{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:58:50Z","timestamp":1787313530780,"version":"build-2736575974"},"reference-count":133,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["R01DC014712 (MAR)"],"award-info":[{"award-number":["R01DC014712 (MAR)"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["R01DC014997 (JTL)"],"award-info":[{"award-number":["R01DC014997 (JTL)"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["T32DC000022 (AW)"],"award-info":[{"award-number":["T32DC000022 (AW)"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Synaptic Neurosci."],"abstract":"<jats:p>\n                    Hearing depends on glutamatergic synaptic transmission mediated by \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by &amp;gt; 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives &amp;gt;5 h\n                    <jats:italic>in vitro<\/jats:italic>\n                    , and elimination half-lives\n                    <jats:italic>in vivo<\/jats:italic>\n                    of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC\n                    <jats:sub>50<\/jats:sub>\n                    ~ 73 \u03bcM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection.\n                  <\/jats:p>","DOI":"10.3389\/fnsyn.2021.680621","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T04:12:47Z","timestamp":1625458367000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors"],"prefix":"10.3389","volume":"13","author":[{"given":"Amit","family":"Walia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choongheon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared","family":"Hartsock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn S.","family":"Goodman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Dolle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec N.","family":"Salt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery T.","family":"Lichtenhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Rutherford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1002\/syn.1047","article-title":"Electron microscopic immunocytochemical detection of PSD-95, PSD-93, SAP-102, and SAP-97 at postsynaptic, presynaptic, and nonsynaptic sites of adult and neonatal rat visual cortex","volume":"40","author":"Aoki","year":"2001","journal-title":"Synapse"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2161","DOI":"10.1523\/JNEUROSCI.3915-14.2015","article-title":"Individual differences reveal correlates of hidden hearing","volume":"35","author":"Bharadwaj","year":"2015","journal-title":"Deficits"},{"key":"B3","doi-asserted-by":"publisher","first-page":"F633","DOI":"10.1152\/ajprenal.1998.275.5.F633","article-title":"Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function","volume":"275","author":"Blanco","year":"1998","journal-title":"Am. J. Physiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.heares.2019.02.016","article-title":"The search for noise-induced cochlear synaptopathy in humans: Mission impossible?","volume":"377","author":"Bramhall","year":"2019","journal-title":"Hear. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"509","DOI":"10.3766\/jaaa.14100","article-title":"Speech perception ability in noise is correlated with auditory brainstem response wave I amplitude","volume":"26","author":"Bramhall","year":"2015","journal-title":"J. Am. Acad. Audiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/S0006-8993(99)01970-8","article-title":"Characterization of AMPA receptor populations in rat brain cells by the use of subunit-specific open channel blocking drug, IEM-1460","volume":"846","author":"Buldakova","year":"1999","journal-title":"Brain Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1242\/jeb.198.1.1","article-title":"Functional significance of the beta-subunit for heterodimeric P-type","volume":"198","author":"Chow","year":"1995","journal-title":"ATPases"},{"key":"B8","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.conb.2006.05.012","article-title":"Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond","volume":"16","author":"Cull-Candy","year":"2006","journal-title":"Curr. Opin. Neurobiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1937","DOI":"10.4155\/bio-2016-0112","article-title":"High-throughput method for the quantitation of metabolites and co-factors from homocysteine-methionine cycle for nutritional status assessment","volume":"8","author":"Da Silva","year":"2016","journal-title":"Bioanalysis"},{"key":"B10","doi-asserted-by":"publisher","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1121\/1.381980","article-title":"Behavioral, compound action potential, and single unit thresholds: Relationship in normal and abnormal ears","volume":"64","author":"Dallos","year":"1978","journal-title":"J. Acoust. Soc. Am."