Journal article
Protection of cochlear synapses from noise-induced excitotoxic trauma by blockade of Ca2+-permeable AMPA receptors
Proceedings of the National Academy of Sciences - PNAS, Vol.117(7), pp.3828-3838
02/18/2020
DOI: 10.1073/pnas.1914247117
PMCID: PMC7035499
PMID: 32015128
Abstract
Exposure to loud sound damages the postsynaptic terminals of spiral ganglion neurons (SGNs) on cochlear inner hair cells (IHCs), resulting in loss of synapses, a process termed synaptopathy. Glutamatergic neurotransmission via α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type receptors is required for synaptopathy, and here we identify a possible involvement of GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) using IEM-1460, which has been shown to block GluA2-lacking AMPARs. In CBA/CaJ mice, a 2-h exposure to 100-dB sound pressure level octave band (8 to 16 kHz) noise results in no permanent threshold shift but does cause significant synaptopathy and a reduction in auditory brainstem response (ABR) wave-I amplitude. Chronic intracochlear perfusion of IEM-1460 in artificial perilymph (AP) into adult CBA/CaJ mice prevented the decrease in ABR wave-I amplitude and the synaptopathy relative to intracochlear perfusion of AP alone. Interestingly, IEM-1460 itself did not affect the ABR threshold, presumably because GluA2-containing AMPARs can sustain sufficient synaptic transmission to evoke low-threshold responses during blockade of GluA2-lacking AMPARs. On individual postsynaptic densities, we observed GluA2-lacking nanodomains alongside regions with robust GluA2 expression, consistent with the idea that individual synapses have both CP-AMPARs and Ca2+-impermeable AMPARs. SGNs innervating the same IHC differ in their relative vulnerability to noise. We found local heterogeneity among synapses in the relative abundance of GluA2 subunits that may underlie such differences in vulnerability. We propose a role for GluA2-lacking CP-AMPARs in noise-induced cochlear synaptopathy whereby differences among synapses account for differences in excitotoxic susceptibility. These data suggest a means of maintaining normal hearing thresholds while protecting against noise-induced synaptopathy, via selective blockade of CP-AMPARs.
Details
- Title: Subtitle
- Protection of cochlear synapses from noise-induced excitotoxic trauma by blockade of Ca2+-permeable AMPA receptors
- Creators
- Ning Hu - University of IowaMark A Rutherford - Washington University in St. LouisSteven H Green - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.117(7), pp.3828-3838
- DOI
- 10.1073/pnas.1914247117
- PMID
- 32015128
- PMCID
- PMC7035499
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- DC02961 / HHS | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD) DC014712 / HHS | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD) N/A / American Hearing Research Foundation (AHRF) W81XWH-14-1-0494 / DOD | United States Army | MEDCOM | Congressionally Directed Medical Research Programs (CDMRP)
- Language
- English
- Date published
- 02/18/2020
- Academic Unit
- Biology; Otolaryngology
- Record Identifier
- 9983991964702771
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