Gestational flu exposure induces changes in neurochemicals, affiliative hormones and brainstem inflammation, in addition to autism-like behaviors in mice

Miller, Veronica M.; Zhu, Youhua; Bucher, Coralie; McGinnis, Woody R.; Ryan, Lisa K.; Siegel, Allan; Zalcman, Steven S.

doi:10.1016/j.bbi.2013.07.002

Cited by 28 publications

(30 citation statements)

References 49 publications

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“…Multiple animal models of prenatal infection have found evidence of diverse neurobehavioral abnormalities, whether through direct exposure of pregnant mice or rodents to influenza virus, or through non-infectious activation of the maternal immune system (e.g., using RNA poly(I:C) to stimulate an antiviral inflammatory response or lipopolysaccharide to stimulate a bacterial inflammatory response) (Brown and Derkits, 2010;Deverman and Patterson, 2009;Meyer et al, 2011;Miller et al, 2013;Patterson, 2011). The different pattern of associations observed for ASD with and without comorbid intellectual disability reinforces the possibility that higher-functioning and lower-functioning ASD may have different etiologies (Szatmari et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders

Lee¹,

Magnusson²,

Gardner³

et al. 2015

Brain, Behavior, and Immunity

284

227

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Animal models indicate that maternal infection during pregnancy can result in behavioral abnormalities and neuropathologies in offspring. We examined the association between maternal inpatient diagnosis with infection during pregnancy and risk of ASD in a Swedish nationwide register-based birth cohort born 1984-2007 with follow-up through 2011. In total, the sample consisted of 2,371,403 persons with 24,414 ASD cases. Infection during pregnancy was defined from ICD codes. In the sample, 903 mothers of ASD cases (3.7%) had an inpatient diagnosis of infection during pregnancy. Logistic regression models adjusted for a number of covariates yielded odds ratios indicating approximately a 30% increase in ASD risk associated with any inpatient diagnosis of infection. Timing of infection did not appear to influence risk in the total Swedish population, since elevated risk of ASD was associated with infection in all trimesters. In a subsample analysis, infections were associated with greater risk of ASD with intellectual disability than for ASD without intellectual disability. The present study adds to the growing body of evidence, encompassing both animal and human studies, that supports possible immunemediated mechanisms underlying the etiology of ASD.

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Section: Discussionmentioning

confidence: 99%

Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders

Lee¹,

Magnusson²,

Gardner³

et al. 2015

Brain, Behavior, and Immunity

284

227

View full text Add to dashboard Cite

show abstract

“…25 Mouse models support the role of cytokines as putative in core behavioral features of autism: administration of IL-6 during pregnancy alone is enough to induce autism-like traits in the offspring, 9 and it has been proposed that cytokines affect behavior by altering levels of specific hormones, namely oxytocin and serotonin. 26 Further, gene-ontology analysis of all mouse and human CNV genes has shown overrepresentation of immune system function and enrichment for neurodevelopment, specifically, for those within genomic hotspots. 27,28 Postmortem studies also found upregulated immune system genes in autism brains with environmental rather than genetic etiology; these dysregulated immune related genes seemed to also play a role in synaptic development and function.…”

Section: Discussionmentioning

confidence: 99%

Epigenetics of Autism-related Impairment

Mazina

Gerdts²,

Trinh³

et al. 2015

Journal of Developmental &Amp; Behavioral Pediatrics

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Objective Epidemiological data have suggested maternal infection and fever to be associated with increased risk of ASD. Animal studies show that gestational infections perturb fetal brain development and result in offspring with the core features of autism and have demonstrated that behavioral effects of maternal immune activation (MIA) are dependent on genetic susceptibility. The goal of this study was to explore the impact of ASD-associated CNVs and prenatal maternal infection on clinical severity of ASD within a dataset of prenatal history and complete genetic and phenotypic findings. Method We analyzed data from the Simons Simplex Collection sample including 1971 children with a diagnosis of ASD aged 4 to 18 years who underwent array CGH screening. Information on infection and febrile episodes during pregnancy was collected through parent interview. ASD severity was clinically measured through parent-report interview and questionnaires. Results We found significant interactive effects between presence of CNVs and maternal infection during pregnancy on autistic symptomatology, such that individuals with CNVs and history of maternal infection demonstrated increased rates of social communicative impairments and repetitive/restricted behaviors. In contrast, no significant interactions were found between presence of CNVs and prenatal infections on cognitive and adaptive functioning of individuals with ASD. Conclusion Our findings support a gene-environment interaction model of autism impairment, in that individuals with ASD-associated CNVs are more susceptible to the effects of maternal infection and febrile episodes in pregnancy on behavioral outcomes, and suggest that these effects are specific to ASD rather than to global neurodevelopment.

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“…This experiment also demonstrated changes in the catecholaminergic and microglial cell density in the brainstem tissues of male flu-exposed offspring only, suggesting an association between sex-specific alterations and dopamine metabolism and brainstem inflammation [53]. The BALB/c mice used in this experiment are known to be more sensitive to the H3N2 virus than those with the C57Bl/6 background.…”

Section: Microglial Activation In Autismmentioning

confidence: 94%

“…The BALB/c background has a greater Th1-type response than the C57Bl/6 background, which has a greater Th2-type response [54]. The authors suggested that the genetic alterations in the maternal Th1 responses contribute to the developmental abnormalities in the offspring after gestational viral exposure [53]. …”

Section: Microglial Activation In Autismmentioning

confidence: 99%

Role of Microglia in Autism: Recent Advances

Takano¹

2015

Dev Neurosci

106

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The neurobiological basis for autism remains poorly understood. However, the neuroinflammation processes play an important role in the induction of autistic behavioral changes. Microglial cells can exhibit widely differing functions during brain development, including synaptogenesis and stem cell proliferation, in addition to playing a role in the innate immunity. Mounting evidence indicates that microglial activation or dysfunction can profoundly affect neural development, resulting in neurodevelopmental disorders, including autism. These mechanisms in autism have been investigated using neuropathological studies of human autopsy brains, a large number of murine experimental models and in vivo neuroimaging studies of the human brain. The purpose of this review is to discuss microglial activation or dysfunction and to highlight the detrimental role that microglia play in the development of autism. The recent advances presented in this review support that further elucidation of the mechanisms and kinetics of microglial responses will help to establish a window for therapeutic intervention in individuals with autism.

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Gestational flu exposure induces changes in neurochemicals, affiliative hormones and brainstem inflammation, in addition to autism-like behaviors in mice

Cited by 28 publications

References 49 publications

Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders

Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders

Epigenetics of Autism-related Impairment

Role of Microglia in Autism: Recent Advances

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