Embryonic exposure to valproic acid affects the histaminergic system and the social behaviour of adult zebrafish (<scp><i>Danio rerio</i></scp>)

Baronio, Diego; Puttonen, Henri; Sundvik, Maria; Semenova, Svetlana; Lehtonen, Essi; Panula, Pertti

doi:10.1111/bph.14124

Cited by 50 publications

(69 citation statements)

References 63 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to several reports on the effect of VPA on the serotonergic system, studies on zebrafish have shown that VPA treatment also affects key genes in other monoaminergic systems, in particular dopamine [ 19 ]. We thus analyzed genes involved in dopamine synthesis and metabolism in zebrafish larvae from the two different strains treated with our administration regimens (1 µM VPA for 24 or 48 h).…”

Section: Resultsmentioning

confidence: 99%

“…The discrepancy among our study and previous studies that did not report neurotoxic effect of VPA at higher concentrations, may be explained by the genetic differences of the inbred strains used in the studies. Zimmermann et al [ 15 ] did not report the strain of the animals used in their study, while Baronio et al [ 19 ] used the Turku strain. This study reported a high mortality rate (above 50%) in larvae treated with 50 µM, a high level of deformities and arrested development using 35 µM VPA, while no significant effects on mortality were reported by 25 µM VPA treatment [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Zimmermann et al [ 15 ] did not report the strain of the animals used in their study, while Baronio et al [ 19 ] used the Turku strain. This study reported a high mortality rate (above 50%) in larvae treated with 50 µM, a high level of deformities and arrested development using 35 µM VPA, while no significant effects on mortality were reported by 25 µM VPA treatment [ 19 ]. Our data is also supported by Li et al [ 22 ], who used a mixed AB-TU strain.…”

Section: Discussionmentioning

confidence: 99%

“…Histone deacetylases (HDACs) inhibition mediated by VPA has also been shown to directly inhibit ascl1b expression, causing the selective failure of serotonergic identity [ 18 ], a reduction of histaminergic neurons, changes in the expression of key genes of other monoaminergic systems, including dopamine, and decreased adult brain levels of noradrenaline and dopamine metabolites [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Micromolar Valproic Acid Doses Preserve Survival and Induce Molecular Alterations in Neurodevelopmental Genes in Two Strains of Zebrafish Larvae

et al. 2020

View full text Add to dashboard Cite

Autism spectrum disorders (ASDs) comprise a genetically heterogeneous group of conditions characterized by a multifaceted range of impairments and multifactorial etiology. Epidemiological studies have identified valproic acid (VPA), an anticonvulsant used to treat epilepsy, as an environmental factor for ASDs. Based on these observations, studies using embryonic exposure to VPA have been conducted in many vertebrate species to model ASD. The zebrafish is emerging as a popular model in biomedical research to study the molecular pathways involved in nervous system disorders. VPA exposure in zebrafish larvae has been shown to produce a plethora of effects on social, motor and anxiety behavior, and several genetic pathways altered by VPA have been described. However, the doses and regimen of administration reported in the literature are very heterogenous, creating contradictory results and posing serious limits to the interpretation of VPA action on neurodevelopment. To shed light on the toxic effect of VPA, we tested micromolar concentrations of VPA, using exposure for 24 and 48 h in two different zebrafish strains. Our results show that micromolar doses of VPA mildly affect embryo survival but are sufficient to induce molecular alterations in neurodevelopmental genes previously shown to be influenced by VPA, with substantial differences between strains.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Micromolar Valproic Acid Doses Preserve Survival and Induce Molecular Alterations in Neurodevelopmental Genes in Two Strains of Zebrafish Larvae

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Interestingly, the old-generation H3R antagonist ciproxifan attenuates at least some sociability deficits and stereotypies present in the animal model of autism induced by valproic acid (VPA) 1 . Notably, embryonic exposure to VPA causes several molecular and neurochemical changes in zebrafish, which continue into adulthood and accompany impaired sociability, demonstrating the possible association between brain histaminergic system and the outcomes related to neuropsychiatric disorders 20 . In the postmortem dorsolateral prefrontal cortex of 13 human subjects with ASD, significant alterations in the expression of key histamine genes, including all HR subtypes H1-4Rs, have been observed, signifying the involvement of modulated histaminergic signaling in the brain of ASD subjects 21 .…”

Section: Introductionmentioning

confidence: 99%

The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism

Eissa

Jayaprakash

Azimullah

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests. Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of different brain disorders, e.g., cognitive impairments. Therefore, the effects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15 mg/kg, i.p.) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, i.p.) were evaluated using the three-chamber test (TCT), marble burying test (MBT), nestlet shredding test (NST), and elevated plus maze (EPM) test. The results showed that VPA-exposed mice exhibited significantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15 mg/kg, i.p.). VPA-exposed mice presented a significantly higher percentage of buried marbles in MBT and shredded nestlet significantly more in NST compared to the control groups. However, VPA-exposed animals pretreated with DL77 (10 or 15 mg/kg, i.p.) buried a reduced percentage of marbles in MBT and presented a significantly lower percentage of shredding behavior in NST. On the other hand, pretreatment with DL77 (5, 10, or 15 mg/kg, i.p.) failed to restore the disturbed anxiety levels and hyperactivity observed in VPA-exposed animals in EPM, whereas the reference drug donepezil (DOZ, 1 mg/kg, i.p.) significantly palliated the anxiety and reduced the hyperactivity measures of VPA-exposed mice. Furthermore, pretreatment with DL77 (10 or 15 mg/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinflammatory cytokines IL-1β, IL-6 and TNF-α exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue. Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an effective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data.

show abstract

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Embryonic exposure to valproic acid affects the histaminergic system and the social behaviour of adult zebrafish (Danio rerio)

Cited by 50 publications

References 63 publications

Micromolar Valproic Acid Doses Preserve Survival and Induce Molecular Alterations in Neurodevelopmental Genes in Two Strains of Zebrafish Larvae

Micromolar Valproic Acid Doses Preserve Survival and Induce Molecular Alterations in Neurodevelopmental Genes in Two Strains of Zebrafish Larvae

The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism

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

Contact Info

Product

Resources

About