},{"key":"B12","first-page":"727","article-title":"Antagonist binding profiles of five cloned human muscarinic receptor subtypes","volume":"256","author":"D\u00f6rje","year":"1991","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B13","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1097\/AUD.0b013e3181ba748c","article-title":"Predicting auditory nerve survival using the compound action potential","volume":"31","author":"Earl","year":"2010","journal-title":"Ear Hearing"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2981","DOI":"10.1111\/j.1460-9568.2004.03772.x","article-title":"Transient Ca2+-permeable AMPA receptors in postnatal rat primary auditory neurons","volume":"20","author":"Eybalin","year":"2004","journal-title":"Eur. J. Neurosci"},{"key":"B15","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.neuroscience.2019.11.051","article-title":"Noise-induced cochlear synaptopathy with and without sensory cell loss","volume":"427","author":"Fernandez","year":"2020","journal-title":"Neuroscience"},{"key":"B16","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.heares.2018.11.002","article-title":"Tonotopy in calcium homeostasis and vulnerability of cochlear hair cells","volume":"376","author":"Fettiplace","year":"2019","journal-title":"Hear. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1152\/jn.00164.2013","article-title":"Noise-induced cochlear neuropathy is selective for fibers with low spontaneous rates","volume":"110","author":"Furman","year":"2013","journal-title":"J. Neurophysiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"8721","DOI":"10.1523\/JNEUROSCI.19-20-08721.1999","article-title":"Time course and permeation of synaptic AMPA receptors in cochlear nuclear neurons correlate with input","volume":"19","author":"Gardner","year":"1999","journal-title":"J. Neurosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"7428","DOI":"10.1523\/JNEUROSCI.21-18-07428.2001","article-title":"Correlation of AMPA receptor subunit composition with synaptic input in the mammalian cochlear nuclei","volume":"21","author":"Gardner","year":"2001","journal-title":"J. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/0896-6273(95)90076-4","article-title":"Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS","volume":"15","author":"Geiger","year":"1995","journal-title":"Neuron"},{"key":"B21","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/nn796","article-title":"Transmitter release at the hair cell ribbon synapse","volume":"5","author":"Glowatzki","year":"2002","journal-title":"Nat. Neurosci."},{"key":"B22","first-page":"289","article-title":"Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine alpha 4 beta 2 receptor","volume":"276","author":"Gopalakrishnan","year":"1996","journal-title":"J. Pharmacol. Exp. Ther"},{"key":"B23","doi-asserted-by":"publisher","first-page":"17025","DOI":"10.1523\/JNEUROSCI.0457-12.2012","article-title":"Transmitter release from cochlear hair cells is phase locked to cyclic stimuli of different intensities and Frequencies","volume":"32","author":"Goutman","year":"2012"},{"key":"B24","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1152\/jn.00016.2020","article-title":"Electrophysiological markers of cochlear function correlate with hearing-in-noise performance among audiometrically normal subjects","volume":"124","author":"Grant","year":"2020","journal-title":"J. Neurophysiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"3631","DOI":"10.1073\/pnas.97.7.3631","article-title":"Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death","volume":"97","author":"Grooms","year":"2000","journal-title":"Proc. Natl. Acad. Sci"},{"key":"B26","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.heares.2018.03.008","article-title":"Impaired speech perception in noise with a normal audiogram: No evidence for cochlear synaptopathy and no relation to lifetime noise exposure","volume":"364","author":"Guest","year":"2018","journal-title":"Hear. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1097\/01.aud.0000240507.83072.e7","article-title":"Olivocochlear efferents: anatomy, physiology, function, and the measurement of efferent effects in humans","volume":"27","author":"Guinan","year":"2006","journal-title":"Ear Hear."},{"key":"B28","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/s00216-016-0003-1","article-title":"High-throughput and simultaneous quantitative analysis of homocysteine-methionine cycle metabolites and co-factors in blood plasma and cerebrospinal fluid by isotope dilution LC-MS\/MS","volume":"409","author":"Guiraud","year":"2017","journal-title":"Anal. Bioanal. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/nrn.2016.37","article-title":"Synaptic AMPA receptor composition in development, plasticity and disease","volume":"17","author":"Henley","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"19945","DOI":"10.1038\/s41598-020-76553-w","article-title":"Synaptic migration and reorganization after noise exposure suggests regeneration in a mature mammalian cochlea","volume":"10","author":"Hickman","year":"2020","journal-title":"Sci. Rep."