FGF22 protects hearing function from gentamycin ototoxicity by maintaining ribbon synapse number

Hear Res. 2016 Feb;332:39-45. doi: 10.1016/j.heares.2015.11.011. Epub 2015 Dec 2.

Abstract

Inner hair cell (IHC) ribbon synapses of cochlea play important role in transmitting sound signal into auditory nerve and are sensitive to ototoxicity. However, ototoxic damage of ribbon synapses is not understood clearly. Roles of fibroblast growth factor 22 (FGF22) on synapse formation were explored under gentamycin ototoxicity. 6-week-old mice were injected intraperitoneally once daily with 50-150 mg/kg gentamicin for 10 days. Immunostaining with anti- GluR2&3/CtBP2 was used to estimate the number of ribbon synapses in the cochlea. Expression of FGF22 and myocyte enhancer factor 2D (MEF2D) was assayed with RT-PCR. Expression and localization of FGF22 protein were visualized with anti-FGF22 immunostaining. Hearing thresholds were assessed using auditory brainstem responses. Gentamicin administration caused reduction in ribbon synapse number and hearing impairment without effect on hair cells in CBA/J mouse model. Immunohistochemistry showed that FGF22 protein was expressed in IHCs, but not OHCs of cochlea. Gentamycin attenuated expression of FGF22 but enhanced expression of MEF2D. Cochlear infusion of recombinant FGF22 inhibited expression of MEF2D, preserved ribbon synapses, and restored hearing function impaired by gentamycin. FGF22 restores hearing loss through maintaining ribbon synapse number, likely via inhibition of MEF2D. Activating FGF22 might provide the conceptual basis for the therapeutic strategies.

Keywords: FGF22; Hearing loss; Inner hair cell; MEF2D; Synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Animals
  • Auditory Threshold / drug effects
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Evoked Potentials, Auditory, Brain Stem / drug effects
  • Fibroblast Growth Factors / administration & dosage*
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Gentamicins*
  • Hair Cells, Auditory, Inner / drug effects*
  • Hair Cells, Auditory, Inner / metabolism
  • Hair Cells, Auditory, Inner / pathology
  • Hearing / drug effects
  • Hearing Loss / chemically induced
  • Hearing Loss / metabolism
  • Hearing Loss / pathology
  • Hearing Loss / prevention & control*
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism
  • Male
  • Mice, Inbred CBA
  • Phosphoproteins / metabolism
  • Receptors, AMPA / metabolism
  • Synapses / drug effects*
  • Synapses / metabolism
  • Synapses / pathology
  • Time Factors

Substances

  • DNA-Binding Proteins
  • Fgf22 protein, mouse
  • Gentamicins
  • MEF2 Transcription Factors
  • Mef2d protein, mouse
  • Phosphoproteins
  • Receptors, AMPA
  • glutamate receptor ionotropic, AMPA 3
  • Fibroblast Growth Factors
  • Ctbp2 protein, mouse
  • glutamate receptor ionotropic, AMPA 2