Expression of the Eight GABA<sub>A</sub> Receptor α Subunits in the Developing Zebrafish Central Nervous System

Monesson-Olson, Bryan D.; McClain, Jon J.; Case, Abigail; Dorman, Hanna E.; Turkewitz, Daniel R.; Steiner, Aaron B.; Downes, Gerald B.

doi:10.1101/244590

Cited by 5 publications

(3 citation statements)

References 52 publications

(22 reference statements)

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“…Zebrafish appear to be an appropriate in vivo model for continuation of this research as subunits α6b, β3, and γ2 are known to be expressed in the optic tectum and cerebellum in adult zebrafish, and it is hypothesized that an α6bβ3γ2 combination is possible ( Cocco et al, 2017 ). Similarly, larval zebrafish have been found to express α1, α2a, α6b, β3, and γ2 in the optic tectum at 5 dpf ( Monesson-Olson et al, 2018 ; Sadamitsu et al, 2021 ). In vivo experimentation using GABA A R subunit targeted knock-outs is a possible avenue to further confirm the role of GABA A R subunits α2 and α6 in TETS toxicity.…”

Section: Discussionmentioning

confidence: 94%

“…Zebrafish express the full range of GABA A R subunits, including single homologs of α1, α3, α4, α5, β1, β2, β3, β4, ρ1, γ1, γ2, γ3, and δ subunits, and two paralogs for the α2 (gabra2a and gabra2b), α6 (gabrb6a and gabra6b), ρ2 (gabrr2a and gabrr2b), ρ3 (gabrr3a and gabrr3b), and π (gabrp and gabrz) subunits ( Monesson-Olson et al, 2018 ). At the protein-encoding level, these receptors exhibit 60–98% homology with human GABA A R subunits ( Klee et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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The efficacy of γ-aminobutyric acid type A receptor (GABA AR) subtype-selective positive allosteric modulators in blocking tetramethylenedisulfotetramine (TETS)-induced seizure-like behavior in larval zebrafish with minimal sedation

Mundy¹,

Pressly²,

Carty³

et al. 2021

Toxicology and Applied Pharmacology

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The chemical threat agent tetramethylenedisulfotetramine (TETS) is a γ-aminobutyric acid type A receptor (GABA A R) antagonist that causes life threatening seizures. Currently, there is no specific antidote for TETS intoxication. TETS-induced seizures are typically treated with benzodiazepines, which function as nonselective positive allosteric modulators (PAMs) of synaptic GABA A Rs. The major target of TETS was recently identified as the GABA A R α2β3γ2 subtype in electrophysiological studies using recombinantly expressed receptor combinations. Here, we tested whether these in vitro findings translate in vivo by comparing the efficacy of GABA A R subunit-selective PAMs in reducing TETS-induced seizure behavior in larval zebrafish. We tested PAMs targeting α1, α2, α2/3/5, α6, ß2/3, ß1/2/3, and δ subunits and compared their efficacy to the benzodiazepine midazolam (MDZ). The data demonstrate that α2- and α6-selective PAMs (SL-651,498 and SB-205384, respectively) were effective at mitigating TETS-induced seizure-like behavior. Combinations of SB-205384 and MDZ or SL-651,498 and 2–261 (ß2/3-selective) mitigated TETS-induced seizure-like behavior at concentrations that did not elicit sedating effects in a photomotor behavioral assay, whereas MDZ alone caused sedation at the concentration required to stop seizure behavior. Isobologram analyses suggested that SB-205384 and MDZ interacted in an antagonistic fashion, while the effects of SL-651,498 and 2–261 were additive. These results further elucidate the molecular mechanism by which TETS induces seizures and provide mechanistic insight regarding specific countermeasures against this chemical convulsant.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

The efficacy of γ-aminobutyric acid type A receptor (GABA AR) subtype-selective positive allosteric modulators in blocking tetramethylenedisulfotetramine (TETS)-induced seizure-like behavior in larval zebrafish with minimal sedation

Mundy¹,

Pressly²,

Carty³

et al. 2021

Toxicology and Applied Pharmacology

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“…6A), the chief inhibitory neurotransmitter in the developmentally mature central nervous system and its precursor, glutamine (Fig. 6B) 40 . Nitrate treatment caused a significant 22% reduction in the abundance of glutamine and 19% reduction in GABA in zebrafish brains.…”

