A New Neurobehavioral Model of Autism in Mice: Pre- and Postnatal Exposure to Sodium Valproate

Wagner, George C.; Reuhl, Kenneth R.; Cheh, Michelle A.; McRae, Paulette A.; Halladay, Alycia

doi:10.1007/s10803-006-0117-y

Cited by 229 publications

(185 citation statements)

References 53 publications

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“…Several case studies (Christianson et al, 1994;Williams and Hersh, 1997;Williams et al, 2001), as well as a population study (Moore et al, 2000), reported a link between the administration of the anticonvulsant drug VPA during pregnancy and the risk of giving birth to an autistic child. Although several rodent studies explored and established the teratogenic effects of prolonged VPA administration during pregnancy in general (Vorhees 1987a, b) and in the context of autism (Narita et al, 2002;Wagner et al, 2006), we chose the VPA rat model of autism proposed by Rodier et al (1996). This model focuses specifically at the time of neural tube closure on gestational day 12.5, which is believed to be a particularly vulnerable time point for insults that may produce autistic symptoms.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Fear Conditioning and Amygdala Processing in an Animal Model of Autism

Markram

Rinaldi

Mendola

et al. 2007

Neuropsychopharmacol

318

257

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A core feature of autism spectrum disorders is the impairment in social interactions. Among other brain regions, a deficit in amygdala processing has been suggested to underlie this impairment, but whether the amygdala is processing fear abnormally in autism, is yet not clear. We used the valproic acid (VPA) rat model of autism to (a) screen for autism-like symptoms in rats, (b) test for alterations in amygdala-dependent fear processing, and (c) evaluate neuronal reactivity and synaptic plasticity in the lateral amygdala by means of in vitro single-cell electrophysiological recordings. VPA-treated animals displayed several symptoms common to autism, among them impaired social interactions and increased repetitive behaviors. Furthermore, VPA-treated rats were more anxious and exhibited abnormally high and longer lasting fear memories, which were overgeneralized and harder to extinguish. On the cellular level, the amygdala was hyperreactive to electrical stimulation and displayed boosted synaptic plasticity as well as a deficit in inhibition. We show for the first time enhanced, overgeneralized and resistant conditioned fear memories in an animal model of autism. Such hyperfear could be caused by the hyperreactivity and hyperplasticity found in the lateral amygdala, which may in turn be due to a deficit in the inhibitory system of the amygdala. We hypothesize an 'aversive world' syndrome that could, even if not a primary cause of the disorder itself, underlie some core symptoms in autism, such as impairments in social interactions and resistance to rehabilitation.

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Section: Discussionmentioning

confidence: 99%

Abnormal Fear Conditioning and Amygdala Processing in an Animal Model of Autism

Markram

Rinaldi

Mendola

et al. 2007

Neuropsychopharmacol

318

257

View full text Add to dashboard Cite

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“…[31][32][33] Wagner and colleagues 34,35 investigated abnormalities in neonatal and juvenile mice relevant to neurodevelopmental disorders using sets of behavioral tasks for sensorimotor abilities, learning and memory, and other functional domains. The researchers utilized a test for juvenile play to reveal reduced social interaction in a genetic model for autism, the Engrailed 2 null mouse.…”

Section: Behavioral Phenotyping Of Mouse Modelsmentioning

confidence: 99%

“…253 In mice, exposure to valproic acid while in utero leads to behavioral retardation and regression during neonatal and juvenile development. 35 One hypothesis for the mechanism of teratogenic action for valproic acid is through effects on the expression of Hox (homeobox) genes. 232,254 These genes encode transcription factors that are important in regulating early development.…”

Section: Mouse Models Of Environmental Contributions To Autism Etiologymentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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“…Inbred mouse strains, transgenic mouse models and mice with prior teratogen exposure exhibit varying degrees of face and construct validity for one or more of the core deficits observed in ASD (Wagner et al, 2006;Silverman et al, 2010;Peça et al, 2011). Given that genomic variants likely account for 0.5-2% of total ASD cases (Pinto et al, 2010), we were interested to complement existing studies on animal models by determining the extent to which an environmental risk factor might provide face and construct validity.…”

Section: Introductionmentioning

confidence: 99%

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder

et al. 2012

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Publication information Neuropharmacology, 63 (4): 750-760Publisher Elsevier Item record/more information http://hdl.handle.net/10197/3779 Publisher's statementThis is the author's version of a work that was accepted for publication in Neuropharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuropharmacology (VOL 63, ISSUE4, (2012) inhibitor, has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). We have evaluated the face validity of this model in terms of social cognition deficits which are a major core symptom of ASD. We employed the social approach avoidance paradigm as a measure of social reciprocity, detection of biological motion that is crucial to social interactions, and spatial learning as an indicator of dorsal stream processing of social cognition and found each parameter to be significantly impaired in Wistar rats with prior in utero exposure to VPA. We found no significant change in the expression of neural cell adhesion molecule polysialylation state (NCAM PSA), a measure of construct validity, but a complete inability to increase its glycosylation state which is necessary to mount the neuroplastic response associated with effective spatial learning. Finally, in all cases, we found chronic HDAC inhibition, with either pan-specific or HDAC1-3 isoform-specific inhibitors, to significantly ameliorate deficits in both social cognition and its associated neuroplastic response. We conclude that in utero exposure to VPA provides a robust animal model for the social cognitive deficits of ASD and a potential screen for the development of novel therapeutics for this condition. 2 RUNNING TITLESocial deficit amelioration in rat autism model KEY WORDSHistone deacetylase; SAHA; MS-275; social interaction; biological motion; spatial learning; synaptic plasticity; NCAM PSA. ABBREVIATIONS

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A New Neurobehavioral Model of Autism in Mice: Pre- and Postnatal Exposure to Sodium Valproate

Cited by 229 publications

References 53 publications

Abnormal Fear Conditioning and Amygdala Processing in an Animal Model of Autism

Abnormal Fear Conditioning and Amygdala Processing in an Animal Model of Autism

Advances in behavioral genetics: mouse models of autism

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder

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