Prades I Abadias, Silvia; (2020) Purinergic signalling in the auditory nerve: Functional expression of P2X and P2Y receptors in cochlear glial cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Sensory and non-sensory cells of the inner ear express numerous P2X and P2Y receptor subtypes, suggesting purines play various roles in hearing. Spiral ganglion neurons (SGNs), the primary afferents in the auditory nerve, rely on satellite glial cells (SGCs) and Schwann cells (SCs) for their long-term survival. This project examined the role of P2X7 receptors (P2X7Rs) as mediators of neuro-glial interactions in the auditory nerve, and their potential as therapeutic targets. In transgenic reporter mice where EGFP expression is driven by the P2X7R promoter, cytoplasmic EGFP localised to SGCs and SCs, but was absent from SGNs and auditory nerve CNS glia. In spiral ganglion primary cultures from these mice, EGFP was detected only in Sox10-positive glia. Functional EGFP-tagged P2X7Rs in BAC transgenic mice localised to the membranes of SGCs and SCs, but not those of SGNs. Comparable patterns of expression were observed using a P2X7R-specific nanobody on mouse cochlea, and a commercial antibody on rat cochlea. These data identify an expression of P2X7Rs that is specific to peripheral glia within the auditory nerve. The properties of glial P2X7Rs were studied in rat spiral ganglion primary cultures. The P2X7R agonist BzATP activated instantaneous increases of intracellular calcium concentration, an effect dependent on extracellular calcium. BzATP application activated glial uptake of the large fluorescent molecule YO-PRO-1 within minutes, an effect slowed by selective P2X7R antagonists. Prolonged (6-hour) incubation in BzATP or ATP activated apoptotic cell death in glia, though cells were resistant to shorter (1-hour) exposures. Together, the data demonstrate functional P2X7R expression specifically in peripheral glia within the auditory nerve. Their functional properties suggest P2X7R activation may activate the uptake or release of large molecules in the neuro-glial space. This mechanism may be neuroprotective, to preserve auditory nerve function during conditions of stress.

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