Insulin-like growth factor 1 promotes cochlear synapse regeneration after excitotoxic trauma in vitro

Abstract

In the context of acquired sensorineural hearing loss (SNHL), cochlear hair cells have long been thought to be among the most vulnerable elements in mammalian cochleae. However, recent studies have indicated that the synaptic connection between inner hair cells (IHC) and spiral ganglion neurons (SGN) can be an important target for the treatment of SNHL. Our previous studies in patients with sudden SNHL demonstrated delayed and gradual hearing recovery following topical application of insulin-like growth factor 1 (IGF-1), suggesting that not only protective but also regenerative mechanisms may account for hearing recovery after treatment with IGF-1. We then hypothesized that IGF-1 has the potential to drive the regeneration of IHC–SGN synapses. To test this hypothesis, we investigated the effects of IGF-1 on IHC–SGN synapses using cochlear explant cultures from postnatal day 2 mice that had been damaged by exposure to the excitatory amino acids N-methyl-d-aspartate and kainate. Cochlear explants that lost IHC–SGN synapses upon exposure to excitatory amino acids were cultured with exogenous IGF-1 for an additional 48 h. We observed increased numbers of IHC–SGN synapses after exogenous IGF-1 application. Pharmacological inhibition of the IGF-1 receptor attenuated the restoration of IHC–SGN synapses by exogenous IGF-1. These findings indicated that IGF-1 induces regeneration of IHC–SGN synapses in cochlear explant cultures from postnatal day 2 mice. Therefore, in a future study we will perform in vivo experiments using adult mice to ascertain the effects of IGF-1 on the regeneration of IHC–SGN synapses.