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1016\/0092-8674(93)90622-W","article-title":"RNA editing of AMPA receptor subunit GluR-B: a base-paired intron-exon structure determines position and efficiency","volume":"75","author":"Higuchi","year":"1993","journal-title":"Cell"},{"key":"B32","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1007\/s10162-014-0476-6","article-title":"Systemic lipopolysaccharide compromises the blood-labyrinth barrier and increases entry of serum fluorescein into the perilymph","volume":"15","author":"Hirose","year":"2014","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1126\/science.1709304","article-title":"Ca2+ permeability of KA-AMPA\u2013gated glutamate receptor channels depends on subunit composition","volume":"252","author":"Hollmann","year":"1991","journal-title":"Science"},{"key":"B34","doi-asserted-by":"publisher","first-page":"6857","DOI":"10.1523\/JNEUROSCI.0123-05.2005","article-title":"Where is the spike generator of the cochlear nerve? Voltage-gated sodium channels in the mouse cochlea","volume":"25","author":"Hossain","year":"2005","journal-title":"J. Neurosci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"3828","DOI":"10.1073\/pnas.1914247117","article-title":"Protection of cochlear synapses from noise-induced excitotoxic trauma by blockade of Ca2+-permeable AMPA receptors","volume":"117","author":"Hu","year":"2020","journal-title":"Proc. Natl. Acad. Sci"},{"key":"B36","doi-asserted-by":"publisher","first-page":"529","DOI":"10.3109\/00016488109138538","article-title":"Labyrinthine barriers and cochlear homeostasis","volume":"91","author":"Juhn","year":"1981","journal-title":"Acta Oto-laryngol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1038\/nature03418","article-title":"Hair cell synaptic ribbons are essential for synchronous auditory signalling","volume":"434","author":"Khimich","year":"2005","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"4434","DOI":"10.1523\/JNEUROSCI.2228-18.2019","article-title":"Vesicular glutamatergic transmission in noise-induced loss and repair of cochlear ribbon synapses","volume":"39","author":"Kim","year":"2019","journal-title":"J. Neurosci"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1523\/JNEUROSCI.3437-15.2016","article-title":"Maturation of NaV and KV channel topographies in the auditory nerve spike initiator before and after developmental onset of hearing function","volume":"36","author":"Kim","year":"2016","journal-title":"J. Neurosci"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2115","DOI":"10.1523\/JNEUROSCI.4985-05.2006","article-title":"Acceleration of age-related hearing loss by early noise exposure: evidence of a misspent youth","volume":"26","author":"Kujawa","year":"2006","journal-title":"J. Neurosci"},{"key":"B41","doi-asserted-by":"publisher","first-page":"14077","DOI":"10.1523\/JNEUROSCI.2845-09.2009","article-title":"Adding insult to injury: cochlear nerve degeneration after \u201ctemporary\u201d noise-induced hearing loss","volume":"29","author":"Kujawa","year":"2009","journal-title":"J. Neurosci"},{"key":"B42","doi-asserted-by":"publisher","first-page":"3005","DOI":"10.1523\/JNEUROSCI.22-08-03005.2002","article-title":"A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons","volume":"22","author":"Kumar","year":"2002","journal-title":"J. Neurosci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.conb.2006.05.004","article-title":"Calcium-permeable AMPA channels in neurodegenerative disease and ischemia","volume":"16","author":"Kwak","year":"2006","journal-title":"Curr. Opin. Neurobiol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"4864","DOI":"10.1523\/JNEUROSCI.20-13-04864.2000","article-title":"Long-term specification of AMPA receptor properties after synapse formation","volume":"20","author":"Lawrence","year":"2000","journal-title":"J. Neurosci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1111\/j.1476-5381.1994.tb13157.x","article-title":"Pharmacological characterization of the human histamine H2 receptor stably expressed in Chinese hamster ovary cells","volume":"112","author":"Leurs","year":"1994","journal-title":"Br. J. Pharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1016\/j.neuron.2014.08.027","article-title":"Phase-locking precision is enhanced by multiquantal release at an auditory hair cell ribbon synapse","volume":"83","author":"Li","year":"2014","journal-title":"Neuron"},{"key":"B47","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1523\/JNEUROSCI.3389-10.2011","article-title":"Opposing gradients of ribbon size and AMPA receptor expression underlie sensitivity differences among cochlear-nerve\/hair-cell synapses","volume":"31","author":"Liberman","year":"2011","journal-title":"J. Neurosci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/0378-5955(80)90007-6","article-title":"Morphological differences among radial afferent fibers in the cat cochlea: an electron-microscopic study of serial sections","volume":"3","author":"Liberman","year":"1980","journal-title":"Hear. Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"927","DOI":"10.12688\/f1000research.11310.1","article-title":"Noise-induced and age-related hearing loss: new perspectives and potential therapies","volume":"6","author":"Liberman","year":"2017","journal-title":"F1000Res"},{"key":"B50","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1250\/ast.41.59","article-title":"Hidden hearing loss: Primary neural degeneration in the noise-damaged and aging cochlea","volume":"41","author":"Liberman","year":"2020","journal-title":"Acoust. Sci. Techn."},{"key":"B51","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1097\/AUD.0b013e31825f9bd3","article-title":"A new auditory threshold estimation technique for low frequencies: proof of concept","volume":"34","author":"Lichtenhan","year":"2013","journal-title":"Ear. Hear."},{"key":"B52","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.jneumeth.2016.08.005","article-title":"Drug delivery into the cochlear apex: improved control to sequentially affect finely spaced regions along the entire length of the cochlear spiral","volume":"273","author":"Lichtenhan","year":"","journal-title":"J. Neurosci. Methods"},{"key":"B53","doi-asserted-by":"publisher","first-page":"e0175236","DOI":"10.1371\/journal.pone.0175236","article-title":"Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: effects on physiological and histological measurements","volume":"12","author":"Lichtenhan","year":"2017","journal-title":"PLoS ONE"},{"key":"B54","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.heares.2015.09.001","article-title":"Medial olivocochlear efferent reflex inhibition of human cochlear nerve responses","volume":"333","author":"Lichtenhan","year":"","journal-title":"Hear. Res."},{"key":"B55","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1007\/s10162-011-0277-0","article-title":"Primary neural degeneration in the Guinea pig cochlea after reversible noise-induced threshold shift","volume":"12","author":"Lin","year":"2011","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B57","first-page":"121","article-title":"Comparison of human, mouse, rat, and guinea pig histamine h4 receptors reveals substantial pharmacological species variation","volume":"299","author":"Liu","year":"2001","journal-title":"J. Pharmacol. Exp. Ther"},{"key":"B58","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.tins.2007.01.006","article-title":"Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death","volume":"30","author":"Liu","year":"2007","journal-title":"Trends Neurosci."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1124\/mol.55.6.1101","article-title":"Cloning and functional expression of the human histamine H3 receptor","volume":"55","author":"Lovenberg","year":"1999","journal-title":"Mol. Pharmacol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"2981","DOI":"10.1523\/JNEUROSCI.2565-18.2019","article-title":"Presynaptic diversity revealed by Ca2+-permeable AMPA receptors at the calyx of held synapse","volume":"39","author":"Lujan","year":"2019","journal-title":"J. Neurosci"},{"key":"B61","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1111\/j.1469-7793.1997.655ba.x","article-title":"Block of open channels of recombinant AMPA receptors and native AMPA\/kainate receptors by Adamantane derivatives","volume":"505","author":"Magazanik","year":"1997","journal-title":"J. Physiol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.neuroscience.2016.04.024","article-title":"Changes of AMPA receptor properties in the neocortex and hippocampus following pilocarpine-induced status epilepticus in rats","volume":"327","author":"Malkin","year":"2016","journal-title":"Neuroscience"},{"key":"B63","doi-asserted-by":"publisher","first-page":"4457","DOI":"10.1523\/JNEUROSCI.16-14-04457.1996","article-title":"Organization of AMPA receptor subunits at a glutamate synapse: a quantitative immunogold analysis of hair cell synapses in the rat organ of Corti","volume":"16","author":"Matsubara","year":"1996","journal-title":"J. Neurosci."},{"key":"B64","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1097\/AUD.0b013e3181c351f2","article-title":"Drug delivery for treatment of inner ear disease: current state of knowledge","volume":"31","author":"McCall","year":"2010","journal-title":"Ear Hear."},{"key":"B65","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1002\/(SICI)1096-9861(19960722)371:2<208::AID-CNE2>3.0.CO;2-6","article-title":"Ultrastructural differences among afferent synapses on cochlear hair cells: correlations with spontaneous discharge rate","volume":"371","author":"Merchan-Perez","year":"1996","journal-title":"J. Comp. Neurol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1038\/nn.2293","article-title":"Tuning of synapse number, structure and function in the cochlea","volume":"12","author":"Meyer","year":"2009","journal-title":"Nat. Neurosci."