupling in the gerbil cochlea.

ABSTRACT

OBJECTIVE: To gain insight into molecular and cellular mechanisms regulating cochlear potassium (K+) recycling, including the possible effects of mutations in the gene, which encodes the gap junction protein connexin 26. Intercellular K+ flux was manipulated in vivo by infusion of the gap junction uncoupler proadifen (SKF-525A) into perilymph. Functional and structural alterations induced by gap junction blockade were assessed by electrophysiological and morphologic analysis. STUDY DESIGN: Laboratory study using an animal model. METHODS: Physiological effects of acute and chronic uncoupling of gap junctions in the Mongolian gerbil inner ear were evaluated by measurement of compound action potential (CAP) thresholds and input-output (I/O) functions, distortion product otoacoustic emissions (DPOAE), and the endocochlear potential (EP). Morphologic changes were assessed by electron microscopy. RESULTS: Acute exposures to proadifen resulted in large decreases in EP values, DPOAE magnitudes, and CAP I/O maximum amplitudes and an increase in high-frequency CAP thresholds. These physiological changes were accompanied by vacuolization of type II and type V fibrocytes in the lateral wall of the cochlea. Chronic treatments revealed some recovery in EP values and CAP thresholds, which showed a relatively flat 15- to 20-dB elevation across frequencies. CONCLUSIONS: Gap junctions play a significant role in normal cochlear function. In particular they appear to be essential for maintaining the EP, an activity that could be related to their participation in K+ recycling. Thus, hearing losses associated with mutations in the gene that alter the expression or function of connexin 26 may result from a diminished capacity to recycle K+ from perilymph back to the stria vascularis and a consequent decline in the EP.