Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus.

Summary

In brain slices containing the dorsal cochlear nucleus, principal neurons showed a tinnitus-specific increase in spontaneous firing (hyperactivity), seen only in noise-exposed mice that go on to develop tinnitus, and only in DCN regions tuned to high frequencies. This hyperactivity depended on reduced Kv7.2/3 channel activity, caused by a shift in the channels' voltage-dependence to more positive voltages. A pharmacological manipulation that shifted Kv7 voltage-dependence back to more negative voltages prevented tinnitus from developing in vivo, pointing to a specific, previously unknown drug target.

Key findings

• Tinnitus-specific DCN hyperactivity occurs only in noise-exposed mice that develop tinnitus, only in high-frequency-tuned regions.
• Reduced Kv7.2/3 (KCNQ2/3) channel activity, via a voltage-dependence shift, is essential for this hyperactivity and for tinnitus induction.
• Pharmacologically shifting Kv7 voltage-dependence back to normal prevented tinnitus development in vivo.
• Identifies Kv7.2/3 as a novel biological target for tinnitus-preventing drugs.