Susceptibility of larval zebrafish to the seizurogenic activity of GABA type A receptor antagonists

Suren B. Bandara, Dennis R. Carty, Vikrant Singh, Danielle J. Harvey, Natalia Vasylieva, Brandon Pressly, Heike Wulff, Pamela J. Lein

Research output: Contribution to journalArticle

Abstract

Previous studies demonstrated that pentylenetetrazole (PTZ), a GABA type A receptor (GABAAR) antagonist, elicits seizure-like phenotypes in larval zebrafish (Danio rerio). Here, we determined whether the GABAAR antagonists, tetramethylenedisulfotetramine (TETS) and picrotoxin (PTX), both listed as credible chemical threat agents, similarly trigger seizures in zebrafish larvae. Larvae of three, routinely used laboratory zebrafish lines, Tropical 5D, NHGRI and Tupfel long fin, were exposed to varying concentrations of PTZ (used as a positive control), PTX or TETS for 20 min at 5 days post fertilization (dpf). Acute exposure to PTZ, PTX or TETS triggered seizure behavior in the absence of morbidity or mortality. While the concentration-effect relationship for seizure behavior was similar across zebrafish lines for each GABAAR antagonist, significantly less TETS was required to trigger seizures relative to PTX or PTZ. Recordings of extracellular field potentials in the optic tectum of 5 dpf Tropical 5D zebrafish confirmed that all three GABAAR antagonists elicited extracellular spiking patterns consistent with seizure activity, although the pattern varied between chemicals. Post-exposure treatment with the GABAAR positive allosteric modulators (PAMs), diazepam, midazolam or allopregnanolone, attenuated seizure behavior and activity but did not completely normalize electrical field recordings in the optic tectum. These data are consistent with observations of seizure responses in mammalian models exposed to these same GABAAR antagonists and PAMs, further validating larval zebrafish as a higher throughput-screening platform for antiseizure therapeutics, and demonstrating its appropriateness for identifying improved countermeasures for TETS and other convulsant chemical threat agents that trigger seizures via GABAAR antagonism.

Original languageEnglish (US)
Pages (from-to)220-234
Number of pages15
JournalNeuroToxicology
Volume76
DOIs
StatePublished - Jan 2020

Fingerprint

tetramethylenedisulfotetramine
GABA-A Receptor Antagonists
Zebrafish
Picrotoxin
Pentylenetetrazole
Seizures
GABA-A Receptors
Modulators
Optics
Pregnanolone
Convulsants
Superior Colliculi
Midazolam
Fertilization
Diazepam
National Human Genome Research Institute (U.S.)
Larva
Screening
Throughput

Keywords

  • Chemical threat agents
  • Picrotoxin
  • Seizures
  • Tetramethylenedisulfotetramine
  • TETS
  • Zebrafish

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

Susceptibility of larval zebrafish to the seizurogenic activity of GABA type A receptor antagonists. / Bandara, Suren B.; Carty, Dennis R.; Singh, Vikrant; Harvey, Danielle J.; Vasylieva, Natalia; Pressly, Brandon; Wulff, Heike; Lein, Pamela J.

In: NeuroToxicology, Vol. 76, 01.2020, p. 220-234.

Research output: Contribution to journalArticle

Bandara, Suren B. ; Carty, Dennis R. ; Singh, Vikrant ; Harvey, Danielle J. ; Vasylieva, Natalia ; Pressly, Brandon ; Wulff, Heike ; Lein, Pamela J. / Susceptibility of larval zebrafish to the seizurogenic activity of GABA type A receptor antagonists. In: NeuroToxicology. 2020 ; Vol. 76. pp. 220-234.
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