Biology subjects

Zhai, T.-Y.

Publications and source records attributed to Zhai, T.-Y..

3 recordsLinked to original sources

bioRxiv2026

Upregulation of ATP-purinergic P2x2 receptors in the cochlea over-amplifies hearing sensitivity leading to hyperacusis and attenuation by antagonists

Hearing hypersensitivity (hyperacusis) is a common hearing stress and can cause many psychological diseases, e.g., anxiety, learning disabilities, and attention-deficit/hyperactivity disorder (ADHD). Here, we report an unexpected finding that the upregulation of P2x2 ATP-purinergic receptors in the cochlea links to hyperacusis generation. We found that P2x2 expression in the cochlea but not in auditory centers was upregulated in the hyperacusis generated by Cx26 deficiency. Overexpression of P2x2 in the cochlea also caused hyperacusis. Conversely, downregulation of P2x2 expression or administration of P2x2 antagonists attenuated hyperacusis. We further found that upregulation of P2x2 receptors in the cochlea increased outer hair cell (OHC) electromotility through the post-transcription functional modulation to potentiate active cochlear amplification leading to hearing hypersensitivity. Such enhancements in OHC electromotility and active cochlear amplification were also suppressed by P2x2 receptor antagonists. Overall, these findings demonstrate that P2x2-mediated ATP-purinergic signaling in the cochlea plays a critical role in hyperacusis generation; targeting P2x2 receptors can attenuate hyperacusis stress, which may also offer a therapeutic strategy for other related psychological comorbidities. Significance statementHearing hypersensitivity is a common hearing stress and can cause many other psychological disorders. However, little is known about the underlying genetic and cellular mechanisms. Also, it lacks efficient drugs for their treatments in the clinic. In this study, we found that upregulation of P2x2 ATP-purinergic receptors in the cochlea can potentiate outer hair cell electromotility, which is an active cochlear amplifier in mammals and can increase hearing sensitivity and frequency selectivity, through post-transcription functional modulation to enhance active cochlear amplification leading to hearing hypersensitivity. These enhancements can be inhibited by administrations of P2x2 receptor antagonists both in vitro and in vivo. These findings revealed a new genetic and cellular mechanism underlying hyperacusis generation and opened a new avenue to develop an efficient therapy for this common hearing stress and other associated psychological comorbidities.

physiology↗

bioRxiv2025

Promotion of new expression of connexin gene Cx46 (GJA3) in the cochlea after Cx26 (GJB2) deficiency

Connexin 26 (Cx26, GJB2) mutations induce a high incidence of hearing loss, responsible for 70-80% of nonsyndromic hearing loss. The pathological changes mainly locate in the cochlea. However, the genetic changes in the cochlea after deficiency of Cx26 remail unclear, which hampers to fully understand the underlying deafness mechanisms to develop therapeutic interventions. In this study, we employed bulk Poly(A) RNA-Seq technique and found that Cx26 deficiency could cause many genes up-regulating and down-regulating in the cochlea. A significant change was that Cx46 (GJA3), which is like Cx26 but expresses in the eye rather than the ear normally, had a remarkable upregulation and occurred in the cochlea after Cx26 deficiency. Immunofluorescent staining confirmed that Cx46 had expression in the cochlea and integrated into the gap junction networks among the cochlear supporting cells and in the cochlear lateral wall at the same location as Cx26 expression. Moreover, newly expressed Cx46 could be found in the same gap junctional plaques with Cx26. In addition, this promotion of new Cx46 expression is Cx26-specific; there was no promotion of Cx46 expression in the cochlea after deletion of Cx30 (GJB6), which also predominantly co-expresses with Cx26 in the cochlea. These data demonstrated that Cx26 deficiency could promote Cx26-like Cx46 expression in the cochlea for compensation. This finding also provides a new cue for developing a genetic approach to treat this common hereditary deafness induced by GJB2 mutations. HighlightO_LINew Cx46 compensatively expresses in the cochlea after Cx26 deficiency C_LIO_LICx46 expression occurs in the same location as Cx26 in the cochlea C_LIO_LICx46 promotion is Cx26-specific, no expression in the Cx30 KO cochlea C_LI

genetics↗

bioRxiv2024

ATP-gated P2x7 receptor is a major channel type at type II auditory nerves and required for hearing sensitivity efferent controlling and noise protection

Hearing sensitivity and noise protection are mediated and determined by negative feedback of the cochlear efferent system. Type II auditory nerves (ANs) innervate outer hair cells (OHCs) in the cochlea and provide an input to this efferent control. However, little is known about underlying channel information. Here, we report that ATP-gated P2x7 receptor had a predominant expression at type II ANs and the synaptic areas under inner hair cells and OHCs with lateral and medial olivocochlear efferent nerves. Knockout (KO) of P2x7 increased hearing sensitivity with enhanced acoustic startle response (ASR), auditory brainstem response (ABR), and cochlear microphonics (CM) by increasing OHC electromotility, an active cochlear amplifier in mammals. P2x7 KO also increased susceptibility to noise. Middle level noise exposure could impair active cochlear mechanics resulting in permanent hearing loss in P2x7 KO mice. These data demonstrate that P2x7 receptors have a critical role in type II AN function and the cochlear efferent system to control hearing sensitivity; deficiency of P2x7 receptors can impair the cochlear efferent suppression leading to hearing oversensitivity and susceptibility to noise.

neuroscience↗