Ca2+-permeable AMPARs mediate glutamatergic transmission and excitotoxic damage at the hair cell ribbon synapse

Joy Y. Sebe, Soyoun Cho, Lavinia Sheets, Mark A. Rutherford, Henrique von Gersdorff, David W. Raible

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

We report functional and structural evidence for GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs) at the mature hair cell ribbon synapse. By using the methodological advantages of three species (of either sex), we demonstrate that CP-AMPARs are present at the hair cell synapse in an evolutionarily conserved manner. Via a combination of in vivo electrophysiological and Ca2+ imaging approaches in the larval zebrafish, we show that hair cell stimulation leads to robust Ca2+ influx into afferent terminals. Prolonged application of AMPA caused loss of afferent terminal responsiveness, whereas blocking CP-AMPARs protects terminals from excitotoxic swelling. Immuno his to chemical analysis of AMPAR subunits in mature rat cochlea show regions within synapses lacking the GluA2 subunit. Paired recordings from adult bullfrog auditory synapses demonstrate that CP-AMPARs mediate a major component of glutamatergic transmission. Together, our results support the importance of CP-AMPARs in mediating transmission at the hair cell ribbon synapse. Further, excess Ca2+ entry via CP-AMPARs may underlie afferent terminal damage following excitotoxic challenge, suggesting that limiting Ca2+ levels in the afferent terminal may protect against cochlear synaptopathy associated with hearing loss.

Original languageEnglish (US)
Pages (from-to)6162-6175
Number of pages14
JournalJournal of Neuroscience
Volume37
Issue number25
DOIs
StatePublished - Jun 21 2017

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Keywords

  • Cochlear synaptopathy
  • Excitotoxicity
  • GCaMP
  • Noise overexposure
  • Zebrafish

ASJC Scopus subject areas

  • Neuroscience(all)

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