Thomas M. Coate

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 ( Sema3a K108N ) show cochleae with grossly normal patterns of IHC innervation. However, genetic sparse labeling and three‐dimensional reconstructions of individual SGNs show that cochleae from Sema3a K108N mice lacked the normal synaptic distribution of type I SGNs. Additionally, Sema3a K108N 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. Ca 2+ 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.