University of Groningen
Molecular composition and function of the spiral ganglion neuron peripheral synapse in mice
Reijntjes, Daniël Onne Jilt
DOI:
10.33612/diss.93524048
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2019
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Reijntjes, D. O. J. (2019). Molecular composition and function of the spiral ganglion neuron peripheral synapse in mice. University of Groningen. https://doi.org/10.33612/diss.93524048
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
135
Summary
In this thesis I studied the composition and function of the SGN peripheral synapse in order to examine functional differences between subgroups of SGNs. This line of research is based on the premise that the peripheral synaptic connections are thought to be the most vulnerable part of the auditory system to noise and age-related damage and thus, the first stage where we could intervene in the development of treatments to prevent and/or reverse acquired hearing loss. In addition, the SGNs are known to be heterogeneous in their physiological responses but it is unclear where these functional differences come from. To better understand which processes shape this physiological heterogeneity and contribute to the loss of SGN peripheral synapses, it is paramount to understand the molecular machinery and their function in these synapses.
In chapter 2 we reviewed the main mechanisms that shape the physiological re-sponses of the SGNs in a complex we termed the afferent signalling complex. These mechanisms consist of glutamate signalling, voltage gated ion channel function, and regulation by the lateral efferent system. It is likely that complex interactions be-tween these mechanisms ultimately determine the physiological responses of the SGNs, and, therefore, SGN heterogeneity and vulnerability.
In chapter 3 we examined the gene expression of ion channels in the SGNs and organ of Corti by performing RNA sequencing experiments on tissues from the organ of Corti and spiral ganglia. In particular, we focused on genes encoding the novel sodium-activated potassium channels expressed in the SGNs. We showed that gene transcript for these genes was localized in the SGNs, that SGNs expressed sodium-activated potassium conductances, and that mice with a genetic deletion of these genes showed auditory deficits.
In chapter 4 we further examined the contribution of these ion channels to ac-quired hearing loss by examining the vulnerability of knockout mice to age-related and noise-induced hearing loss. Indeed, loss of these novel sodium-activated potas-sium channels made these mice more vulnerable to acquired hearing loss, suggesting an important regulatory role for these ion channels.
In chapter 5 we developed a method to evaluate size gradients of synaptic proteins between synapses on either the pillar or modiolar side of the inner hair cells that are thought to correspond to subgroups of SGNs. We found further evidence substanti-ating size gradients in a presynaptic protein, but inconsistencies in size gradients for postsynaptic proteins. These results imply a reconsideration of previous hypotheses concerning subgroup functionality is necessary. Furthermore, this method can be used in the future to assess pre- and postsynaptic size gradients in knockout mice for our novel sodium-activated potassium channels.
To summarize, in this dissertation we outline an afferent signalling complex that regulates SGN function through three main mechanisms, glutamate signalling, ion channel function, and extrinsic input from the lateral efferent system. We further show the existence of novel sodium-activated potassium channels in SGNs, that likely regulate SGN excitability and possibly contribute to SGN heterogeneity. In addition, loss of these sodium-activated potassium channels results in exacerbated hearing loss. Furthermore, we show that size gradients in presynaptic proteins are consis-tent across mouse strains, but size gradients in postsynaptic proteins are not.
