Researchers have identified in an animal model the molecular mechanisms behind resilience to noise-induced tinnitus and a possible drug therapy that could reduce susceptibility to this chronic and sometimes debilitating condition. The findings by a team from the University of Pittsburgh School of Medicine were published online in the journal eLife.
Tinnitus is typically induced by exposure to loud noise and causes whistling, clicking, roaring and other phantom sounds. It is estimated that 5 to 15 percent of Americans suffer from tinnitus, said Thanos Tzounopoulos, Ph.D., associate professor and member of the auditory research group in the Department of Otolaryngology, Pitt School of Medicine, where he also holds the auditory physiology endowed chair.
The study results build on previous research in mouse models demonstrating that tinnitus is associated with hyperactivity of dorsal cochlear nucleus (DCN) cells, which fire impulses even when there is no actual sound to perceive. The team’s work has shown that this hyperactivity is caused by a reduction in tiny channels, called KCNQ channels, through which potassium ions travel in and out of the cell. Based on this finding, KCNQ channel activators have emerged as clinical candidates for preventing the development of tinnitus.
“However, a significant percentage of people are exposed to loud sounds and never develop tinnitus, and there was little known about why that is. That’s what we set out to examine in this study,” Dr. Tzounopoulos said.
This newest study found that mice that are exposed to loud noise but do not develop tinnitus show a transient reduction in KCNQ2/3 channel activity, which is followed by a recovery of KCNQ2/3 activity and a reduction in hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity, another channel through which positively charged ions travel in and out of the cell.
The investigators believe a combination of drugs that enhance KCNQ2/3 channel activity and reduce HCN channel activity could promote resilience and reduce susceptibility to tinnitus.
“We have already developed novel activators of KCNQ2/3 channels. The next step, in collaboration with Dr. Peter Wipf, a medicinal chemist from the University of Pittsburgh, is to develop specific blockers of HCN channels,” Dr. Tzounopoulos said.
About this neurology research
Co-authors of the paper are Shuang Li, Ph.D., and Bopanna I. Kalappa, Ph.D., of Pitt’s Department of Otolaryngology.
Funding: The project was funded by the Department of Defense Peer Reviewed Medical Research Program grant PR093405, Joint Warfighter Medical Research Program grant W81XWH-14-1-0117 and by the National Institutes of Health grant R01-DC007905.
Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus
Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells. This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise-exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in DCN fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days. Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity. Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus.
“Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus” by Shuang Li, Bopanna I Kalappa, and Thanos Tzounopoulos in eLife. Published online August 27 2015 doi:10.7554/eLife.07242