The effects of prenatal exposure to valproic acid on the initial development of serotonergic neurons

Oyabu, Akiko; Narita, Minoru; Tashiro, Yasura

doi:10.1016/j.ijdevneu.2013.01.006

Cited by 19 publications

(20 citation statements)

References 45 publications

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“…They found that the index could distinguish between neurotoxic and non-neurotoxic chemicals. Recently, Jacob et al used the antibody to label serotonergic neurons and revealed that serotonergic differentiation failed in a zebrafish model of fetal valproate syndrome (Jacob et al 2014), which is highly consistent with rodent models of fetal valproate syndrome (Miyazaki et al 2005;Kuwagata et al 2009;Oyabu et al 2013).…”

Section: Neuroimagingmentioning

confidence: 67%

Zebrafish as a systems toxicology model for developmental neurotoxicity testing

Nishimura

Murakami

Ashikawa

et al. 2015

Congenital Anomalies

166

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The developing brain is extremely sensitive to many chemicals. Exposure to neurotoxicants during development has been implicated in various neuropsychiatric and neurological disorders, including autism spectrum disorder, attention deficit hyperactive disorder, schizophrenia, Parkinson's disease, and Alzheimer's disease. Although rodents have been widely used for developmental neurotoxicity testing, experiments using large numbers of rodents are timeconsuming, expensive, and raise ethical concerns. Using alternative non-mammalian animal models may relieve some of these pressures by allowing testing of large numbers of subjects while reducing expenses and minimizing the use of mammalian subjects. In this review, we discuss some of the advantages of using zebrafish in developmental neurotoxicity testing, focusing on central nervous system development, neurobehavior, toxicokinetics, and toxicodynamics in this species. We also describe some important examples of developmental neurotoxicity testing using zebrafish combined with gene expression profiling, neuroimaging, or neurobehavioral assessment. Zebrafish may be a systems toxicology model that has the potential to reveal the pathways of developmental neurotoxicity and to provide a sound basis for human risk assessments.

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Section: Neuroimagingmentioning

confidence: 67%

Zebrafish as a systems toxicology model for developmental neurotoxicity testing

Nishimura

Murakami

Ashikawa

et al. 2015

Congenital Anomalies

166

View full text Add to dashboard Cite

show abstract

“…[47][48][49][50][51] A growing body of evidence suggests that the state-like and oscillatory interactions of gene products within and extending from the Shh signaling pathway (Figure 3), 49,50,52,53 and modulated by environmental factors, could constitute the basis for the wide range of phenotypic manifestations of BPAD. [54][55][56] Antidepressant drugs, 57 including lithium, 58 and electroconvulsive therapy 59 have been shown to alter Shh signaling. Glycogen synthase kinase 3 (GSK3; GSK3α/GSK3β) is a target of lithium and has a central role in Shh signaling.…”

Section: Discussionmentioning

confidence: 99%

Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder

et al. 2014

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Ellis-van Creveld syndrome, an autosomal recessively inherited chondrodysplastic dwarfism, is frequent among Old Order Amish of Pennsylvania. Decades of longitudinal research on bipolar affective disorder (BPAD) revealed cosegregation of high numbers of EvC and Bipolar I (BPI) cases in several large Amish families descending from the same pioneer. Despite the high prevalence of both disorders in these families, no EvC individual has ever been reported with BPI. The proximity of the EVC gene to our previously reported chromosome 4p16 BPAD locus with protective alleles, coupled with detailed clinical observations that EvC and BPI do not occur in the same individuals, led us to hypothesize that the genetic defect causing EvC in the Amish confers protection from BPI. This hypothesis is supported by a significant negative association of these two disorders when contrasted with absence of disease (P=0.029, Fisher's exact test, two-sided, verified by permutation to estimate the null distribution of the test statistic). As homozygous Amish EVC mutations causing EvC dwarfism do so by disrupting sonic hedgehog (Shh) signaling, our data implicate Shh signaling in the underlying pathophysiology of BPAD. Understanding how disrupted Shh signaling protects against BPI could uncover variants in the Shh pathway that cause or increase risk for this and related mood disorders.

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“…Interestingly, the s-allele of the 5-HTTLPR has also been associated with anxiety (Kenna et al, 2012 ) and cognitive deficits (Weiss et al, 2014 ), which are also prominent in patients with ASD, as mentioned above. Since prenatal valproate significantly affects serotonergic neurotransmission (Miyazaki et al, 2005 ; Oyabu et al, 2013 ), the present study investigates the potential interaction between valproate and a genetic reduction of the SERT. More specifically, we injected heterozygous SERT knock-out and wildtype rats prenatally with a moderate dose (400 mg/kg s.c.) of valproate and investigated the behavior of the offspring in two models for anxiety (elevated plus maze and novelty suppressed feeding) and two models assessing cognition and information processing (latent inhibition and prepulse inhibition).…”

Section: Introductionmentioning

confidence: 99%

Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition

2016

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There is ample evidence that prenatal exposure to valproate (or valproic acid, VPA) enhances the risk of developing Autism Spectrum Disorders (ASD). In line with this, a single injection of VPA induces a multitude of ASD-like symptoms in animals, such as rats and mice. However, there is equally strong evidence that genetic factors contribute significantly to the risk of ASD and indeed, like most other psychiatric disorders, ASD is now generally thought to results from an interaction between genetic and environmental factors. Given that VPA significantly impacts on the serotonergic system, and serotonin has strong biochemical and genetic links to ASD, we aimed to investigate the interaction between genetic reduction in the serotonin transporter and prenatal valproate administration. More specifically, we exposed both wildtype (SERT+/+) rats and rats heterozygous for the serotonin transporter deletion (SERT+/−) to a single injection of 400 mg/kg VPA at gestational day (GD) 12. The offspring, in adulthood, was assessed in four different tests: Elevated Plus Maze and Novelty Suppressed Feeding as measures for anxiety and prepulse inhibition (PPI) and latent inhibition as measures for cognition and information processing. The results show that prenatal VPA significantly increased anxiety in both paradigm, reduced PPI and reduced conditioning in the latent inhibition paradigm. However, we failed to find a significant gene–environment interaction. We propose that this may be related to the timing of the VPA injection and suggest that whereas GD12 might be optimal for affecting normal rat, rats with a genetically compromised serotonergic system may be more sensitive to VPA at earlier time points during gestation. Overall our data are the first to investigate gene * environmental interactions in a genetic rat model for ASD and suggest that timing may be of crucial importance to the long-term outcome.

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The effects of prenatal exposure to valproic acid on the initial development of serotonergic neurons

Cited by 19 publications

References 45 publications

Zebrafish as a systems toxicology model for developmental neurotoxicity testing

Zebrafish as a systems toxicology model for developmental neurotoxicity testing

Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder

Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition

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