PUBLICATION

Augmentation of spinal cord glutamatergic synaptic currents in zebrafish primary motoneurons expressing mutant human TARDBP (TDP-43)

Authors
Petel Légaré, V., Harji, Z.A., Rampal, C.J., Allard-Chamard, X., Rodríguez, E.C., Armstrong, G.A.B.
ID
ZDB-PUB-190627-6
Date
2019
Source
Scientific Reports   9: 9122 (Journal)
Registered Authors
Armstrong, Gary A.B.
Keywords
none
MeSH Terms
  • Mutation*
  • Humans
  • Animals
  • DNA-Binding Proteins/genetics*
  • Gene Expression
  • Glutamic Acid/metabolism
  • Electrophysiological Phenomena*
  • Synapses/metabolism
  • Synapses/physiology*
  • Zebrafish*
  • Spinal Cord/physiology*
  • Motor Neurons/cytology
  • Motor Neurons/metabolism*
(all 13)
PubMed
31235725 Full text @ Sci. Rep.
Abstract
Though there is compelling evidence that de-innervation of neuromuscular junctions (NMJ) occurs early in amyotrophic lateral sclerosis (ALS), defects arising at synapses in the spinal cord remain incompletely understood. To investigate spinal cord synaptic dysfunction, we took advantage of a zebrafish larval model and expressed either wild type human TARDBP (wtTARDBP) or the ALS-causing G348C variant (mutTARDBP). The larval zebrafish is ideally suited to examine synaptic connectivity between descending populations of neurons and spinal cord motoneurons as a fully intact spinal cord is preserved during experimentation. Here we provide evidence that the tail-beat motor pattern is reduced in both frequency and duration in larvae expressing mutTARDBP. In addition, we report that motor-related synaptic depolarizations in primary motoneurons of the spinal cord are shorter in duration and fewer action potentials are evoked in larvae expressing mutTARDBP. To more thoroughly examine spinal cord synaptic dysfunction in our ALS model, we isolated AMPA/kainate-mediated glutamatergic miniature excitatory post-synaptic currents in primary motoneurons and found that in addition to displaying a larger amplitude, the frequency of quantal events was higher in larvae expressing mutTARDBP when compared to larvae expressing wtTARDBP. In a final series of experiments, we optogenetically drove neuronal activity in the hindbrain and spinal cord population of descending ipsilateral glutamatergic interneurons (expressing Chx10) using the Gal4-UAS system and found that larvae expressing mutTARDBP displayed abnormal tail-beat patterns in response to optogenetic stimuli and augmented synaptic connectivity with motoneurons. These findings indicate that expression of mutTARDBP results in functionally altered glutamatergic synapses in the spinal cord.
Genes / Markers
Figures
Figure Gallery (3 images)
Show all Figures
Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
js3Tg; nns18Tgstandard conditionsLong-pecIFL
1 - 1 of 1
Show
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
js3TgTransgenic Insertion
    ml2TgTransgenic Insertion
      nns18TgTransgenic Insertion
        1 - 3 of 3
        Show
        Human Disease / Model
        Human Disease Fish Conditions Evidence
        amyotrophic lateral sclerosisTAS
        1 - 1 of 1
        Show
        Sequence Targeting Reagents
        No data available
        Fish
        Fish
        js3Tg; nns18Tg
        1 - 1 of 1
        Show
        Antibodies
        Name Type Antigen Genes Isotypes Host Organism
        Ab3-mycmonoclonal
          		IgG2aMouse
          1 - 1 of 1
          Show
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          ChRWREFGChRWR
          EGFPEFGEGFP
          GAL4FFEFGGAL4FF
          GFPEFGGFP
          1 - 4 of 4
          Show
          Mapping
          No data available
          Your Input Welcome
          We welcome your input and comments. Please use this form to recommend updates to the information in ZFIN. We appreciate as much detail as possible and references as appropriate. We will review your comments promptly.
          Citation
          Petel Légaré, V., Harji, Z.A., Rampal, C.J., Allard-Chamard, X., Rodríguez, E.C., Armstrong, G.A.B. (2019) Augmentation of spinal cord glutamatergic synaptic currents in zebrafish primary motoneurons expressing mutant human TARDBP (TDP-43). Scientific Reports. 9:9122.