Embryological exposure to valproic acid induces social interaction deficits in zebrafish (Danio rerio): A developmental behavior analysis

Zimmermann, Fernanda Francine; Gaspary, Karina Vidarte; Leite, Carlos Eduardo; Cognato, Giana de Paula; Bonan, Carla Denise

doi:10.1016/j.ntt.2015.10.002

Cited by 70 publications

(84 citation statements)

References 61 publications

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“…This was in accordance with a previous study and might indicate that VPA exposure causes anxiety in zebrafish larvae [34]. In a previous study, VPA exposure caused anxiety in larval zebrafish and resulted in social interaction deficits in adults [34]. Therefore, the observed effects on locomotor activity at the larval stage in our study could be linked to ASD-like behaviour.…”

Section: Discussionsupporting

confidence: 94%

“…We found that locomotor activity in zebrafish larvae slightly increased following exposure to 25 μM VPA. This was in accordance with a previous study and might indicate that VPA exposure causes anxiety in zebrafish larvae [34]. In a previous study, VPA exposure caused anxiety in larval zebrafish and resulted in social interaction deficits in adults [34].…”

Section: Discussionsupporting

confidence: 93%

“…The test tools for social behaviour in the zebrafish larvae stage have not yet been completely developed. Therefore, instead of social behaviour, locomotor activity and anxiety have been used as markers of the ASD phenotype in ASD toxicity tests involving zebrafish embryos [32, 34, 58]. Thus, in the present study, we analysed locomotor activity in zebrafish larvae after VPA exposure as a behavioural endpoint.…”

Section: Discussionmentioning

confidence: 99%

“…The test solutions were prepared in E3 medium, 0.292 g NaCl, 0.013 g KCl, 0.044 g CaCl, and 0.081 g MgSO 4 in Millipore water (1 L). The exposure concentrations (0, 12.5, 25, 50, 100 μM of VPA) were determined according to previous studies [31, 34]. Normal zebrafish embryos were randomly distributed into test solutions of VPA for 120 h. All exposure experiments were conducted in accordance with protocols approved by the Institutional Animal Care and Use Committee (IACUC) of the Korea Institute of Toxicology (Protocol No.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, zebrafish are emerging as a new alternative model for ASD research [25, 28, 30]. However, transcriptome analysis and comparison studies focused on ASD have not yet been conducted with the zebrafish model [31–34]. …”

Section: Introductionmentioning

confidence: 99%

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Plausibility of the zebrafish embryos/larvae as an alternative animal model for autism: A comparison study of transcriptome changes

et al. 2018

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Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder characterized by impaired or abnormal social interaction and communication and by restricted and repetitive behaviour. ASD is highly prevalent in Asia, Europe, and the United States, and the frequency of ASD is growing each year. Recent epidemiological studies have indicated that ASD may be caused or triggered by exposure to chemicals in the environment, such as those in the air or water. Thus, toxicological studies are needed to examine chemicals that might be implicated. However, the experimental efficiency of existing experimental models is limited, and many models represent challenges in terms of animal welfare. Thus, alternative ASD animal models are necessary. To address this, we examined the efficacy of the zebrafish embryo/larva as an alternative model of ASD. Specifically, we exposed zebrafish to valproic acid (0, 12.5, 25, 50, or 100 μM), which is a chemical known to induce autism-like effects. We then analysed subsequent developmental, behavioural, and transcriptomic changes. We found that 100 μM and 50 μM valproic acid decreased the hatching rate and locomotor activity of zebrafish embryos/larvae. Transcriptomic analysis revealed significant alterations in a number of genes associated with autism, such as adsl, mbd5, shank3, and tsc1b. Additionally, we found changes in gene ontology that were also reported in previous studies. Our findings indicate that zebrafish embryos/larvae and humans with ASD might have common physiological pathways, indicating that this animal model may represent an alternative tool for examining the causes of and potential treatments for this illness.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plausibility of the zebrafish embryos/larvae as an alternative animal model for autism: A comparison study of transcriptome changes

et al. 2018

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Duloxetine ameliorates valproicacid‐inducedhyperactivity, anxiety‐like behavior, and social interaction deficits in zebrafish

