Ephrin‐A3 is required for tonotopic map precision and auditory functions in the mouse auditory brainstem

• Published in: Journal of comparative neurology (1911) Vol. 529; no. 16; pp. 3633 - 3654
• Main Authors: Hoshino, Natalia, Altarshan, Yazan, Alzein, Ahmad, Fernando, Amali M., Nguyen, Hieu T., Majewski, Emma F., Chen, Vincent C.‐F., Rochlin, M. William, Yu, Wei‐Ming
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-11-2021; Wiley Subscription Services, Inc
• Subjects: Acoustic Stimulation; Animals; Audiometry, Pure-Tone; Auditory discrimination; Auditory nerve; auditory nerve fiber; Auditory system; Axon guidance; Brain Mapping; Brain stem; Brain Stem - physiology; Cochlea; Cochlear nuclei; cochlear nucleus; Cochlear Nucleus - physiology; Ephrin-A3 - genetics; Ephrin-A3 - physiology; ephrin‐A3; Evoked Potentials, Auditory, Brain Stem - genetics; Evoked Potentials, Auditory, Brain Stem - physiology; Female; frequency discrimination; Hearing; Hearing - physiology; Innervation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Pitch Discrimination; RRID: AB_2156476; RRID: AB_2314836; RRID: AB_2532109; RRID: AB_2564645; RRID: AB_2744644; RRID: AB_531793; RRID: AB_887864; RRID: AB_94881; Sensory systems; spiral ganglion neurons; tonotopy; RRID: AB_2156476; RRID: AB_94881; tonotopy; RRID: AB_887864; RRID: AB_531793; spiral ganglion neurons; cochlear nucleus; ephrin-A3; auditory nerve fiber; RRID: AB_2564645; RRID: AB_2532109; RRID: AB_2744644; frequency discrimination; RRID: AB_2314836
• ISSN: 0021-9967; 1096-9861
• DOI: 10.1002/cne.25213

Tonotopy is a prominent feature of the vertebrate auditory system and forms the basis for sound discrimination, but the molecular mechanism that underlies its formation remains largely elusive. Ephrin/Eph signaling is known to play important roles in axon guidance during topographic mapping in other sensory systems, so we investigated its possible role in the establishment of tonotopy in the mouse cochlear nucleus. We found that ephrin‐A3 molecules are differentially expressed along the tonotopic axis in the cochlear nucleus during innervation. Ephrin‐A3 forward signaling is sufficient to repel auditory nerve fibers in a developmental stage‐dependent manner. In mice lacking ephrin‐A3, the tonotopic map is degraded and isofrequency bands of neuronal activation upon pure tone exposure become imprecise in the anteroventral cochlear nucleus. Ephrin‐A3 mutant mice also exhibit a delayed second wave in auditory brainstem responses upon sound stimuli and impaired detection of sound frequency changes. Our findings establish an essential role for ephrin‐A3 in forming precise tonotopy in the auditory brainstem to ensure accurate sound discrimination.
We investigated the molecular basis of tonotopic map formation in the mouse auditory brainstem. We found that the axon guidance cue ephrin‐A3 is differentially expressed along the tonotopic map in the mouse auditory brainstem. Ephrin‐A3 is sufficient to repel growing auditory nerve fibers in vitro. In mice lacking ephrin‐A3, the tonotopic map is degraded in the anteroventral cochlear nucleus, and auditory activation patterns and the ability to discriminate sound frequency changes are also impaired.