Ingram JL, Peckham SM, Tisdale B, Rodier PM. Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 22: 319-324

Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, 14642, Rochester, NY, USA.
Neurotoxicology and Teratology (Impact Factor: 2.76). 05/2000; 22(3):319-24. DOI: 10.1016/S0892-0362(99)00083-5
Source: PubMed


Abnormalities in anatomy and function of the cranial nerve motor nuclei have been demonstrated in some people with autism and can be modeled in rats by exposure to valproic acid during neural tube closure. Reductions in Purkinje cell number and cerebellar volume, particularly of the posterior lobe, have also been reported in people with autism. Thus, a stereological examination of cerebellar morphology was undertaken in valproate-exposed rats. Compared to controls, rats exposed to a single dose of 600-mg/kg sodium valproate on embryonic day 12.5 had significantly fewer Purkinje cells in the cerebellar vermis and a reduction short of significant in the hemispheres. The diminished cell numbers reflect reductions in tissue volume throughout the cerebellum, rather than cell density, which was unaffected in all regions. Within the vermis, the reduction in volume was significantly greater in the posterior lobe than in the anterior lobe. The results parallel those reported for human cases of autism.

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    • "Purkinje cells in the posterior lobes of the cerebellum (Ingram et al., 2000). "
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    ABSTRACT: Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets.
    Behavioural pharmacology 09/2015; 26(6):522-540. DOI:10.1097/FBP.0000000000000163 · 2.15 Impact Factor
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    • "Single administration of VPA (600 mg/kg) on gestational day (GD) 12.5 shows abnormal pain sensitivity in the adulthood, which is similar to the human autistic patients [5] [14] [15]. Neuroanatomical disorder including a decreased number of neuron in the cranial nerve motor nuclei, cerebellar abnormality [16] and lower number of purkinje cells in the cerebellar vermis [17] in the offspring has been reported after the prenatal VPA administration on GD 12.5. "
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    ABSTRACT: Prenatal exposure to valproic acid on gestational day 12.5 may lead to the impaired behaviour in the offspring, which is similar to the human autistic symptoms. To the contrary, astaxanthin shows neuroprotective effect by its antioxidant mechanism. We aimed to (i) develop mice model of autism and (ii) investigate the effect of astaxanthin on such model animals. Valproic acid (600 mg/kg) was administered intraperitoneally to the pregnant mice on gestational day 12.5. Prenatal valproic acid-exposed mice were divided into 2 groups on postnatal day 25 and astaxanthin (2 mg/kg) was given to the experimental group (VPA_AST, n = 10) while saline was given to the control group (VPA, n = 10) for 4 weeks. Behavioural test including social interaction, open field and hot-plate were conducted on postnatal day 25 and oxidative stress markers such as lipid peroxidation, advanced protein oxidation product, nitric oxide, glutathione, and activity of superoxide dismutase and catalase were estimated on postnatal day 26 to confirm mice model of autism and on postnatal day 56 to assess the effect of astaxanthin. On postnatal day 25, prenatal valproic acid-exposed mice exhibited (i) delayed eye opening (ii) longer latency to respond painful stimuli, (iii) poor sociability and social novelty and (iv) high level of anxiety. In addition, an increased level of oxidative stress was found by determining different oxidative stress markers. Treatment with astaxanthin significantly (p < 0.05) improved the behavioural disorder and reduced the oxidative stress in brain and liver. In conclusion, prenatal exposure to valproic day in pregnant mice leads to the development of autism-like features. Astaxanthin improves the impaired behaviour in animal model of autism presumably by its antioxidant activity.
    Behavioural Brain Research 02/2015; 30. DOI:10.1016/j.bbr.2015.02.041 · 3.03 Impact Factor
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    • "Valproic acid, a common anticonvulsant, has a teratogenic effect when administered during pregnancy. Its application between gravidity days 11.5 and 12.5 affects the development of the central nervous system, leading to various neuroanatomical changes (Rodier et al., 1996, 1997; Ingram et al., 2000; Markram et al., 2008; Rinaldi et al., 2008; Sui and Chen, 2012) as well as changes in behaviour related to autistic symptoms (Schneider and Przewlocki, 2005; Dufour-Rainfray et al., 2010; Bambini-Junior et al., 2011; Foley et al., 2012; Sandhya et al., 2012). Studies on VPA rats have revealed alterations in various aspects of complex social behaviour . "
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    ABSTRACT: Autism is a neurodevelopmental disorder characterised by the disruption of social interactions. Autistic animal models play a crucial role in neurophysiologic research on this disorder. One of these models is based on rats that have been prenatally treated with valproic acid - VPA rats. The aim of our study performed with this model was to investigate changes in sociability and gene expression of neuropeptides and receptors involved in regulating social behaviour. We focused on gene expression in the hypothalamus, where the neuropeptides oxytocin (OT) and arginine-vasopressin (AVP) are produced, as well as oxytocin receptors (OTR) in certain neuronal structures involved in the creation of social abilities. Our research showed that VPA rats spent more time in the part with an unknown animal and less time in the central part of a three chamber sociability test apparatus than control animals. The latency period of VPA rats before initiating social contact was decreased. In addition, during weaning, VPA female rats spent more time in direct interaction with an unknown rat. We also found that adult VPA rats had an increased expression of OT in the hypothalamic supraoptic and paraventricular nuclei and of OTR in the medial prefrontal cortex, piriform cortex, cortex-amygdala transition zone and the region of the basolateral and basomedial amygdaloid nuclei compared with controls. To sum up, we observed that a single prenatal injection of VPA increased social behaviour and gene expression of OT and OTR in neurological structures connected with the social behaviour of rats. One unanticipated finding was the absence of one of the core symptoms of autism in VPA rats, suggesting a decreased ability to understand intraspecific communication signals. Copyright © 2015. Published by Elsevier Inc.
    Pharmacology Biochemistry and Behavior 02/2015; 131. DOI:10.1016/j.pbb.2015.01.021 · 2.78 Impact Factor
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