PUBLICATION
L-type voltage-gated calcium channel agonists mitigate hearing loss and modify ribbon synapse morphology in the zebrafish model of Usher syndrome type 1
- Authors
- Koleilat, A., Dugdale, J.A., Christenson, T.A., Bellah, J.L., Lambert, A.M., Masino, M.A., Ekker, S.C., Schimmenti, L.A.
- ID
- ZDB-PUB-201229-31
- Date
- 2020
- Source
- Disease models & mechanisms 13(11): (Journal)
- Registered Authors
- Ekker, Stephen C., Masino, Mark A., Schimmenti, Lisa A.
- Keywords
- Hair cell, Hearing loss, Ribbon synapse, Zebrafish, myo7aa
- MeSH Terms
-
- Animals
- Calcium Channels, L-Type/metabolism*
- Disease Models, Animal
- Eye Proteins/metabolism
- Guanylate Kinases/metabolism
- Hair Cells, Auditory/metabolism
- Hair Cells, Auditory/pathology
- Hearing Loss/complications
- Hearing Loss/pathology*
- Larva/metabolism
- Mechanotransduction, Cellular
- Mutation/genetics
- Myosins/genetics
- Myosins/metabolism
- Reflex, Startle
- Stereocilia/pathology
- Stereocilia/ultrastructure
- Swimming
- Synapses/pathology*
- Synapses/ultrastructure
- Usher Syndromes/complications
- Usher Syndromes/pathology*
- Zebrafish/physiology*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 33361086 Full text @ Dis. Model. Mech.
Citation
Koleilat, A., Dugdale, J.A., Christenson, T.A., Bellah, J.L., Lambert, A.M., Masino, M.A., Ekker, S.C., Schimmenti, L.A. (2020) L-type voltage-gated calcium channel agonists mitigate hearing loss and modify ribbon synapse morphology in the zebrafish model of Usher syndrome type 1. Disease models & mechanisms. 13(11):.
Abstract
The mariner (myo7aa-/- ) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in myo7aa-/- mutants, we focused on the ribbon synapse and evaluated ultrastructure, number and distribution of immunolabeled ribbons, and postsynaptic densities. By transmission electron microscopy, we determined that myo7aa-/- zebrafish have fewer glutamatergic vesicles tethered to ribbon synapses, yet maintain a comparable ribbon area. In myo7aa-/- hair cells, immunolocalization of Ctbp2 showed fewer ribbon-containing cells in total and an altered distribution of Ctbp2 puncta compared to wild-type hair cells. myo7aa-/- mutants have fewer postsynaptic densities - as assessed by MAGUK immunolabeling - compared to wild-type zebrafish. We quantified the circular swimming behavior of myo7aa-/- mutant fish and measured a greater turning angle (absolute smooth orientation). It has previously been shown that L-type voltage-gated calcium channels are necessary for ribbon localization and occurrence of postsynaptic density; thus, we hypothesized and observed that L-type voltage-gated calcium channel agonists change behavioral and synaptic phenotypes in myo7aa-/- mutants in a drug-specific manner. Our results indicate that treatment with L-type voltage-gated calcium channel agonists alter hair cell synaptic elements and improve behavioral phenotypes of myo7aa-/- mutants. Our data support that L-type voltage-gated calcium channel agonists induce morphological changes at the ribbon synapse - in both the number of tethered vesicles and regarding the distribution of Ctbp2 puncta - shift swimming behavior and improve acoustic startle response.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping