NEUROTROPHIN-3 REGULATES RIBBON SYNAPSE DENSITY IN THE COCHLEA AND INDUCES SYNAPSE REGENERATION AFTER ACOUSTIC TRAUMA

WAN, G; GÓMEZ CASATI, ME; LIBERMAN, MC; CORFAS, G

Ann Harbor

Congreso; TRI Tinnitus Conference; 2015

Aims/Objectives: Noise exposure induces damage to the inner ear, in many cases primarily to the synapses between inner hair cells (IHCs) and spiral ganglion neurons. This synaptopathy leads to permanent hearing impairment, even if it only transiently elevates threshold, and has been suggested to contribute to the pathogenesis of tinnitus. Understanding the mechanisms that regulate the formation of IHC synapses could help in the development of approaches to protect or regenerate these synapses in the damaged ear. The aims of this study were to test the roles of the neurotrophins Ntf3 and Bdnf in the formation and maintenance of IHC synapses, and their ability to influence the noise-induced synaptopathy. Methods: We used cell-specific inducible gene recombination in mice to eliminate or over-express either Ntf3 or Bdnf in either IHCs or supporting cells in neonatal or adult mice and analyzed the effect of these manipulations on IHC synapse development and their loss after noise exposure. Results: Supporting cell-derived Ntf3 is required for the formation and maintenance of hair cell ribbon synapses in the postnatal cochlea, while Bdnf is necessary for the formation of vestibular HC synapses. Moreover, supporting cell-derived Ntf3, but not Bbnf, promotes recovery of cochlear function and ribbon synapse regeneration after acoustic trauma. Conclusions: These results indicate that supporting cells of the sensory epithelia are the key source of these neurotrophins in the postnatal inner ear and that these trophic factors play critical roles in the formation of HC synapses. Importantly, we show that increasing the availability of Ntf3, but not Bdnf, promotes recovery of both cochlear responses and IHC synapses after acoustic trauma, even when Ntf3 expression is induced after noise exposure. These results point to Ntf3 as a promising target for the treatment of noise-induced hearing loss, which could be also beneficial for tinnitus.