et al. 2021

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Syndromic autism spectrum disorders (ASDs) are characterized by impaired social communication and repetitive/stereotyped behaviors. Currently available therapeutic agents against ASD have limited efficacy. Thus, searching for novel and effective drugs ameliorating core symptoms, in particular social deficits, is of utmost importance. Duloxetine (DLX), an antidepressant that has been identified as an agonist mimetic for the cell adhesion molecule L1, exhibits beneficial functions in vitro and in vivo. Therefore, in this study, we focused on the rapid and persistent neuroprotective function of DLX following valproic acid (VPA)‐triggered hyperactivity, anxiety‐like behavior and social deficits in zebrafish. Embryonic exposure to VPA reduced survival in a dose‐ and time‐dependent manner, delayed hatching, and also resulted in a significant number of malformed larvae. After initial dose–response experiments in zebrafish larvae, 10 μM VPA exposure between 0.33 and 4.5 days post fertilization (dpf) was identified as an effective concentration that led to an early and persistent ASD‐like phenotype in zebrafish. ASD‐like elevated acetylcholine esterase (AChE) activity and reduced Akt–mTOR signaling was observed in zebrafish whole brain. Acute administration of DLX (4.5–6 dpf) reduced the VPA‐induced ASD‐like phenotype in zebrafish larvae. Additionally, such early‐life acute DLX treatment had long‐term effects in ameliorating social impairments, hyperactivity, and anxiety‐like behaviors through adulthood. This was accompanied by reduced AChE activity and by normalized Akt–mTOR signaling. Overall, DLX treatment showed a long‐term therapeutic effect on autistic‐like behaviors, and alteration of AChE activity and Akt–mTOR signaling were identified as crucial in the VPA‐induced ASD zebrafish model.

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Toxicity and teratogenicity effects of valproic acid on zebrafish (Danio rerio) embryos in relation to autism spectrum disorder

Saleh Hodin,

Chong,

Bakar

et al. 2023

Birth Defects Research

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Valproic acid (VPA) is a widely prescribed antiepileptic drug with various medicinal efficacies. Accumulated evidence implied that prenatal exposure to VPA is highly associated with autism spectrum disorder (ASD). In this study, the zebrafish were exposed to a set of VPA concentrations (0, 5, 10, 20, 40, 80, 160, 320, 640, 1280, and 2560 μM) at 5 h post fertilization (hpf) to 120 hpf. The adverse effects of VPA were extensively studied through the evaluations on the mortality, heartbeats, spontaneous tail coiling, and hatching rate. Morphological observations were conducted at 120 hpf, following the exposure termination. Basic locomotor responses and anxiety‐like behavioral alterations evaluated for behavioral impairments are the hallmark feature of ASD. The exposure to VPA at teratogenic concentrations reduced the aforementioned parameters in a dose‐dependent manner (p ≤ .05). At the selected non‐teratogenic concentrations of VPA, the treated larvae demonstrated profound alterations of basic locomotor responses. No significant changes of anxiety and thigmotactic behaviors were observed on the VPA‐treated fish compared to the control (p ≥ .005). This study depicted that embryonic zebrafish exposure to VPA produced significant toxicity and teratogenicity effects as well as the alterations of basic behavioral responses. Overall, this study provides a fundamental insight of the toxicity effects at morphological and behavioral levels to facilitate the understanding of ASD mechanisms at different molecular levels.

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Embryological exposure to valproic acid induces social interaction deficits in zebrafish (Danio rerio): A developmental behavior analysis

Cited by 70 publications

References 61 publications

Plausibility of the zebrafish embryos/larvae as an alternative animal model for autism: A comparison study of transcriptome changes

Plausibility of the zebrafish embryos/larvae as an alternative animal model for autism: A comparison study of transcriptome changes

Duloxetine ameliorates valproicacid‐inducedhyperactivity, anxiety‐like behavior, and social interaction deficits in zebrafish

Toxicity and teratogenicity effects of valproic acid on zebrafish (Danio rerio) embryos in relation to autism spectrum disorder

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