Hidden hearing loss—which can make conversations hard to follow in noisy settings—resists study. It doesn’t register in standard hearing tests. Also, it has been associated with factors that tend to accompany each other, muddying causation. These factors include acoustic overexposure, ototoxic drugs, and aging. Another factor is synaptopathy, or the loss of synapses between spiral ganglion neurons and inner hair cells (IHCs). It may be the trickiest factor to evaluate, since it cannot be assessed directly in human subjects.

To clarify the role of synaptopathy in hidden hearing loss, scientists at Michigan Medicine’s Kresge Hearing Research Institute studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC-supporting cells. The researchers had previously used similar methods—increasing the amount of the neurotrophic factor neurotrophin-3 in the inner ear—to promote the recovery of auditory responses in mice that had experienced acoustic trauma, and to improve hearing in middle-aged mice. But in their new study, the scientists used the same approach with otherwise healthy young mice.

The scientists, who were led by Gabriel Corfas, PhD, director of the Kresge Institute, reported their findings in PLOS Biology, in an article titled, “From hidden hearing loss to supranormal auditory processing by neurotrophin 3-mediated modulation of inner hair cell synapse density.”

“As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds,” the article’s authors wrote. “We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels.”

As in previous studies, the researchers altered the expression of the Ntf3 to increase the number of synapses between inner hair cells and neurons. “We knew that providing Ntf3 to the inner ear in young mice increased the number of synapses between inner hair cells and auditory neurons, but we did not know what having more synapses would do to hearing,” Corfas said. “We now show that animals with extra inner ear synapses have normal thresholds—what an audiologist would define as normal hearing—but they can process the auditory information in supranormal ways.”

Two groups of young mice were created and studied: one in which synapses were reduced, and a second—the supranormal hearing mice—in which synapses were increased.

“Previously, we have used that same molecule to regenerate synapses lost due to noise exposure in young mice, and to improve hearing in middle-aged mice, when they already start showing signs of age-related hearing loss,” said Corfas. “This suggests that this molecule has the potential to improve hearing in humans in similar situations. The new results indicate the regenerating synapses or increasing their numbers will improve their auditory processing.”

Both groups of mice underwent a Gap-Prepulse Inhibition test, which measures their ability to detect very brief auditory stimuli. For this test, the subject is placed in a chamber with a background noise, then a loud tone that startles the mouse is presented alone or preceded by a very brief silent gap. That gap, when detected by the mouse, reduces the startle response. Researchers then determine how long the silent gap needs to be for the mice to detect it.

Mice with fewer synapses required a much longer silent gap. That result supports a hypothesis about the relationship between synapse density and hidden hearing loss in humans. People with hidden hearing loss may struggle to understand speech—or discern sounds in the presence of background noise. Results of the Gap-Prepulse Inhibition test had been previously shown to be correlated with auditory processing in humans.

Less expected, however, were the results of the subjects with increased synapses. Not only did they show enhanced peaks in measured Acoustic Brain Stem response, but the mice also performed better on the Gap-Prepulse Inhibition test, suggesting an ability to process an increased amount of auditory information.

“[Our] results indicate that IHC synaptopathy causes temporal processing deficits predicted in hidden hearing loss,” the authors of the PLOS Biology article noted. “Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies.”

IHC loss had once been believed to be the primary cause of hearing loss in humans as we age. Now, however, it’s understood that the loss of IHC synapses can be the first event in the hearing loss process, making therapies that preserve, regenerate, and/or increase synapses exciting possible approaches for treating some hearing disorders.

“We were surprised to find that when we increased the number of synapses, the brain was able to process the extra auditory information,” Corfas remarked. “And those subjects performed better than the control mice in the behavioral test.

“Some neurodegenerative disorders also start with loss of synapses in the brain. Therefore, the lessons from the studies in the inner ear could help in finding new therapies for some of these devastating diseases.”

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