Neurotrophin-3 from Supporting Cells Modulates Synapse Number and auditory function in the Postnatal Cochlea

GUOQIANG, W; GOMEZ CASATI, ME; LIBERMAN MC; CORFAS G

Congreso; The Association for Research in Otolaryngology, midwinter meeting; 2012

Neurotrophin-3 (NT-3) in the developing inner ear is critical for survival of spiral ganglion neurons, but its roles in the postnatal cochlea remain unclear. In the adult, NT-3 is expressed by both inner hair cells (IHCs) and their associated supporting cells, in an apex > base gradient. To explore the postnatal roles of supporting-cell derived NT-3, we generated supporting cell-specific NT-3 knockout and overexpression mice using proteolipid protein (PLP)-dependent expression of CreER(t) recombinase. Recombination of the conditional alleles was induced by tamoxifen at early postnatal ages (P1-P7). Knockout of NT-3 in supporting cells resulted in a 10–20 dB elevation of ABR thresholds at high frequencies (22-45 kHz), without any change in DPOAE thresholds. Immunostaining cochlear whole mounts for ribeye protein revealed a reduction of > 50% in the number of IHC synaptic ribbons in the basal half of the cochlea. Conversely, overexpression of NT-3 by supporting cells resulted in a 10–15 dB decrease in ABR thresholds at high frequencies and a parallel reduction in DPOAE thresholds. Correspondingly, cochlear immunostaining showed a 50% increase in the number of IHC synaptic ribbons in the basal turn. These results show that supporting cell-derived NT-3 is critical for synapse formation/maintenance in the postnatal cochlea and that its effects are greatest in the basal turn, where endogenous NT-3 expression is lowest.