In utero exposure to valproic acid and autism — A current review of clinical and animal studies

doi:10.1016/J.NTT.2013.01.004

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In utero exposure to valproic acid and autism — A current review of clinical and animal studies

Journal Article•DOI•

In utero exposure to valproic acid and autism — A current review of clinical and animal studies

Florence I. Roullet¹, Jonathan Lai¹, Jane A. Foster¹•Institutions (1)

McMaster University¹

01 Mar 2013-Neurotoxicology and Teratology (Neurotoxicol Teratol)-Vol. 36, pp 47-56

TL;DR: A review of clinical studies that examined pregnancy outcomes of VPA use as well as the related animal studies that investigated anatomical, behavioral, molecular, and physiological outcomes related to in utero VPA exposure.

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About: This article is published in Neurotoxicology and Teratology.The article was published on 2013-03-01. It has received 334 citations till now. The article focuses on the topics: Autism.

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Journal Article•DOI•

The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis?

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Roman M. Stilling¹, Marcel van de Wouw¹, Gerard Clarke¹, Catherine Stanton¹, Timothy G. Dinan¹, John F. Cryan¹ - Show less +2 more•Institutions (1)

University College Cork¹

01 Oct 2016-Neurochemistry International

TL;DR: A critical review of the literature on butyrate and its effects on multiple aspects of host physiology with a focus on brain function and behaviour is provided and it is hypothesised that butyrates and other volatile SCFAs produced by microbes may be involved in regulating the impact of the microbiome on behaviour including social communication.

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512 citations

Cites background from "In utero exposure to valproic acid ..."

...In addition, high doses of the monocarboxylic HDAC inhibitors propionate or valproate, administered either systemically to the mother during pregnancy or intraventricular in adulthood were repeatedly shown to induce autistic-like symptoms in animal models (Chomiak et al., 2013; Macfabe, 2012; MacFabe et al., 2011, 2007; Roullet et al., 2013; Thomas et al., 2012), suggesting extreme care has to be given to evaluation of the potential use of SCFAs in treatment of ASDs....
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Journal Article•DOI•

The bowel and beyond: the enteric nervous system in neurological disorders

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Meenakshi Rao¹, Michael D. Gershon¹•Institutions (1)

Columbia University¹

01 Sep 2016-Nature Reviews Gastroenterology & Hepatology

TL;DR: Evidence for ENS dysfunction is reviewed in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease, and animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions.

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Abstract: The enteric nervous system (ENS) is large, complex and uniquely able to orchestrate gastrointestinal behaviour independently of the central nervous system (CNS). An intact ENS is essential for life and ENS dysfunction is often linked to digestive disorders. The part the ENS plays in neurological disorders, as a portal or participant, has also become increasingly evident. ENS structure and neurochemistry resemble that of the CNS, therefore pathogenic mechanisms that give rise to CNS disorders might also lead to ENS dysfunction, and nerves that interconnect the ENS and CNS can be conduits for disease spread. We review evidence for ENS dysfunction in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease. Animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions. Moreover, the neurotropic pathogen, varicella zoster virus (VZV), unexpectedly establishes latency in enteric and other autonomic neurons that do not innervate skin. VZV reactivation in these neurons produces no rash and is therefore a clandestine cause of gastrointestinal disease, meningitis and strokes. The gut-brain alliance has raised consciousness as a contributor to health, but a gut-brain axis that contributes to disease merits equal attention.

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374 citations

Journal Article•DOI•

Altered gut microbiota and activity in a murine model of autism spectrum disorders.

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Caroline G M de Theije¹, Harm Wopereis², Mohamed Ramadan¹, Tiemen van Eijndthoven, Jolanda Lambert, Jan Knol², Johan Garssen¹, Aletta D. Kraneveld¹, Raish Oozeer - Show less +5 more•Institutions (2)

Utrecht University¹, Wageningen University and Research Centre²

01 Mar 2014-Brain Behavior and Immunity

TL;DR: Findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring, which open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation.

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Abstract: Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders with evidence of genetic predisposition. Intestinal disturbances are reported in ASD patients and compositional changes in gut microbiota are described. However, the role of microbiota in brain disorders is poorly documented. Here, we used a murine model of ASD to investigate the relation between gut microbiota and autism-like behaviour. Using next generation sequencing technology, microbiota composition was investigated in mice in utero exposed to valproic acid (VPA). Moreover, levels of short chain fatty acids (SCFA) and lactic acid in caecal content were determined. Our data demonstrate a transgenerational impact of in utero VPA exposure on gut microbiota in the offspring. Prenatal VPA exposure affected operational taxonomic units (OTUs) assigned to genera within the main phyla of Bacteroidetes and Firmicutes and the order of Desulfovibrionales, corroborating human ASD studies. In addition, OTUs assigned to genera of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis were especially associated with male VPA-exposed offspring. The microbial differences of VPA in utero-exposed males deviated from those observed in females and was (i) positively associated with increased levels of caecal butyrate as well as ileal neutrophil infiltration and (ii) inversely associated with intestinal levels of serotonin and social behaviour scores. These findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring. These results open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation.