},{"key":"B67","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1113\/jphysiol.2002.033472","article-title":"The density of AMPA receptors activated by a transmitter quantum at the climbing fibre-Purkinje cell synapse in immature rats","volume":"549","author":"Momiyama","year":"2003","journal-title":"J. Physiol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/nrneurol.2016.10","article-title":"Auditory neuropathy\u2013neural and synaptic mechanisms","volume":"12","author":"Moser","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/S0378-5955(98)00136-1","article-title":"Recovery of the human compound action potential following prior stimulation","volume":"124","author":"Murnane","year":"1998","journal-title":"Hear. Res."},{"key":"B70","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1007\/BF00971514","article-title":"Characterization of quisqualate recognition sites in rat brain tissue using DL-[3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and a filtration assay","volume":"12","author":"Murphy","year":"1987","journal-title":"Neurochem. Res."},{"key":"B71","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1007\/s10162-006-0034-y","article-title":"Demonstration of a longitudinal concentration gradient along scala tympani by sequential sampling of perilymph from the cochlear apex","volume":"7","author":"Mynatt","year":"2006","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"2338","DOI":"10.1523\/JNEUROSCI.15-03-02338.1995","article-title":"Expression of AMPA, kainate, and NMDA receptor subunits in cochlear and vestibular ganglia","volume":"15","author":"Niedzielski","year":"1995","journal-title":"J. Neurosci"},{"key":"B73","doi-asserted-by":"publisher","first-page":"eaao0935","DOI":"10.1126\/scitranslmed.aao0935","article-title":"Delivery of therapeutics to the inner ear: The challenge of the blood-labyrinth barrier","volume":"11","author":"Nyberg","year":"2019","journal-title":"Sci. Transl. Med"},{"key":"B74","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1113\/jphysiol.1995.sp020519","article-title":"AMPA receptors with high Ca2+ permeability mediate synaptic transmission in the avian auditory pathway","volume":"482","author":"Otis","year":"1995","journal-title":"J. Physiol"},{"key":"B75","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/S0378-5955(00)00122-2","article-title":"The AMPA receptors of auditory neurons","volume":"147","author":"Parks","year":"2000","journal-title":"Hear. Res."},{"key":"B76","doi-asserted-by":"publisher","first-page":"30","DOI":"10.3389\/fnsyn.2021.678575","article-title":"Maturation of heterogeneity in afferent synapse ultrastructure in the mouse cochlea","volume":"13","author":"Payne","year":"2021","journal-title":"Front. Synapt. Neurosci."},{"key":"B77","doi-asserted-by":"publisher","first-page":"3923","DOI":"10.1002\/j.1460-2075.1987.tb02733.x","article-title":"Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors","volume":"6","author":"Peralta","year":"1987","journal-title":"EMBO J."},{"key":"B78","doi-asserted-by":"publisher","first-page":"7922","DOI":"10.1523\/JNEUROSCI.20-21-07922.2000","article-title":"Developmental changes in synaptic AMPA and NMDA receptor distribution and AMPA receptor subunit composition in living hippocampal neurons","volume":"20","author":"Pickard","year":"2000","journal-title":"J. Neurosci."},{"key":"B79","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.phrs.2015.11.016","article-title":"Chronic nicotine and withdrawal affect glutamatergic but not nicotinic receptor expression in the mesocorticolimbic pathway in a region-specific manner","volume":"103","author":"Pistillo","year":"2016","journal-title":"Pharmacol. Res."},{"key":"B80","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.heares.2016.10.028","article-title":"Effects of noise exposure on young adults with normal audiograms I: Electrophysiology","volume":"344","author":"Prendergast","year":"2017","journal-title":"Hear. Res."},{"key":"B81","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1002\/cne.903410209","article-title":"Excitatory amino acid antagonists protect cochlear auditory neurons from excitotoxicity","volume":"341","author":"Puel","year":"1994","journal-title":"J. Comp. Neurol"},{"key":"B82","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1097\/00001756-199806220-00037","article-title":"Excitotoxicity and repair of cochlear synapses after noise-trauma induced hearing loss","volume":"9","author":"Puel","year":"1998","journal-title":"Neuroreport"},{"key":"B83","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1121\/1.414508","article-title":"Olivocochlear reflex assays: effects of contralateral sound on compound action potentials versus ear-canal distortion products","volume":"99","author":"Puria","year":"1996","journal-title":"J. Acoust. Soci. Am."