ERBB2 is a Key Mediator in Hearing Restoration in Noise-Deafened Young Adult Mice

Abstract

AbstractNoise-induced hearing loss (NIHL) affects over ten million adults in the United States, and has no biological treatment. We hypothesized that activation of signaling from ERBB2 receptors in cochlear supporting cells could mitigate cochlear damage. We adopted a new timeline for assessing mitigation that parallels hearing recovery from damage in avians. We drove expression of a constitutively active variant of ERBB2 (CA-ERBB2) in cochlear supporting cells three days after permanent noise damage in young adult mice. Between 100-200 supporting cells in the apical cochlea expressed a lineage marker, indicating competence to express CA-ERBB2. Hearing thresholds were assessed with auditory brainstem response tests, and hearing recovery was assessed over a ninety-day period. Mice harboring CA-ERBB2 capability had similar hearing thresholds to control littermates prior to noise exposure, immediately after, and 30-days after. Sixty and ninety days after noise exposure, CA-ERBB2+ mice demonstrated a partial but significant reversal of NIHL threshold shifts at one in five frequencies tested, which was in the region of CA-ERBB2 expression. We evaluated inner and outer hair cell (IHC and OHC) survival, synaptic preservation, stereociliary morphology, and IHC cytoskeletal alterations with histological techniques. Improved IHC and OHC survival were observed in the basal cochlea. No differences were seen in synaptic numbers or IHC cytoskeletal alterations, but more stereocilia may have been preserved. These data indicate, for the first time, that ERBB2 signaling in supporting cells can promote hair cell survival and partial functional recovery, and that permanent threshold shifts from noise may be partially reversed in mice.