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333 citations

Journal Article•DOI•

The valproic acid-induced rodent model of autism.

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Chiara Nicolini¹, Margaret Fahnestock¹•Institutions (1)

McMaster University¹

01 Jan 2018-Experimental Neurology

TL;DR: The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics, highlighting its importance and reliability as an environmentally-induced animal model of autism.

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314 citations

Journal Article•DOI•

Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition.

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William Mandy¹, Meng-Chuan Lai•Institutions (1)

University College London¹

01 Mar 2016-Journal of Child Psychology and Psychiatry

TL;DR: Future investigations should consider the specificity of risks for ASC versus other atypical neurodevelopmental trajectories, timing of risk and protective mechanisms, animal model systems to study mechanisms underlying gene-environment interplay, and longitudinal studies to elucidate how rGE plays out over time.

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Abstract: Background Although autism spectrum condition (ASC) is strongly genetic in origin, accumulating evidence points to the critical roles of various environmental influences on its emergence and subsequent developmental course. Methods A developmental psychopathology framework was used to synthesise literature on environmental factors associated with the onset and course of ASC (based on a systematic search of the literature using PubMed, PsychInfo and Google Scholar databases). Particular emphasis was placed on gene–environment interplay, including gene–environment interaction (G × E) and gene–environment correlation (rGE). Results Before conception, advanced paternal and maternal ages may independently enhance offspring risk for ASC. Exogenous prenatal risks are evident (e.g. valproate and toxic chemicals) or possible (e.g. selective serotonin reuptake inhibitors), and processes endogenous to the materno-foeto-placental unit (e.g. maternal diabetes, enhanced steroidogenic activities and maternal immune activation) likely heighten offspring vulnerability to ASC. Folate intake is a prenatal protective factor, with a particular window of action around 4 weeks preconception and during the first trimester. These prenatal risks and protective mechanisms appear to involve G × E and potentially rGE. A variety of perinatal risks are related to offspring ASC risk, possibly reflecting rGE. Postnatal social factors (e.g. caregiver–infant interaction, severe early deprivation) during the first years of life may operate through rGE to influence the likelihood of manifesting a full ASC phenotype from a ‘prodromal’ phase (a proposal distinct to the discredited and harmful ‘refrigerator mother hypothesis’); and later postnatal risks, after the full manifestation of ASC, shape life span development through transactions mediated by rGE. There is no evidence that vaccination is a postnatal risk for ASC. Conclusions Future investigations should consider the specificity of risks for ASC versus other atypical neurodevelopmental trajectories, timing of risk and protective mechanisms, animal model systems to study mechanisms underlying gene–environment interplay, large-sample genome–envirome designs to address G × E and longitudinal studies to elucidate how rGE plays out over time. Clinical and public health implications are discussed.

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186 citations

Cites background from "In utero exposure to valproic acid ..."

...The case for in utero valproate as a causal risk factor for ASC has been strengthened by its use to create one of the most influential animal models of the condition: rats and mice exposed to it in utero show a profile of behavioural features that may correspond to the social, communication and flexibility difficulties seen in humans with ASC (Roullet et al., 2013)....
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...In utero valproate exposure in humans is associated with an array of neurodevelopmental atypicalities beyond ASC, including attention-deficit/hyperactivity disorder (ADHD), dyspraxia and low IQ (Roullet et al., 2013)....
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...…strengthened by its use to create one of the most influential animal models of the condition: rats and mice exposed to it in utero show a profile of behavioural features that may correspond to the social, communication and flexibility difficulties seen in humans with ASC (Roullet et al., 2013)....
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References

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Journal Article•DOI•

Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells

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Martin Göttlicher, Saverio Minucci¹, Ping Zhu, Oliver H. Krämer, Annemarie Schimpf, Sabrina Giavara¹, Jonathan P. Sleeman, Francesco Lo Coco², Clara Nervi², Pier Giuseppe Pelicci¹, Thorsten Heinzel - Show less +7 more•Institutions (2)

European Institute of Oncology¹, Sapienza University of Rome²

17 Dec 2001-The EMBO Journal

TL;DR: Valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients, and tumor growth and metastasis formation are significantly reduced in animal experiments, suggesting that it might serve as an effective drug for cancer therapy.

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Abstract: Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.

