Mouse models reveal P2X2 receptor-mediated hearing adaptation is an indicator of noise-induced hearing loss vulnerability

Abstract

Transgenic mouse models targeting the P2rx2 gene encoding the ATP-gated ion channel P2X2R subunit have revealed a cochlear humoral control mechanism where sustained elevation of background noise drives adaptation of hearing sensitivity over several minutes, requiring hours to reset (evident as “temporary threshold shift” in ABR thresholds, and reduction in DPOAE amplitudes; Housley et al. PNAS 2013, Cederholm et al. Purinergic Signalling 2019, Housley et al. Curr. Opinion. Physiol. 2020). Exposure of P2rx2 knockout (KO) mice to sustained noise (85 dB SPL) fails to elicit the ∼15 dB reduction in ABR thresholds that wildtype (WT) controls demonstrate. While acute hearing sensitivity is maintained, when these P2rx2KO mice are exposed to long-term moderate (75 dB SPL) white noise, they develop high frequency hearing loss not seen in WT controls. This “Purinergic Hearing Adaptation” otoprotection postulate is supported by human studies, where P2RX2 loss of function mutations lead to autosomal dominant progressive hearing loss that is exacerbated with exposure to environmental noise (DFNA41; Yan et al. PNAS 2013). Thus, noise-mediated release of ATP into the cochlear partition drives sustained suppression of the “cochlear amplifier,” supporting cochlear sensori-neural function across a lifetime that complements dynamic medial olivocochlear efferent-based otoprotection.