Effects of gap junction uncoupling in the gerbil cochlea.
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.


METHODS
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.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005071:Evoked Potentials / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects*; D005849:Gerbillinae; D008854:Microscopy, Electron; D017084:Otoacoustic Emissions, Spontaneous / Q000187:drug effects; D010498:Perilymph; D011335:Proadifen / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D011335:Proadifen