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1,785 citations

"In utero exposure to valproic acid ..." refers background in this paper

...In vitro, VPA increased histone H4 acetylation (AcH4) in a dose-dependent manner in several types of transformed cells (Gottlicher et al., 2001)....
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Journal Article•DOI•

Epidemiological surveys of autism and other pervasive developmental disorders: an update.

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Eric Fombonne¹•Institutions (1)

Montreal Children's Hospital¹

01 Aug 2003-Journal of Autism and Developmental Disorders

TL;DR: There is evidence that changes in case definition and improved awareness explain much of the upward trend of rates in recent decades, however, available epidemiological surveys do not provide an adequate test of the hypothesis of a changing incidence of PDDs.

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Abstract: This paper was commissioned by the committee on the Effectiveness of Early Education in Autism of the National Research Council (NRC). It provides a review of epidemiological studies of pervasive developmental disorders (PDD) which updates a previously published article (The epidemiology of autism: a review. Psychological Medicine 1999; 29: 769–786). The design, sample characteristics of 32 surveys published between 1966 and 2001 are described. Recent surveys suggest that the rate for all forms of PDDs are around 30/10,000 but more recent surveys suggest that the estimate might be as high as 60/10,000. The rate for Asperger disorder is not well established, and a conservative figure is 2.5/10,000. Childhood disintegrative disorder is extremely rare with a pooled estimate across studies of 0.2/10,000. A detailed discussion of the possible interpretations of trends over time in prevalence rates is provided. There is evidence that changes in case definition and improved awareness explain much of the upward trend of rates in recent decades. However, available epidemiological surveys do not provide an adequate test of the hypothesis of a changing incidence of PDDs.

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1,607 citations

"In utero exposure to valproic acid ..." refers background in this paper

...This finding has clinical relevance as it aimed to better understand the basis for the male:female imbalanced ratio in autism (Fombonne, 2003)....
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Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008

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Jon Baio

30 Mar 2012

TL;DR: This report provides updated ASD prevalence estimates from the 2008 surveillance year, representing 14 ADDM areas in the United States and characteristics of the population of children with ASDs are described, as well as detailed comparisons of the 2008 findings with those for the 2002 and 2006 surveillance years.

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Abstract: According to this report, autism spectrum disorders (ASDs) are characterised by impairments in social interaction and communication and by restricted, repetitive, and stereotyped patterns of behaviour and symptoms are typically apparent before the age of three. The complex nature of these disorders, coupled with a lack of biologic markers for diagnosis and changes in clinical definitions over time, creates challenges in monitoring the prevalence of ASDs. Accurate reporting of data is essential to understand the prevalence of ASDs in the population and can help direct research. The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance system that estimates the prevalence of ASDs and describes other characteristics among children aged 8 years whose parents or guardians reside within 14 ADDM sites in the United States. This report focuses on the prevalence of ASDs in 2008.

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1,564 citations

Journal Article•DOI•

Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice

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Sheryl S. Moy¹, Jessica J. Nadler¹, Antonio Perez¹, Ryan P. Barbaro¹, Josephine M. Johns, Terry Magnuson², Terry Magnuson¹, Joseph Piven², Jacqueline N. Crawley³, Jacqueline N. Crawley¹ - Show less +6 more•Institutions (3)

University of North Carolina at Chapel Hill¹, Center for Autism and Related Disorders², National Institutes of Health³

01 Oct 2004-Genes, Brain and Behavior

TL;DR: A new standardized procedure to quantitate sociability and preference for social novelty in mice provides a method to assess tendencies for social avoidance in mouse models of autism.

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Abstract: Deficits in social interaction are important early markers for autism and related neurodevelopmental disorders with strong genetic components. Standardized behavioral assays that measure the preference of mice for initiating social interactions with novel conspecifics would be of great value for mutant mouse models of autism. We developed a new procedure to assess sociability and the preference for social novelty in mice. To quantitate sociability, each mouse was scored on measures of exploration in a central habituated area, a side chamber containing an unfamiliar conspecific (stranger 1) in a wire cage, or an empty side chamber. In a secondary test, preference for social novelty was quantitated by presenting the test mouse with a choice between the first, now-familiar, conspecific (stranger 1) in one side chamber, and a second unfamiliar mouse (stranger 2) in the other side chamber. Parameters scored included time spent in each chamber and number of entries into the chambers. Five inbred strains of mice were tested, C57BL/6J, DBA/2J, FVB/NJ, A/J and B6129PF2/J hybrids. Four strains showed significant levels of sociability (spend- ing more time in the chamber containing stranger 1 than in the empty chamber) and a preference for social novelty (spending more time in the chamber containing stranger 2 than in the chamber containing the now-familiar stranger 1). These social preferences were observed in both male and female mice, and in juveniles and adults. The exception was A/J, a strain that demonstrated a preference for the central chamber. Results are discussed in terms of potential applications of the new methods, and the proper controls for the interpretation of social behavior data, including assays for health, relevant sensory abilities and motor functions. This new standardized procedure to quantitate sociability and preference for social novelty in mice provides a method to assess tendencies for social avoidance in mouse models of autism.