},{"key":"B84","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1002\/cne.22007","article-title":"Synapse-to-synapse variation in mean synaptic vesicle size and its relationship with synaptic morphology and function","volume":"514","author":"Qu","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1002\/ana.23570","article-title":"Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus","volume":"72","author":"Rajasekaran","year":"2012","journal-title":"Ann. Neurol"},{"key":"B86","doi-asserted-by":"publisher","first-page":"4998","DOI":"10.1523\/JNEUROSCI.14-08-04998.1994","article-title":"Pathway-specific variants of AMPA receptors and their contribution to neuronal signaling","volume":"14","author":"Raman","year":"1994","journal-title":"J. Neurosci."},{"key":"B87","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/0378-5955(95)00004-N","article-title":"Recovery of the compound action potential following prior stimulation: evidence for a slow component that reflects recovery of low spontaneous-rate auditory neurons","volume":"83","author":"Relkin","year":"1995","journal-title":"Hear. Res."},{"key":"B88","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/0378-5955(83)90031-X","article-title":"Functional significance of dendritic swelling after loud sounds in the guinea pig cochlea","volume":"9","author":"Robertson","year":"1983","journal-title":"Hear. Rese."},{"key":"B89","doi-asserted-by":"publisher","first-page":"3375","DOI":"10.1007\/s00429-017-1408-0","article-title":"The number and distribution of AMPA receptor channels containing fast kinetic GluA3 and GluA4 subunits at auditory nerve synapses depend on the target cells","volume":"222","author":"Rubio","year":"2017","journal-title":"Brain Struct. Funct."},{"key":"B90","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1111\/j.1469-7793.1999.0667p.x","article-title":"AMPA-preferring glutamate receptors in cochlear physiology of adult guinea-pig","author":"Ruel","year":"1999","journal-title":"J. Physiol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"4773","DOI":"10.1523\/JNEUROSCI.4511-11.2012","article-title":"Spike encoding of neurotransmitter release timing by spiral ganglion neurons of the cochlea","volume":"32","author":"Rutherford","year":"2012","journal-title":"J. Neurosci"},{"key":"B92","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/978-1-4939-3031-9_5","article-title":"\u201cThe ribbon synapse between type i spiral ganglion neurons and inner hair cells,\u201d","volume-title":"The Primary Auditory Neurons of the Mammalian Cochlea","author":"Rutherford","year":"2016"},{"key":"B93","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1113\/JP279189","article-title":"Encoding sound in the cochlea: from receptor potential to afferent discharge","volume":"599","author":"Rutherford","year":"2021","journal-title":"J. Physiol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/0378-5955(94)90201-1","article-title":"Protection from noise-induced hearing loss by prior exposure to a nontraumatic stimulus: role of the middle ear muscles","volume":"72","author":"Ryan","year":"1994","journal-title":"Hear. Res."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1835","DOI":"10.1121\/1.1903521","article-title":"Rate versus level functions for auditory-nerve fibers in cats: tone-burst stimuli","volume":"56","author":"Sachs","year":"1974","journal-title":"J. Acoust. Soc. Am."},{"key":"B96","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.heares.2017.12.010","article-title":"Communication pathways to and from the inner ear and their contributions to drug delivery","volume":"362","author":"Salt","year":"2018","journal-title":"Hear. Res."},{"key":"B97","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1121\/1.4789005","article-title":"Large endolymphatic potentials from low-frequency and infrasonic tones in the guinea pig","volume":"133","author":"Salt","year":"2013","journal-title":"J. Acoust. Soc. Am."},{"key":"B98","doi-asserted-by":"publisher","first-page":"2017","DOI":"10.1523\/ENEURO.0377-17.2017","article-title":"Study of the size and shape of synapses in the juvenile rat somatosensory cortex with 3D electron microscopy","volume":"5","author":"Santuy","year":"2018","journal-title":"eNeuro"},{"key":"B99","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/S0896-6273(00)00159-8","article-title":"RIBEYE, a component of synaptic ribbons: a protein's journey through evolution provides insight into synaptic ribbon function","volume":"28","author":"Schmitz","year":"2000","journal-title":"Neuron"},{"key":"B100","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.neuron.2012.03.034","article-title":"High-resolution proteomics unravel architecture and molecular diversity of native AMPA receptor complexes","volume":"74","author":"Schwenk","year":"2012","journal-title":"Neuron"},{"key":"B101","doi-asserted-by":"publisher","first-page":"6162","DOI":"10.1523\/JNEUROSCI.3644-16.2017","article-title":"Ca(2+)-Permeable AMPARs mediate glutamatergic transmission and excitotoxic damage at the hair cell ribbon synapse","volume":"37","author":"Sebe","year":"2017","journal-title":"J. Neurosci."