Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3β/β-catenin pathway

Go, Hyo Sang; Kim, Ki Chan; Choi, Chang Soon; Jeon, Se Jin; Kwon, Kyoung Ja; Han, Seol‐Heui; Lee, Jongmin; Cheong, Jae Hoon; Ryu, Jong Hoon; Kim, Chong-Hyun; Ko, Kwang Ho; Shin, Chan Young

doi:10.1016/j.neuropharm.2012.07.028

Cited by 95 publications

(87 citation statements)

References 68 publications

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“…In this way, Wnt signaling stimulates translation and cell growth by activating the TSC-mTOR pathway in cancer cells, myocardial cells and synapses. VPA exposure activated the WNT/GSK-3β/β-catenin pathway, and inhibition of this pathway attenuated the effects of VPA (Go et al, 2012). Consistent with these reports, inhibition of Wnt signaling by sulindac significantly decreases the levels of p-GSK3β and p-mTOR in VPA-exposed rats.…”

Section: Discussionsupporting

confidence: 82%

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

Qin

Dai

Yin

2016

Molecular and Cellular Neuroscience

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Section: Discussionsupporting

confidence: 82%

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

Qin

Dai

Yin

2016

Molecular and Cellular Neuroscience

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“…Glycogen synthase kinase 3 beta (GSK3β), which is regulated by Wnt/β-catenin signaling pathway, has an essential role in the regulation of neurogenesis wherein its overexpression is correlated with macrocephaly and VPA-induced ASD phenotypes2728. We isolated the neocortex in F1 and F3 mice fetus at embryonic day 14 and examined the expression of phosphorylated GSK3β (pGSK3β).…”

Section: Resultsmentioning

confidence: 99%

The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy

Choi

Gonzales

Kim

et al. 2016

Sci Rep

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106

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Autism spectrum disorder (ASD) is a heterogeneously pervasive developmental disorder in which various genetic and environmental factors are believed to underlie its development. Recently, epigenetics has been suggested as a novel concept for ASD aetiology with a proposition that epigenetic marks can be transgenerationally inherited. Based on this assumption of epigenetics, we investigated the transgenerational inheritance of ASD-like behaviours and their related synaptic changes in the VPA animal model of ASD. The first generation (F1) VPA-exposed offspring exhibited autistic-like impaired sociability and increased marble burying. They also showed increased seizure susceptibility, hyperactivity and decreased anxiety. We mated the VPA-exposed F1 male offspring with naïve females to produce the second generation (F2), and then similarly mated the F2 to deliver the third generation (F3). Remarkably, the autism-like behavioural phenotypes found in F1 persisted to the F2 and F3. Additionally, the frontal cortices of F1 and F3 showed some imbalanced expressions of excitatory/inhibitory synaptic markers, suggesting a transgenerational epigenetic inheritance. These results open the idea that E/I imbalance and ASD-like behavioural changes induced by environmental insults in mice can be epigenetically transmitted, at least, to the third generation. This study could help explain the unprecedented increase in ASD prevalence.

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“…Two notions support this assumption. For one, ex vivo NPCs seem to maintain their properties after taking them out of the whole organism, which was shown by compound effects in in vivo-ex vivo comparisons (Foti et al 2013;Go et al 2012;L'Episcopo et al 2013). Secondly, the 3D format of cultures with cell-cell communication and interaction supports physiological cellular functions and thus in vivo-relevant responses toward xenobiotics (Alépée et al 2014;Yamada and Cukierman 2007).…”

Section: Discussionmentioning

confidence: 99%

Comparative human and rat neurospheres reveal species differences in chemical effects on neurodevelopmental key events

et al. 2015

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The developing brain is highly vulnerable to the adverse effects of chemicals, resulting in neurodevelopmental disorders in humans. Currently, animal experiments in the rat are the gold standard for developmental neurotoxicity (DNT) testing; however, these guideline studies are insufficient in terms of animal use, time and costs and bear the issue of species extrapolation. Therefore, the necessity for alternative methods that predict DNT of chemicals faster, cheaper and with a high predictivity for humans is internationally agreed on. In this respect, we developed an in vitro model for DNT key event screening, which is based on primary human and rat neural progenitor cells grown as neurospheres. They are able to mimic basic processes of early fetal brain development and enable an investigation of species differences between humans and rodents in corresponding cellular models. The goal of this study was to investigate to what extent human and rat neurospheres were able to correctly predict the DNT potential of a well-characterized training set of nine chemicals by investigating effects on progenitor cell proliferation, migration and neuronal differentiation in parallel to cell viability, and to compare these chemical responses between human and rat neurospheres. We demonstrate that (1) by correlating these human and rat in vitro results to existing in vivo data, human and rat neurospheres classified most compounds correctly and thus may serve as a valuable component of a modular DNT testing strategy and (2) human and rat neurospheres differed in their sensitivity to most chemicals, reflecting toxicodynamic species differences of chemicals.

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Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3β/β-catenin pathway

Cited by 95 publications

References 68 publications

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy

Comparative human and rat neurospheres reveal species differences in chemical effects on neurodevelopmental key events

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