Today's journal article
Riffault C, Condamine S, Cerutti A, Bouleau Y, Boué-Grabot E, Dulon D. Medial olivocochlear efferent modulation of cochlear micromechanics requires P2X4 receptor in outer hair cells.
- J Neurosci. 2025 Oct 23:e0760252025.
- doi: 10.1523/JNEUROSCI.0760-25.2025.
- Epub ahead of print. PMID: 41130801.
- Available online at: https://www.jneurosci.org/content/early/2025/10/21/JNEUROSCI.0760-25.2025.long
Why I picked this article
Our sense of hearing is fine-tuned by input from the central auditory system in the brain. The medial olivocochlear (MOC) system is a brain‑to‑ear feedback loop that can adjust the sensitivity of the cochlea. Neurons from MOC pathway form synaptic connections with outer hair cells to adjust cochlear gain and protect from noise.
P2X4 is an ATP‑gated ion channel. This research first found that P2X4 is in the outer hair cells of the cochlea. Researchers then used a transgenic mouse model to show P2X4's relevance to the MOC modulation of cochlear micromechanics.
Some of the research findings
Constitutive and conditional P2X4mCherry knock‑in mice (either sex) model was used to study the P2X4 expression (by mCherry fluorescence):
- Strong P2X4 expression in outer hair cells from postnatal stages to adulthood.
- P2X4 was concentrated at the intracellular apical region near the "Hensen’s body" in the outer hair cells.
- P2X4 overlapped with lysosomal marker.
- P2X4 was also detected at the basal efferent synaptic membrane of OHCs.
From part of Figure 3A. Red =Where P2X4 may be found. Riffault et al. (2025)
Hearing and micromechanics in knock‑out mice:- Two transgenic lines were used:
- Constitutive P2X4 knock‑out (P2X4KO)
- Conditional P2X4 knock-out mice (Myo15‑Cre:P2X4KO), where the P2X4 was specifically knocked out in hair cells only.
- ConstitutiveP2X4KO mice had lower ABR thresholds and shorter ABR latencies compared to the control group mice.
- DPOAE, which measures the function of outer hair cells, were enhanced in P2X4KO and in Conditional knock‑out (Myo15‑Cre:P2X4KO) mice.
- This is consistent with increased outer hair cell electromotile gain.
- Contralateral acoustic stimulation suppressed DPOAEs in wild‑type, but this inhibitory effect was reduced in P2X4‑deficient mice.
Noise exposure and P2X4 deficiency were compared: - White noise 95 dB SPL for 12 h reduced hearing sensitivity in both genotypes with partial recovery.
- DPOAEs recovered faster in P2X4KO.
Hearing and micromechanics in knock‑out mice:
- Two transgenic lines were used:
- Constitutive P2X4 knock‑out (P2X4KO)
- Conditional P2X4 knock-out mice (Myo15‑Cre:P2X4KO), where the P2X4 was specifically knocked out in hair cells only.
- ConstitutiveP2X4KO mice had lower ABR thresholds and shorter ABR latencies compared to the control group mice.
- DPOAE, which measures the function of outer hair cells, were enhanced in P2X4KO and in Conditional knock‑out (Myo15‑Cre:P2X4KO) mice.
- This is consistent with increased outer hair cell electromotile gain.
- Contralateral acoustic stimulation suppressed DPOAEs in wild‑type, but this inhibitory effect was reduced in P2X4‑deficient mice.
Noise exposure and P2X4 deficiency were compared:
- White noise 95 dB SPL for 12 h reduced hearing sensitivity in both genotypes with partial recovery.
- DPOAEs recovered faster in P2X4KO.
Haruna's takeaway
This is such an exciting paper. We had a very strong interest in P2X4 receptors in the cochlea. P2X4 was very robustly expressed in the outer and inner hair cells in the rat cochlea, in our study. The functional study is very exciting; it seems to suggest that the P2X4 may normally dampen the cochlear gain by modulating outer hair cell contractility (which, when P2X4 was lost, outer hair cells became more electromobile). This will now highlight the second purinergic receptor involved in cochlear gain tuning (P2X2 is another receptor).
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This is Haruna's 86/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.