},{"key":"B102","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1016\/j.celrep.2012.05.004","article-title":"Differences in AMPA and kainate receptor interactomes facilitate identification of AMPA receptor auxiliary subunit GSG1L","volume":"1","author":"Shanks","year":"2012","journal-title":"Cell Rep."},{"key":"B103","doi-asserted-by":"publisher","first-page":"2783","DOI":"10.1523\/JNEUROSCI.20-08-02783.2000","article-title":"UB-165: a novel nicotinic agonist with subtype selectivity implicates the alpha4beta2* subtype in the modulation of dopamine release from rat striatal synaptosomes","volume":"20","author":"Sharples","year":"2000","journal-title":"J. Neurosci."},{"key":"B104","doi-asserted-by":"publisher","first-page":"e81566","DOI":"10.1371\/journal.pone.0081566","article-title":"Ribbon synapse plasticity in the cochleae of Guinea pigs after noise-induced silent damage","volume":"8","author":"Shi","year":"2013","journal-title":"PLoS ONE"},{"key":"B105","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1016\/j.cell.2018.07.007","article-title":"Sensory neuron diversity in the inner ear is shaped by activity","volume":"174","author":"Shrestha","year":"2018","journal-title":"Cell"},{"key":"B106","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/0378-5955(92)90105-V","article-title":"Spontaneous synaptic potentials from afferent terminals in the guinea pig cochlea","volume":"59","author":"Siegel","year":"1992","journal-title":"Hear. Res."},{"key":"B107","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/0014-2999(91)90063-V","article-title":"[3H]CGP 39653: a new N-methyl-D-aspartate antagonist radioligand with low nanomolar affinity in rat brain","volume":"192","author":"Sills","year":"1991","journal-title":"Eur. J. Pharmacol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1177\/000348946006900413","article-title":"LXXXI middle ear muscle protection from the acoustic trauma of loud continuous sound an electrophysiological study in cats","volume":"69","author":"Simmons","year":"1960","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"B109","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1111\/j.1476-5381.1996.tb16699.x","article-title":"Regulation of the human histamine H1 receptor stably expressed in Chinese hamster ovary cells","volume":"117","author":"Smit","year":"1996","journal-title":"Br. J. Pharmacol."},{"key":"B110","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/0092-8674(91)90568-J","article-title":"RNA editing in brain controls a determinant of ion flow in glutamate-gated channels","volume":"67","author":"Sommer","year":"1991","journal-title":"Cell"},{"key":"B111","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1089\/neu.2008.0532","article-title":"Calcium-permeable AMPA receptors appear in cortical neurons after traumatic mechanical injury and contribute to neuronal fate","volume":"25","author":"Spaethling","year":"2008","journal-title":"J. Neurotr."},{"key":"B112","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.heares.2006.07.014","article-title":"Synaptic alterations at inner hair cells precede spiral ganglion cell loss in aging C57BL\/6J mice","volume":"221","author":"Stamataki","year":"2006","journal-title":"Hear. Res."},{"key":"B113","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1097\/AUD.0000000000000107","article-title":"Auditory function in normal-hearing, noise-exposed human ears","volume":"36","author":"Stamper","year":"2015","journal-title":"Ear. Hear."},{"key":"B114","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1002\/neu.10078","article-title":"Development of the specialized AMPA receptors of auditory neurons","volume":"52","author":"Sugden","year":"2002","journal-title":"J. Neurobiol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/S0378-5955(01)00397-5","article-title":"Effect of noise exposure on blood-labyrinth barrier in guinea pigs","volume":"164","author":"Suzuki","year":"2002","journal-title":"Hear. Res."},{"key":"B116","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/sj.bjp.0703043","article-title":"Voltage-dependent block of native AMPA receptor channels by dicationic compounds","volume":"129","author":"Tikhonov","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"B117","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.neuropharm.2007.11.014","article-title":"Organic blockers escape from trapping in the AMPA receptor channels by leaking into the cytoplasm","volume":"54","author":"Tikhonova","year":"2008","journal-title":"Neuropharmacology"},{"key":"B118","doi-asserted-by":"publisher","first-page":"2373","DOI":"10.1016\/S0021-9258(17)41954-5","article-title":"A threonine residue in the seventh transmembrane domain of the human A1 adenosine receptor mediates specific agonist binding","volume":"269","author":"Townsend-Nicholson","year":"1994","journal-title":"J. Biol. Chem."