Age-related changes in P2Y receptor signalling in mouse cochlear supporting cells

• Published in: The Journal of physiology 2023-10, Vol.601 (19), p.4375-4395
• Main Authors: Hool, Sarah A, Jeng, Jing-Yi, Jagger, Daniel J, Marcotti, Walter, Ceriani, Federico
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - physiology; Age; Aged; Aging; Animals; Calcium - metabolism; Calcium imaging; Calcium signalling; Cochlea; Developmental stages; Down-regulation; Geriatrics; Hair cells; Hearing Loss; Hearing protection; Homeostasis; Humans; Infant; Mammals - metabolism; Metabotropic receptors; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neuroscience; Organ of Corti; Purine P2Y receptors; Purine receptors; Receptor mechanisms; Receptors, Purinergic - metabolism; Receptors, Purinergic P2Y; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y2; Sensory epithelium; Up-regulation
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP284980

Our sense of hearing depends on the function of a specialised class of sensory cells, the hair cells, which are found in the organ of Corti of the mammalian cochlea. The unique physiological environment in which these cells operate is maintained by a syncitium of non-sensory supporting cells, which are crucial for regulating cochlear physiology and metabolic homeostasis. Despite their importance for cochlear function, the role of these supporting cells in age-related hearing loss, the most common sensory deficit in the elderly, is poorly understood. Here, we investigated the age-related changes in the expression and function of metabotropic purinergic receptors (P2Y , P2Y and P2Y ) in the supporting cells of the cochlear apical coil. Purinergic signalling in supporting cells is crucial during the development of the organ of Corti and purinergic receptors are known to undergo changes in expression during ageing in several tissues. Immunolabelling and Ca imaging experiments revealed a downregulation of P2Y receptor expression and a decrease of purinergic-mediated calcium responses after early postnatal stages in the supporting cells. An upregulation of P2Y receptor expression was observed in the aged cochlea when compared to 1 month-old adults. The aged mice also had significantly larger calcium responses and displayed calcium oscillations during prolonged agonist applications. We conclude that supporting cells in the aged cochlea upregulate P2Y and P2Y receptors and display purinergic-induced Ca responses that mimic those observed during pre-hearing stages of development, possibly aimed at limiting or preventing further damage to the sensory epithelium. KEY POINTS: Age-related hearing loss is associated with lower hearing sensitivity and decreased ability to understand speech. We investigated age-related changes in the expression and function of metabotropic purinergic (P2Y) receptors in cochlear non-sensory supporting cells of mice displaying early-onset (C57BL/6N) and late-onset (C3H/HeJ) hearing loss. The expression of P2Y , P2Y and P2Y receptors in the supporting cells decreased during cochlear maturation, but that of P2Y and P2Y was upregulated in the aged cochlea. P2Y and P2Y receptors were primarily responsible for the ATP-induced Ca responses in the supporting cells. The degree of purinergic expression upregulation in aged supporting cells mirrored hearing loss progression in the different mouse strains. We propose that the upregulation of purinergi