Cochlear hair cell innervation is dependent on a modulatory function of Semaphorin‐3A.

Background: Proper connectivity between type I spiral ganglion neurons (SGNs) and inner hair cells (IHCs) in the cochlea is necessary for conveying sound information to the brain in mammals. Previous studies have shown that type I SGNs are heterogeneous in form, function and synaptic location on IHCs, but factors controlling their patterns of connectivity are not well understood. Results: During development, cochlear supporting cells and SGNs express Semaphorin‐3A (SEMA3A), a known axon guidance factor. Mice homozygous for a point mutation that attenuates normal SEMA3A repulsive activity (Sema3aK108N) show cochleae with grossly normal patterns of IHC innervation. However, genetic sparse labeling and three‐dimensional reconstructions of individual SGNs show that cochleae from Sema3aK108N mice lacked the normal synaptic distribution of type I SGNs. Additionally, Sema3aK108N cochleae show a disrupted distribution of GLUA2 postsynaptic patches around the IHCs. The addition of SEMA3A‐Fc to postnatal cochleae led to increases in SGN branching, similar to the effects of inhibiting glutamate receptors. Ca2+ imaging studies show that SEMA3A‐Fc decreases SGN activity. Conclusions: Contrary to the canonical view of SEMA3A as a guidance ligand, our results suggest SEMA3A may regulate SGN excitability in the cochlea, which may influence the morphology and synaptic arrangement of type I SGNs. Key Findings: The cochlear components responsible for peripheral auditory transduction include hair cells and afferent spiral ganglion neurons (SGNs).Genetic sparse labeling at different development time points shows the progression of the synaptic location of type I SGNs of different fiber diameters.SEMA3A is expressed by SGNs and epithelial cells adjacent to the hair cells, whereas NRP1 (a SEMA3A receptor) is expressed by SGNs.We have found that Semaphorin‐3A (SEMA3A), a secreted factor known in axon chemo‐repulsion, regulates normal SGN‐hair cell innervation patterns, possibly by modulating SGN activity.SEMA3A is also necessary for the normal distribution of postsynaptic glutamate receptor patches found between type I SGNs and inner hair cells.The results in this report provide new knowledge regarding the maturation of type I SGNs along with an unconventional role for SEMA3A. [ABSTRACT FROM AUTHOR]