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Prades, Silvia; Heard, Gregory; Gale, Jonathan E.; Engel, Tobias; Kopp, Robin; Nicke, Annette; Smith, Katie E. and Jagger, Daniel J. (2021): Functional P2X(7) Receptors in the Auditory Nerve of Hearing Rodents Localize Exclusively to Peripheral Glia. In: Journal of Neuroscience, Vol. 41, No. 12: pp. 2595-2609

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P2X(7) receptors (P2X(7)Rs) are associated with numerous pathophysiological mechanisms, and this promotes them as therapeutic targets for certain neurodegenerative conditions. However, the identity of P2X(7)R-expressing cells in the nervous system remains contentious. Here, we examined P2X(7)R functionality in auditory nerve cells from rodents of either sex, and determined their functional and anatomic expression pattern. In whole-cell recordings from rat spiral ganglion cultures, the purinergic agonist 2',3'-O-(4-benzoylbenzoyl)-ATP (BzATP) activated desensitizing currents in spiral ganglion neurons (SGNs) but non-desensitizing currents in glia that were blocked by P2X(7)R-specific antagonists. In imaging experiments, BzATP gated sustained Ca2+ entry into glial cells. BzATP-gated uptake of the fluorescent dye YO-PRO-1 was reduced and slowed by P2X(7)Rspecific antagonists. In rats, P2X(7)Rs were immuno-localized predominantly within satellite glial cells (SGCs) and Schwann cells (SCs). P2X(7)R expression was not detected in the portion of the auditory nerve within the central nervous system. Mouse models allowed further exploration of the distribution of cochlear P2X(7)Rs. In GENSAT reporter mice, EGFP expression driven via the P2rx7 promoter was evident in SGCs and SCs but was undetectable in SGNs. A second transgenic model showed a comparable cellular distribution of EGFP-tagged P2X(7)Rs. In wild-type mice the discrete glial expression was confirmed using a P2X(7)-specific nanobody construct. Our study shows that P2X(7)Rs are expressed by peripheral glial cells, rather than by afferent neurons. Description of functional signatures and cellular distributions of these enigmatic proteins in the peripheral nervous system (PNS) will help our understanding of ATP-dependent effects contributing to hearing loss and other sensory neuropathies.

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