Listening in Reverse: A Case for Retrograde Signaling During Auditory Inner Hair Cell Ribbon Synapse Maturation

Cochlear inner hair cells (IHCs) conduct rapid, sustained, and temporally precise transmission of acoustic information onto spiral ganglion neurons (SGNs). For this purpose, IHCs utilize highly specialized sensory synapses. During development, these so-called 'ribbon' synapses and their postsynaptic counterparts undergo extensive structural and functional refinement-a process driven by pre-sensory spontaneous activity. The underlying molecular mechanisms remain incompletely understood to date. Interestingly, little is known about the involvement of retrograde feedback provided by postsynaptic SGN terminals to transsynaptically instruct ribbon morphology and presynaptic active zone organization. This review therefore aims to shed light on this phenomenon and assess a potential role of retrograde signaling during IHC ribbon synapse maturation. We first summarize the main mechanisms established for conventional CNS synapses before discussing the current evidence regarding these pathways at IHC-SGN synapses. In particular, we focus on the gasotransmitter nitric oxide, lipid-derived endocannabinoid signaling, and cell adhesion molecules as the most promising candidate pathways. In summary, we propose that differential retrograde signaling may contribute to IHC synaptogenesis, SGN subtype diversification as well as the pruning of afferent contacts during development and might even play an extended functional role in auditory ribbon synapse regulation after hearing onset.