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1,232 citations

"In utero exposure to valproic acid ..." refers methods in this paper

...a Three chamber social behavior apparatus is an established tool for testing sociability and social novelty (Moy et al., 2004); for sociability test, chamber 1 contains a stranger mouse or rat in an inverted cup, the center chamber is empty, and chamber 2 contains an empty inverted cup; for social novelty, chamber 1 contains a familiar mouse or rat in an inverted cup, the center chamber is empty, and chamber 2 contains a stranger mouse or rat in an inverted cup....
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...− Gandal et al. (2010) a Three chamber social behavior apparatus is an established tool for testing sociability and social novelty (Moy et al., 2004); for sociability test, chamber 1 contains a stranger mouse or rat in an inverted cup, the center chamber is empty, and chamber 2 contains an empty…...
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Journal Article•DOI•

Behavioral alterations in rats prenatally exposed to valproic acid: Animal model of autism

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Tomasz Schneider¹, R. Przewlocki², R. Przewlocki¹•Institutions (2)

Polish Academy of Sciences¹, Jagiellonian University²

01 Jan 2005-Neuropsychopharmacology

TL;DR: Interestingly, all behavioral aberrations described in this paper appear before puberty, which could distinguish the VPA rat model of autism from other animal models of neurodevelopmental disorders, especially rodent models of schizophrenia.

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743 citations

"In utero exposure to valproic acid ..." refers background in this paper

...+ Schneider and Przewlocki (2005) and Schneider et al. (2008) t2:6 Adult rats placed in a three-chamber apparatusa VPA rats spent more time in the empty chamber, but did not otherwise show any signs of social behavior deficits....
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...5–12.5 P11 Reduced number of cranial motor neurons in VPA-treated Rodier et al. (1996) t3:9 400 mg/kg t3:10 Sprague Dawley rat E7, E9....
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...Several publications have examined the impact of in utero exposure to VPA on social behavior and stereotypic behaviors (Kataoka et al., 2011; Markram et al., 2008; Roullet et al., 2010; Schneider and Przewlocki, 2005)....
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...Another study (Markram et al., 2008) has reported deficits in social interactions and increased stereotypic behaviors in the Y maze in VPA-treated rats (500 mg/kg)....
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...5 Postnatal and adult time points Autistic-like behaviors in VPA-treated Enrichment reduced autistic-like behaviors in VPA-treated Schneider and Przewlocki (2005) and Schneider et al. (2006) t3:22 C57BL/6 mice E13 P0–P70 Reduced postnatal and adult USVs, reduced social preference, increased self-grooming, and deficits in pre-pulse inhibition in VPA-treated Gandal et al. (2010) t3:23 6 wk+ Increased repetitive behaviors and reduced center entries in the open field in VPA-treated mGluR5-receptor antagonist treatment reduced repetitive behaviors but did not affect open field behavior Mehta et al. (2011) t3:24 800 mg/kg t3:25 Heterogeneous Strain 1 mice E11 P9–P25 Developmental delay in eye opening and olfactory discrimination, reduced social interaction in VPA-treated Roullet et al. (2010) t3:26 P60 Reduced levels of brain derived neurotrophic factor in somatosensory cortex in VPA-treated Reduced levels of neuroligin 3 in hippocampus and somatosensory cortex in VPA-treated Kolozsi et al. (2009) and Roullet et al. (2010) t3:27 Sprague Dawley rat E9 P50 Reduced monoamine levels in brain tissue from VPA-treated Narita et al. (2002) t3:28 5–14 wk Subtle differences in radial arm maze and open field test; no difference in social behavior Narita et al. (2010) t3:29 Wistar rat E9 P7, P12 P63–80 Increased righting time P12 in VPA-treated Elevated basal dopamine levels and increase DA during swim stress in VPA-treated Nakasato et al. (2008) t3:30 P28–43 Hyperactivity in a novel environment, disruptions in circadian rhythm, and increased levels of serotonin in frontal cortex in VPA-treated Tsujino et al. (2007) t3:31 Other t3:32 Wistar rat 470 or 720 mg/kg throughout gestation P15–70 Reduced latency geotaxis, increased activity in open field at P15 in 470 mg/kg VPA-treated Reduced latency to fall from rotorod, increased time in Morris Water Maze probe trial, and reduced cortical volume in 720 mg/kg VPA-treated with correlation of probe trial and brain volume Frisch et al. (2009) t3...
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