Perinatal Influences of Valproate on Brain and Behaviour: An Animal Model for Autism

Ranger, Peter; Ellenbroek, Bart A.

doi:10.1007/7854_2015_404

Cited by 38 publications

(43 citation statements)

References 126 publications

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“…Our data support this hypothesis in an animal model, showing a suppression of predisposed preferences to dynamic as well as static cues to social stimuli in domestic chicks exposed to VPA, a drug used to induce ASD-like behavioral deficits in vertebrate species (Ranger and Ellenbroek, 2016). The observation of a similar impairment in predispositions in different species for both static and dynamic cues suggests a common developmental origin of these social-orienting predispositions.…”

Section: Discussionsupporting

confidence: 84%

Embryonic Exposure to Valproic Acid impairs Social Predispositions for Dynamic Cues of Animate Motion in Newly-Hatched Chicks

Lorenzi

Pross

Rosa‐Salva

et al. 2018

Preprint

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Predispositions to preferentially orient towards cues associated with social partners, such as face-like stimuli or biological and animate motion, appear to guide social behavior from the onset of life. These predispositions have been documented in several vertebrate species including human neonates, young monkeys and newly-hatched domestic chicks. Human newborns at high familiar risk of Autism Spectrum Disorder (ASD) show a remarkable deficit in their attention toward these predisposed stimuli, either static and dynamic, compared to newborns at low risk. A previous study showed that prenatal exposure to valproic acid (VPA) (that in humans increases the risk of developing ASD) impairs the chicks' predisposition to approach naturalistic social stimuli that convey static configurations of features (a stuffed hen), without impairing general cognitive and learning abilities. Here we investigated the effect of VPA exposure on another class of social predispositions, i.e. the spontaneous preference to approach self-propelled objects, namely objects that display autonomous changes in speed. We observed that the preference for stimuli displaying autonomous changes in speed was impaired in VPA-compared to vehicle-injected chicks. Our results indicate an effect of VPA on the development of predisposed orienting mechanisms towards dynamic stimuli, that could be used to investigate the molecular and neurobiological mechanisms underlying ASD early symptoms.

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Section: Discussionsupporting

confidence: 84%

Embryonic Exposure to Valproic Acid impairs Social Predispositions for Dynamic Cues of Animate Motion in Newly-Hatched Chicks

Lorenzi

Pross

Rosa‐Salva

et al. 2018

Preprint

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“…For instance, in one of the most recent, large-scale, population-based studies conducted in Denmark, 4.4% of individuals prenatally exposed to VPA developed ASD, compared to 1.5% of controls not exposed to VPA - indicating a near 3-fold increased risk for ASD in those prenatally exposed to VPA (Christensen et al, 2013 ). In line with these findings, studies in rats and mice have shown that prenatal exposure of VPA [usually a single injection on gestational day (GD) 12] induces increases in repetitive behaviors and disruptions of social behavior (Schneider and Przewlocki, 2005 ; Ranger and Ellenbroek, 2015 ).…”

Section: Introductionmentioning

confidence: 85%

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

2016

Self Cite

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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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“…Although VPA is well tolerated and safe in adults, there is evidence of its teratogenicity [14]. Clinical studies over the years have shown that intrauterine exposure to VPA is associated with birth defects, cognitive impairments, and an increased risk of autism [13].…”

Section: Vpa and The Vpa Animal Modelmentioning

confidence: 99%

“…The compound VPA is a drug widely used as an anticonvulsant and mood stabilizer in the treatment of epilepsy and bipolar disorder [13,14]. Although VPA is well tolerated and safe in adults, there is evidence of its teratogenicity [14].…”

Section: Vpa and The Vpa Animal Modelmentioning

confidence: 99%

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Deckmann

Schwingel

Fontes-Dutra

et al. 2018

Neuroimmunomodulation

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Autism spectrum disorder (ASD) is a highly prevalent developmental disorder characterized by deficits in communication and social interaction and in stereotyped or repetitive behaviors. Besides the classical behavioral dyad, several comorbidities are frequently present in patients with ASD, such as anxiety, epilepsy, sleep disturbances, and gastrointestinal tract dysfunction. Although the etiology of ASD remains unclear, there is supporting evidence for the involvement of both genetic and environmental factors. Valproic acid (VPA) is an anticonvulsant and mood stabilizer that, when used during the gestational period, increases the risk of ASD in the offspring. The animal model of autism induced by prenatal exposure to VPA demonstrates important structural and behavioral features that can be observed in individuals with autism; it is thus an excellent tool for testing new drug targets and developing novel behavioral and drug therapies. In addition, immunological alterations during pregnancy could affect the developing embryo because immune molecules can pass through the placental barrier. In fact, exposure to pathogens during the pregnancy is a known risk factor for ASD, and maternal immune activation can lead to autistic-like features in animals. Interestingly, neuroimmune alterations are common in both autistic individuals and in animal models of ASD. We summarize here the important alterations in inflammatory markers, such as cytokines and chemokines, in patients with ASD and in the VPA animal model.

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Perinatal Influences of Valproate on Brain and Behaviour: An Animal Model for Autism

Cited by 38 publications

References 126 publications

Embryonic Exposure to Valproic Acid impairs Social Predispositions for Dynamic Cues of Animate Motion in Newly-Hatched Chicks

Embryonic Exposure to Valproic Acid impairs Social Predispositions for Dynamic Cues of Animate Motion in Newly-Hatched Chicks

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

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

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