Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex

Abstract

Background: Epidemiological studies suggest that the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia is increased by prenatal exposure to viral or bacterial infection during pregnancy. It is still unclear how activation of the maternal immune response interacts with underlying genetic factors to influence observed ASD phenotypes. Methods: The current study investigated how maternal immune activation (MIA) in mice impacts gene expression in the frontal cortex in adulthood, and how these molecular changes relate to deficits in cognitive flexibility and social behavior, and increases in repetitive behavior that are prevalent in ASD. Poly(I:C) (20 mg/kg) was administered to dams on E12.5 and offspring were tested for social approach behavior, repetitive grooming, and probabilistic reversal learning in adulthood (n = 8 vehicle; n = 9 Poly(I:C)). We employed next-generation high-throughput mRNA sequencing (RNA-seq) to comprehensively investigate the transcriptome profile in frontal cortex of adult offspring of Poly(I:C)-exposed dams. Results: Exposure to poly(I:C) during gestation impaired probabilistic reversal learning and decreased social approach in MIA offspring compared to controls. We found long-term effects of MIA on expression of 24 genes, including genes involved in glutamatergic neurotransmission, mTOR signaling and potassium ion channel activity. Correlations between gene expression and specific behavioral measures provided insight into genes that may be responsible for ASD-like behavioral alterations. Conclusions: These findings suggest that MIA can lead to impairments in cognitive flexibility in mice similar to those exhibited in ASD individuals, and that these impairments are associated with altered gene expression in frontal cortex.

Increased RNA editing in maternal immune activation model of neurodevelopmental disease

“…RNA analysis of fetal brains in the period following the MIA led to several compelling insights and revealed extensive dysregulation in gene sets related to brain and neuronal development. To our knowledge, this is the first time that RNA-seq has been performed during this time period of mouse development following MIA, as most gene expression studies have considered only the adult offspring of MIA 66 – 68 . Since fetal brain tissue at this stage is scant, our results provide information at the level of gene enrichment.…”

Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model

“…For example, in rodents, externally triggering a maternal immune response during pregnancy induces behavioural alterations in adult offspring. These include reduced cognitive flexibility and decreased social exploration, traits of an ASD-like phenotype (70–72). In humans, increased odds of neonatal infections were reported for children with ASD (73).…”

Maternal Immunity in Autism Spectrum Disorders: Questions of Causality, Validity, and Specificity

“…Malkova et al found that poly(I:C) injection during pregnancy resulted in offspring exhibiting the core symptoms of ASD: decreases in sociability and communication and increases in repetitive/stereotypic behaviours [21]. These findings were reproduced by subsequent studies and extended to include other ASD-related symptoms, establishing construct and face validity [10,11,22]. The range of animal models of MIA continues to expand, with more recent models using exposures to Staphylococcal enterotoxin [23], toll-like receptor 7 agonists [24], and allergens [25].…”

“…Meta-analyses and epidemiological studies have reported an association between maternal infection and incidence of ASD in the offspring [ 6 , 7 , 8 ], and certain in utero inflammatory markers have been associated with ASD [ 6 ]. Animal studies of maternal immune activation (MIA) have characterised a prominent pro-inflammatory phenotype with is associated with impairments in communication and stereotypic behaviours [ 9 , 10 , 11 , 12 , 13 ]. Furthermore, transcriptomic and cytokine profiling studies in individuals with ASD have also revealed a state of immune dysregulation and elevated pro-inflammatory cytokines [ 14 , 15 , 16 , 17 ].…”