PT  - JOURNAL ARTICLE
AU  - Joy Y. Sebe
AU  - Soyoun Cho
AU  - Lavinia Sheets
AU  - Mark A. Rutherford
AU  - Henrique von Gersdorff
AU  - David W. Raible
TI  - Ca<sup>2+</sup> permeable AMPARs mediate glutamatergic transmission and excitotoxic damage at the hair cell ribbon synapse
AID  - 10.1523/JNEUROSCI.3644-16.2017
DP  - 2017 May 24
TA  - The Journal of Neuroscience
PG  - 3644-16
4099  - http://www.jneurosci.org/content/early/2017/05/24/JNEUROSCI.3644-16.2017.short
4100  - http://www.jneurosci.org/content/early/2017/05/24/JNEUROSCI.3644-16.2017.full
AB  - We report functional and structural evidence for GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs) at the mature hair cell ribbon synapse. By utilizing 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. Immunohistochemical 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.SIGNIFICANCE STATEMENTA single incidence of noise overexposure causes damage at the hair cell synapse that later leads to neurodegeneration and exacerbates age-related hearing loss. A first step toward understanding cochlear neurodegeneration is to identify the cause of initial excitotoxic damage to the postsynaptic neuron. Using a combination of immunohistochemical, electrophysiological and Ca2+ imaging approaches in evolutionarily divergent species we demonstrate that Ca2+-permeable AMPARs (CP-AMPARs) mediate glutamatergic transmission at the adult auditory hair cell synapse. Overexcitation of the terminal causes Ca2+ accumulation and swelling that can be prevented by blocking CP-AMPARs. We demonstrate that CP-AMPARs mediate transmission at this first order sensory synapse and that limiting Ca2+ accumulation in the terminal may protect against hearing loss.