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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    • "Cerebellar structural differences are associated with social and communication impairments as well as restricted interests and repetitive behaviors, the hallmarks of the ASD diagnosis, in both human studies (Pierce and Courchesne, 2001; Rojas et al., 2006; Riva et al., 2013; D'Mello et al., 2015) and animal models of ASD (Ingram et al., 2000; Brielmaier et al., 2012; Tsai et al., 2012). The cerebellar cortex was consistently abnormal in an analysis of over 26 mouse models of ASD (Ellegood et al., 2015), and cerebellar atrophy is characteristic of one of the most widely used animal models of ASD, the valproic acid model (Ingram et al., 2000). At the genetic level, genes implicated in ASD (e.g., SHANK3, EN2, RORA) are often involved in cerebellar development (see Rogers et al., 2013 for review). "
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    ABSTRACT: The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD.
    Frontiers in Neuroscience 11/2015; 9(110). DOI:10.3389/fnins.2015.00408 · 3.66 Impact Factor
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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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