Section: Metabolomics Resultsmentioning

confidence: 99%

Nitrate and nitrite exposure increases anxiety-like behavior and alters brain metabolomic profile in zebrafish

García-Jaramillo

Beaver

Truong

et al. 2020

Preprint

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IntroductionDietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. Here we tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We also explored the extent to which nitrate and nitrite treatment affected the brain metabolome in order to understand how nitrate and nitrite supplementation may affect indices of cognitive function.MethodsFish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2-4 weeks and free swim, startle response, innate predator avoidance, social cohesion, and shuttle box assays were performed.ResultsNitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment significantly increased anxiety-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted LC-MS/MS analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. An untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment including an 18-19% reduction in the neurotransmitter γ-aminobutyric acid (GABA), and 17-22% reduction in its precursor, glutamine, which may contribute to the increased anxiety-like behavior.ConclusionNitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health but was associated with mild anxiety-like behavior, changes in the brain metabolome, and caused a short-term decrease in executive function or associative learning.

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Behavioral Effects of the Mixture and the Single Compounds Carbendazim, Fipronil, and Sulfentrazone on Zebrafish (Danio rerio) Larvae

Gomes,

da Silva,

Padilha

et al. 2024

Biomedicines

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Pesticides are often detected in freshwater, but their impact on the aquatic environment is commonly studied based on single compounds, underestimating the potential additive effects of these mixtures. Even at low concentrations, pesticides can negatively affect organisms, altering important behaviors that can have repercussions at the population level. This study used a multi-behavioral approach to evaluate the effects of zebrafish larvae exposure to carbendazim (C), fipronil (F), and sulfentrazone (S), individually and mixed. Five behavioral tests, thigmotaxis, touch sensitivity, optomotor response, bouncing ball test, and larval exploratory behavior, were performed to assess potential effects on anxiety, fear, and spatial and social interaction. Significant changes were observed in the performance of larvae exposed to all compounds and their mixtures. Among the single pesticides, exposure to S produced the most behavioral alterations, followed by F and C, respectively. A synergistic effect between the compounds was observed in the C + F group, which showed more behavioral effects than the groups exposed to pesticides individually. The use of behavioral tests to evaluate pesticide mixtures is important to standardize methods and associate behavioral changes with ecologically relevant events, thus creating a more realistic scenario for investigating the potential environmental impacts of these compounds.

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Expression of the Eight GABA_A Receptor α Subunits in the Developing Zebrafish Central Nervous System

Abstract: 21GABA is a robust regulator of both developing and mature neural networks. It exerts was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Cited by 5 publications

References 52 publications

The efficacy of γ-aminobutyric acid type A receptor (GABA AR) subtype-selective positive allosteric modulators in blocking tetramethylenedisulfotetramine (TETS)-induced seizure-like behavior in larval zebrafish with minimal sedation

The efficacy of γ-aminobutyric acid type A receptor (GABA AR) subtype-selective positive allosteric modulators in blocking tetramethylenedisulfotetramine (TETS)-induced seizure-like behavior in larval zebrafish with minimal sedation

Nitrate and nitrite exposure increases anxiety-like behavior and alters brain metabolomic profile in zebrafish

Behavioral Effects of the Mixture and the Single Compounds Carbendazim, Fipronil, and Sulfentrazone on Zebrafish (Danio rerio) Larvae

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Expression of the Eight GABAA Receptor α Subunits in the Developing Zebrafish Central Nervous System

Abstract: 21GABA is a robust regulator of both developing and mature neural networks. It exerts was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Cited by 5 publications

References 52 publications

The efficacy of γ-aminobutyric acid type A receptor (GABA AR) subtype-selective positive allosteric modulators in blocking tetramethylenedisulfotetramine (TETS)-induced seizure-like behavior in larval zebrafish with minimal sedation

The efficacy of γ-aminobutyric acid type A receptor (GABA AR) subtype-selective positive allosteric modulators in blocking tetramethylenedisulfotetramine (TETS)-induced seizure-like behavior in larval zebrafish with minimal sedation

Nitrate and nitrite exposure increases anxiety-like behavior and alters brain metabolomic profile in zebrafish

Behavioral Effects of the Mixture and the Single Compounds Carbendazim, Fipronil, and Sulfentrazone on Zebrafish (Danio rerio) Larvae

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Expression of the Eight GABA_A Receptor α Subunits in the Developing Zebrafish Central Nervous System