Insights Into Inner Ear Repair

Sound-sensitive structures in the inner ear are repaired in a 2-step process. The new findings explain a key step in the maintenance of hearing.

Scanning electron microscopy shows tip links between stereocilia of an inner ear hair cell. The yellow dots in the inset are the immunogold particles that label the proteins that make up the tip link. Credit: G. Frolenkov.

The inner ear contains thousands of sensory cells called hair cells, which help transform sound into electrical signals that the brain can understand. Sitting atop the hair cells are tiny bristly structures called stereocilia. Stereocilia bundles are arranged in 3 V-shaped rows of different heights, with the inner row shortest and outer row tallest.
Thread-like strands called tip links connect the tips of shorter stereocilia to the sides of adjacent taller ones. When sound vibrations enter the inner ear, the stereocilia move, causing the tip links to open ion channels—tiny pores in the cell membrane that let electrically charged molecules (ions) pass through. Potassium and calcium ions enter the hair cell and kick off an electrical signal that eventually travels to the brain, where it’s interpreted as sound.
Tip links break easily with exposure to noise. But they can repair themselves, often within a matter of hours. The breaking of tip links is seen as one of the causes of the temporary hearing loss you might experience after a loud blast of sound (or a loud concert). Once the tip links regenerate, hair cell function usually returns to normal. However, scientists weren’t sure how tip links reassembled.
Tip links are made up of 2 proteins: cadherin-23 (CDH23) at the upper end of the link and protocadherin-15 (PCDH15) at the bottom. Previous research has shown that both CDH23 and PCDH15 are required for normal hearing and vision. Mutations in either of these can cause the hearing loss or deaf-blindness found in Usher syndrome.
A team led by Dr. Gregory I. Frolenkov at the University of Kentucky set out to examine the growth and regeneration of inner ear tip links. Their work was supported by NIH’s National Institute on Deafness and Other Communication Disorders (NIDCD). Results appeared online on June 11, 2013, in PLoS Biology.
The researchers first treated mouse sensory hair cells with a substance that disrupts tip links. Using immunogold labeling—antibodies bound to gold particles—and a scanning electron microscopy technique they developed, the scientists were able to image CDH23 and PCDH15 before, during and after treatment.
The team found that after a tip link is chemically disrupted, a new tip link forms with PCDH15 proteins at both ends instead of the normal combination of CDH23 and PCDH15. Over the next 24 hours, the PCDH15 protein at the upper end is replaced by CDH23. The researchers also found that the temporary PCDH15/PCDH15 tip links cause slightly different electrical responses than the permanent PDCH15/CDH23 links. Additional experiments revealed that when hair cells develop, tip links form using the same 2-step process.
“In the case of deaf individuals who are unable to make functional CDH23, knowledge of this new temporary alliance of PCDH15 proteins to form a weaker, but still functional, tip link could inform treatments that would encourage the double PCDH15 bond to become permanent and maintain at least limited hearing,” says Dr. Tom Friedman, chief of the Laboratory of Molecular Genetics at NIDCD.