Autism spectrum disorders: Integration of the genome, transcriptome and the environment

Vijayakumar, N. Thushara; Judy, M. V.

doi:10.1016/j.jns.2016.03.026

Cited by 50 publications

(34 citation statements)

References 133 publications

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“…Recent studies highlight a link between immune dysfunction and behavioral impairments [105]. For example, the relation between IL-6 and several altered behaviors has already been established in the literature [106][107][108].…”

Section: Neuroimmune Alterations In Asd: From Patients To the Vpa Animentioning

confidence: 98%

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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Section: Neuroimmune Alterations In Asd: From Patients To the Vpa Animentioning

confidence: 98%

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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“…Twin studies indicate that ASD is highly heritable (Hallmayer et al, 2011) and research suggests that familial history of autoimmune diseases like rheumatoid arthritis, celiac disease, and type-1 diabetes increase the risk for an ASD diagnosis (Atladottir et al, 2009). However, the hundreds of genes linked to predisposition and the wide variation in the genomic pattern from individual to individual has made it difficult to identify a distinct genetic marker (Vijayakumar and Judy, 2016). Consequently, research is looking beyond exclusively genetic origins of ASD and considering environmental influences, particularly the connection to immune system perturbations.…”

Section: 0 Introductionmentioning

confidence: 99%

Behavioral impact of maternal allergic-asthma in two genetically distinct mouse strains

Schwartzer

Careaga

Coburn

et al. 2017

Brain, Behavior, and Immunity

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Recent population-based studies of expecting mothers identified a unique profile of immune markers that are associated with an increased risk of having a child diagnosed with autism spectrum disorder (ASD). This immune profile, including increased levels of maternal and placental interleukin (IL)-4 and IL-5, is consistent with an immune response found in an allergic-asthma phenotype. Allergies and asthma reflect an imbalance in immune responses including polarization towards T-helper type 2 (TH2) responses, with both genetic susceptibility and environmental factors affecting this T-cell polarization. Mouse strains provide a known and controlled source of genetic diversity to explore the role of genetic predisposition on environmental factors. In particular, the FVB background exhibits a skew towards TH2-mediated allergic-asthma response in traditional models of asthma whereas the C57 strain exhibits a more blunted TH2 polarized phenotype resulting in an attenuated allergic-asthma response. C57BL/6J (C57) and the sighted FVB.129P2-Pde6b(+) Tyr(c-ch)/Ant (FVB/Ant) lines were selected based on their characteristic high sociability and differing sensitivity to TH2-mediated stimuli. Based on the distinct allergy-sensitive immune responses of these two strains we hypothesized that unique developmental consequences would occur in offspring following maternal allergy-asthma exposure. Female C57 and FVB/Ant dams were primed/sensitized with an exposure to ovalbumin (OVA) before pregnancy, then exposed to either aerosolized OVA or PBS-vehicle throughout gestation. Sera from pregnant dams were analyzed for changes in cytokine profiles using multiplex-arrays and offspring were assessed for changes in autism-like behavioral responses. Analysis of maternal sera revealed elevated IL-4 and IL-5 in OVA-treated dams of both strains but only C57 mice expressed increased levels of IL-1β, IL-6, TNFα, and IL-17. Behavioral assessments revealed strain-dependent changes in juvenile reciprocal social interaction in offspring of maternal allergic asthma dams. Moreover, mice of both strains showed decreased repetitive grooming and increased marble burying behavior when born to OVA-exposed dams. Together, these findings support the important role genetic predisposition plays in the effects of maternal immune activation and underscore differences in ASD-like behavioral outcomes across mouse strains.

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“…First, direct alterations in epigenetic pathways can dramatically alter early embryonic and neonatal neurodevelopment in the same critical periods as autism-associated changes in the brain [5]. Second, mutations in indirect epigenetic effectors can result in autism-spectrum and related disorders, such as Rett syndrome, Fragile X syndrome, and Angelman syndrome [6]. Finally, deficiencies in DNA methylation (DNAm), historically studied in CpG islands in gene promoters as an indicator of transcriptional repression, have previously been implicated in autism [7–9].…”

Section: Introductionmentioning

confidence: 99%

Exaggerated CpH methylation in the autism-affected brain

et al. 2017

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BackgroundThe etiology of autism, a complex, heritable, neurodevelopmental disorder, remains largely unexplained. Given the unexplained risk and recent evidence supporting a role for epigenetic mechanisms in the development of autism, we explored the role of CpG and CpH (H = A, C, or T) methylation within the autism-affected cortical brain tissue.MethodsReduced representation bisulfite sequencing (RRBS) was completed, and analysis was carried out in 63 post-mortem cortical brain samples (Brodmann area 19) from 29 autism-affected and 34 control individuals. Analyses to identify single sites that were differentially methylated and to identify any global methylation alterations at either CpG or CpH sites throughout the genome were carried out.ResultsWe report that while no individual site or region of methylation was significantly associated with autism after multi-test correction, methylated CpH dinucleotides were markedly enriched in autism-affected brains (~2-fold enrichment at p < 0.05 cutoff, p = 0.002).ConclusionsThese results further implicate epigenetic alterations in pathobiological mechanisms that underlie autism.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0119-y) contains supplementary material, which is available to authorized users.

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Autism spectrum disorders: Integration of the genome, transcriptome and the environment

Cited by 50 publications

References 133 publications

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

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

Behavioral impact of maternal allergic-asthma in two genetically distinct mouse strains

Exaggerated CpH methylation in the autism-affected brain

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