ZFIN ID: ZDB-PUB-201229-31
L-type voltage-gated calcium channel agonists mitigate hearing loss and modify ribbon synapse morphology in the zebrafish model of Usher syndrome type 1
Koleilat, A., Dugdale, J.A., Christenson, T.A., Bellah, J.L., Lambert, A.M., Masino, M.A., Ekker, S.C., Schimmenti, L.A.
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.
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.