Eph/ephrin signaling in hearing loss and auditory development: neural connectivity and function

Eph/ephrin signaling regulates both cochlear organization and central auditory connectivity, but how these regional effects contribute to auditory dysfunction remains incompletely understood. Eph receptors and their ephrin ligands mediate contact-dependent, bidirectional signaling that controls cell boundaries, axon guidance, and synaptic connectivity. This review examines Eph/ephrin expression and function across the peripheral and central auditory systems, with spatial connectivity precision as a unifying theme. Animal studies implicate the pathway in cochlear afferent targeting, supporting-cell organization, pillar-cell separation, and the refinement of auditory brainstem and midbrain projections. Disruption can alter auditory brainstem responses, otoacoustic emissions, frequency discrimination, and acoustic startle modulation. In some models, impaired neural responses or frequency discrimination occur despite largely preserved hearing thresholds, highlighting effects on auditory processing beyond sound detection. Human genetic studies have identified candidate associations involving a chromosomal deletion encompassing EFNB2 , a noncoding EPHA10 variant, and combined EPHA2 and SLC26A4 variants, implicating mechanisms such as altered receptor abundance and membrane protein trafficking. A priority is to determine which auditory cell types are affected by patient-derived variants and how these changes alter receptor signaling, neural connectivity, and hearing.