},{"key":"B119","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/S0959-4388(97)80027-X","article-title":"Cellular mechanisms for preservation of timing in central auditory pathways","volume":"7","author":"Trussell","year":"1997","journal-title":"Curr. Opin. Neurob."},{"key":"B120","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1016\/j.neuron.2018.07.027","article-title":"Mechanisms of channel block in calcium-permeable AMPA receptors","volume":"99","author":"Twomey","year":"2018","journal-title":"Neuron"},{"key":"B121","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.heares.2015.04.014","article-title":"Cochlear neuropathy in human presbycusis: Confocal analysis of hidden hearing loss in post-mortem tissue","volume":"327","author":"Viana","year":"2015","journal-title":"Hear Res."},{"key":"B122","doi-asserted-by":"publisher","first-page":"14487","DOI":"10.1038\/ncomms14487","article-title":"Transient auditory nerve demyelination as a new mechanism for hidden hearing loss","volume":"8","author":"Wan","year":"2017","journal-title":"Nat. Commun."},{"key":"B123","doi-asserted-by":"publisher","first-page":"1814","DOI":"10.1152\/jn.00374.2005","article-title":"Synaptic transmission at the cochlear nucleus endbulb synapse during age-related hearing loss in mice","volume":"94","author":"Wang","year":"2005","journal-title":"J. Neurophysiol."},{"key":"B124","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1523\/JNEUROSCI.18-03-01148.1998","article-title":"Endbulb synapses in the anteroventral cochlear nucleus express a specific subset of AMPA-type glutamate receptor subunits","volume":"18","author":"Wang","year":"1998","journal-title":"J. Neurosci"},{"key":"B125","doi-asserted-by":"publisher","first-page":"42","DOI":"10.3389\/fnmol.2011.00042","article-title":"Ca permeable AMPA channels in diseases of the nervous system","volume":"4","author":"Weiss","year":"2011","journal-title":"Front. Mol. Neurosci."},{"key":"B126","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1021\/ci990307l","article-title":"Prediction of physicochemical parameters by atomic contributions","volume":"39","author":"Wildman","year":"1999","journal-title":"J. Chem. Inform. Comp. Sci."},{"key":"B127","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/nrn.2016.39","article-title":"Synaptic mechanisms underlying persistent cocaine craving","volume":"17","author":"Wolf","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"B128","doi-asserted-by":"publisher","first-page":"34","DOI":"10.3389\/fnmol.2012.00034","article-title":"The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain","volume":"5","author":"Wright","year":"2012","journal-title":"Front. Mol. Neurosci."},{"key":"B129","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.neuroscience.2018.07.053","article-title":"Primary neural degeneration in the human cochlea: evidence for hidden hearing loss in the aging ear","volume":"407","author":"Wu","year":"2019","journal-title":"Neuroscience"},{"key":"B130","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/s12868-014-0136-0","article-title":"Noise alters guinea pig's blood-labyrinth barrier ultrastructure and permeability along with a decrease of cochlear Claudin-5 and Occludin","volume":"15","author":"Wu","year":"2014","journal-title":"BMC Neurosci."},{"key":"B131","doi-asserted-by":"publisher","first-page":"4209","DOI":"10.1113\/jphysiol.2011.208066","article-title":"GluA4 is indispensable for driving fast neurotransmission across a high-fidelity central synapse","volume":"589","author":"Yang","year":"2011","journal-title":"J. Physiol."},{"key":"B132","doi-asserted-by":"publisher","first-page":"3168","DOI":"10.1152\/jn.00342.2005","article-title":"Development of a robust central auditory synapse in congenital deafness","volume":"94","author":"Youssoufian","year":"2005","journal-title":"J. Neurophysiol"},{"key":"B133","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1021\/acs.jcim.6b00174","article-title":"SwissSimilarity: a web tool for low to ultra high throughput ligand-based virtual screening","volume":"56","author":"Zoete","year":"2016","journal-title":"J. Chem. Inform. Model."}],"container-title":["Frontiers in Synaptic Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnsyn.2021.680621\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T04:12:54Z","timestamp":1625458374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnsyn.2021.680621\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,5]]},"references-count":133,"alternative-id":["10.3389\/fnsyn.2021.680621"],"URL":"https:\/\/doi.org\/10.3389\/fnsyn.2021.680621","relation":{},"ISSN":["1663-3563"],"issn-type":[{"value":"1663-3563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,5]]},"article-number":"680621"}}