Decreased expression of synaptic genes in the vestibular ganglion of rodents following subchronic ototoxic stress

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• dc.contributor.author Greguske, Erin A.
• dc.contributor.author Maroto, Alberto F.
• dc.contributor.author Borrajo, Mireia
• dc.contributor.author Palou, Aïda
• dc.contributor.author Gut, Marta
• dc.contributor.author Esteve-Codina, Anna
• dc.contributor.author Barrallo-Gimeno, Alejandro
• dc.contributor.author Llorens, Jordi
• dc.date.accessioned 2023-06-19T06:05:45Z
• dc.date.available 2023-06-19T06:05:45Z
• dc.date.issued 2023
• dc.description.abstract The vestibular ganglion contains primary sensory neurons that are postsynaptic to the transducing hair cells (HC) and project to the central nervous system. Understanding the response of these neurons to HC stress or loss is of great interest as their survival and functional competence will determine the functional outcome of any intervention aiming at repair or regeneration of the HCs. We have shown that subchronic exposure to the ototoxicant 3,3'-iminodipropionitrile (IDPN) in rats and mice causes a reversible detachment and synaptic uncoupling between the HCs and the ganglion neurons. Here, we used this paradigm to study the global changes in gene expression in vestibular ganglia using RNA-seq. Comparative gene ontology and pathway analyses of the data from both model species indicated a robust downregulation of terms related to synapses, including presynaptic and postsynaptic functions. Manual analyses of the most significantly downregulated transcripts identified genes with expressions related to neuronal activity, modulators of neuronal excitability, and transcription factors and receptors that promote neurite growth and differentiation. For choice selected genes, the mRNA expression results were replicated by qRT-PCR, validated spatially by RNA-scope, or were demonstrated to be associated with decreased expression of the corresponding protein. We conjectured that decreased synaptic input or trophic support on the ganglion neurons from the HC was triggering these expression changes. To support this hypothesis, we demonstrated decreased expression of BDNF mRNA in the vestibular epithelium after subchronic ototoxicity and also downregulated expression of similarly identified genes (e.g Etv5, Camk1g, Slc17a6, Nptx2, Spp1) after HC ablation with another ototoxic compound, allylnitrile. We conclude that vestibular ganglion neurons respond to decreased input from HCs by decreasing the strength of all their synaptic contacts, both as postsynaptic and presynaptic players.
• dc.description.sponsorship This work was supported by Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación, MCIU/AEI, 10.13039/501100011033, and European Regional Development Fund, FEDER [grant numbers RTI2018-096452-B-I00 and PID2021-124678OB-100], the MCIU/AEI, 10.13039/501100011033, NextGenerationEU/PRTR, ERANET NEURON Program VELOSO [grant number PCI2020-120681-2] and Agència de Gestió d'Ajuts Universitaris i de Recerca, AGAUR, Generalitat de Catalunya [grant number 2017SGR621]. A.E.C. is funded by ISCIII /MINECO and co-funded by FEDER [grant number PT17/0009/0019]. A.B.G is a Serra-Húnter fellow (Generalitat de Catalunya). E.A.G. and M.B. were supported by the Formación del Profesorado Universitario (FPU) program (Ministerio de Universidades).
• dc.format.mimetype application/pdf
• dc.identifier.citation Greguske EA, Maroto AF, Borrajo M, Palou A, Gut M, Esteve-Codina A, Barrallo-Gimeno A, Llorens J. Decreased expression of synaptic genes in the vestibular ganglion of rodents following subchronic ototoxic stress. Neurobiol Dis. 2023 Jun 15;182:106134. DOI: 10.1016/j.nbd.2023.106134
• dc.identifier.doi http://dx.doi.org/10.1016/j.nbd.2023.106134
• dc.identifier.issn 0969-9961
• dc.identifier.uri http://hdl.handle.net/10230/57223
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Neurobiol Dis. 2023 Jun 15;182:106134
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-096452-B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124678OB-100
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PCI2020-120681-2
• dc.rights © 2023 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword BDNF
• dc.subject.keyword Chronic vestibular toxicity
• dc.subject.keyword Mouse
• dc.subject.keyword Nitrile ototoxicity
• dc.subject.keyword Ototoxicity
• dc.subject.keyword RNA-seq
• dc.subject.keyword Rat
• dc.subject.keyword Synaptic uncoupling
• dc.subject.keyword Vestibular ganglion neurons
• dc.subject.keyword Vestibular hair cells
• dc.title Decreased expression of synaptic genes in the vestibular ganglion of rodents following subchronic ototoxic stress
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion