| RRC ID |
51268
|
| 著者 |
Sebe JY, Cho S, Sheets L, Rutherford MA, von Gersdorff H, Raible DW.
|
| タイトル |
Ca2+-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse.
|
| ジャーナル |
J Neurosci
|
| 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. 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 STATEMENT A 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.
|
| 巻・号 |
37(25)
|
| ページ |
6162-6175
|
| 公開日 |
2017-6-21
|
| DOI |
10.1523/JNEUROSCI.3644-16.2017
|
| PII |
JNEUROSCI.3644-16.2017
|
| PMID |
28539424
|
| PMC |
PMC5481947
|
| MeSH |
Animals
Animals, Genetically Modified
Calcium / metabolism*
Electrophysiological Phenomena / physiology
Female
Glutamic Acid / physiology*
Hair Cells, Auditory / physiology*
Male
Physical Stimulation
Presynaptic Terminals / physiology
Rana catesbeiana
Rats
Rats, Wistar
Receptors, AMPA / metabolism*
Synapses / physiology*
Synaptic Transmission / physiology*
Zebrafish
|
| IF |
6.074
|
| 引用数 |
21
|
| リソース情報 |
| ゼブラフィッシュ |
Tg(CM-isl1:GFP) |
