Oncomodulin regulates spontaneous calcium signalling and maturation of afferent innervation in cochlear outer hair cells

Abstract

Cochlear outer hair cells (OHCs) are responsible for the exquisite frequency selectivity and sensitivity of mammalian hearing. During development, the maturation of OHC afferent connectivity is refined by coordinated spontaneous Ca2+ activity in both sensory and non‐sensory cells. Calcium signalling in neonatal OHCs can be modulated by oncomodulin (OCM, β‐parvalbumin), an EF‐hand calcium‐binding protein. Here, we investigated whether OCM regulates OHC spontaneous Ca2+ activity and afferent connectivity during development. Using a genetically encoded Ca2+ sensor (GCaMP6s) expressed in OHCs in wild‐type (Ocm+/+) and Ocm knockout (Ocm−/−) littermates, we found increased spontaneous Ca2+ activity and upregulation of purinergic receptors in OHCs from Ocm−/− cochlea immediately following birth. The afferent synaptic maturation of OHCs was delayed in the absence of OCM, leading to an increased number of ribbon synapses and afferent fibres on Ocm−/− OHCs before hearing onset. We propose that OCM regulates the spontaneous Ca2+ signalling in the developing cochlea and the maturation of OHC afferent innervation. imageKey points Cochlear outer hair cells (OHCs) exhibit spontaneous Ca2+ activity during a narrow period of neonatal development. OHC afferent maturation and connectivity requires spontaneous Ca2+ activity. Oncomodulin (OCM, β‐parvalbumin), an EF‐hand calcium‐binding protein, modulates Ca2+ signals in immature OHCs. Using transgenic mice that endogenously expressed a Ca2+ sensor, GCaMP6s, we found increased spontaneous Ca2+ activity and upregulated purinergic receptors in Ocm−/− OHCs. The maturation of afferent synapses in Ocm−/− OHCs was also delayed, leading to an upregulation of ribbon synapses and afferent fibres in Ocm−/− OHCs before hearing onset. We propose that OCM plays an important role in modulating Ca2+ activity, expression of Ca2+ channels and afferent innervation in developing OHCs.

Lack of Oncomodulin Increases ATP-Dependent Calcium Signaling and Susceptibility to Noise in Adult Mice

“…These results support the idea that OCM plays a unique and indispensable role as a Ca 2+ buffer in developing OHCs. Our previous findings also revealed higher levels of spontaneous Ca 2+ activity, upregulation of purinergic receptors in OHCs, and higher synchronization of Ca 2+ activity in Ocm -/- mice compared to wild-type mice (Yang et al 2023). Additionally, the maturation of afferent synaptic ribbons in Ocm -/- OHCs was delayed, leading to an increased number of ribbon synapses and afferent fibers on OHCs before hearing onset.…”

“…Recent studies show that the absence of OCM increases Ca 2+ signaling in developing OHCs, and reveal that OCM plays a significant role in the synchronization of Ca 2+ activity during cochlear maturation (Murtha et al, 2022; Yang Yang et al, 2023). In Murtha, Yang, et al (2022), we found that the onset of OCM expression alters the level of Ca 2+ signals in OHCs before hearing onset.…”

Damage-evoked signals in cochlear neurons and supporting cells

“…Other studies of cochlear damage have identified additional molecular pathways that may be involved. Calcium homeostasis in small, electrically active hair cells is undoubtedly central to function and dysfunction ( 46 , 47 ), including the generation of spontaneous calcium transients and synaptic maturation ( 48 ). Mitochondria serve as an important sink for cytoplasmic calcium, but additionally as a source of damaging reactive oxygen species during calcium overload ( 49 , 50 ).…”

Calcium-Associated Proteins in Neuroregeneration

“…In adult mammals, OCM can act as a Ca 2+ buffer and likely influence outer hair cell (OHC) motility mechanisms, contributing to sensory hair cell function and playing a crucial role in maintaining hearing function and health [99,100]. Additionally, OCM impacts the development of OHCs and their neonatal afferent innervation by modulating Ca 2+ activity and regulating the expression of key channels and receptors [101,102]. Moreover, OCM has been thought to serve as a factor secreted by macrophages and neutrophils to facilitate nerve regeneration [97].…”