TRPA1 Activation in the Cochlea as an Intrinsic Mechanism of Protection Against Noise-Induced Hearing Loss

TRPA1 channels are sensors for noxious stimuli in a subset of nociceptive neurons. They are also expressed in the mammalian inner ear. Given that Trpa1–/– mice exhibit normal hearing, balance, and sensory mechanotransduction, the function of TRPA1 channels in the inner ear remains unknown. We have found (Velez-Ortega et al., pending resubmission at Nature Communications) that functional TRPA1 channels are present in many sensory and non-sensory (supporting) cells of the cochlear epithelium. However, the supporting Hensen’s cells are the first to be activated by various TRPA1 agonists. TRPA1-initiated Ca2+ responses in Hensen’s cells propagate across the organ of Corti and cause shape changes in the supporting Deiters’ and pillar cells, which are able to contract upon an increase of intracellular Ca2+. Noise exposure is known to increase the oxidative stress in the cochlea and to cause the generation of 4-HNE for several days. Given that 4-HNE can gate TRPA1 channels, we hypothesized that 4-HNE generation after acoustic overstimulation would lead to TRPA1-initiated changes of the supporting cell shape that would alter the geometry and/or stiffness of the organ of Corti and modify cochlear amplification. To test this, we exposed young adult mice to mild noise and evaluated the recovery of hearing thresholds and cochlear amplification over time. Consistent with our hypothesis, we found a longer-lasting inhibition of cochlear amplification in wild type mice than in Trpa1–/– littermates. To better understand the TRPA1-dependent modifications in cochlear mechanics that lead to changes in cochlear amplification, Aim 1 will explore noise-induced changes to the tuning of auditory brainstem responses in wild type and Trpa1–/– mice. Two weeks after the noise exposure, we also observed a relative reduction in the auditory nerve responses compared to brain-stem responses in Trpa1–/– mice, which could represent susceptibility to noise-induced cochlear synaptopathy in the absence of TRPA1. Therefore, Aim 2 will evaluate changes in hair cell ribbon synapses after noise exposure in wild type and Trpa1–/– mice. Our results indicate that the non-sensory supporting cells of the hearing organ detect tissue damage via the activation of TRPA1 channels and subsequently modulate cochlear amplification through active cell shape changes. This novel mechanism of cochlear regulation seems to protect the organ of Corti after acoustic trauma or other types of cochlear injuries. This project will further explore this intrinsic mechanism of protection against noise-induced hearing loss and could lead to the identification of potential therapeutic targets.