Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice

Abstract

It is becoming increasingly apparent that the causes of autism spectrum disorders (ASD) are due to both genetic and environmental factors. Animal studies provide important translational models for elucidating specific genetic or environmental factors that contribute to ASD-related behavioral deficits. For example, mouse research has demonstrated a link between maternal immune activation and the expression of ASD-like behaviors. Although these studies have provided insights into the potential causes of ASD, they are limited in their ability to model the important interactions between genetic variability and environmental insults. This is of particular concern given the broad spectrum of severity observed in the human population, suggesting that subpopulations may be more susceptible to the adverse effects of particular environmental insults. It is hypothesized that the severity of effects of maternal immune activation on ASD-like phenotypes is influenced by the genetic background in mice. To test this, pregnant dams of two inbred strains (that is, C57BL/6J and BTBR T+tf/J) were exposed to the viral mimic polyinosinic-polycytidylic acid (polyI:C), and their offspring were tested for the presence and severity of ASD-like behaviors. To identify differences in immune system regulation, spleens were processed and measured for alterations in induced cytokine responses. Strain-treatment interactions were observed in social approach, ultrasonic vocalization, repetitive grooming and marble burying behaviors. Interestingly, persistent dysregulation of adaptive immune system function was only observed in BTBR mice. Data suggest that behavioral and immunological effects of maternal immune activation are strain-dependent in mice.

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

“…[51][52][53][54][55] Furthermore, maternal exposure during pregnancy to various pathogens and/or the maternal immune response (fever, inflammation) have been associated with significant increased risk of autism spectrum disorder (ASD). [56][57][58][59] In this regard, gestational exposure to the viral mimetic poly(I:C) in rodents resulted in ASD-like behavioral abnormalities in the progeny, 60 and immune cells from the same animals had OXPHOS deficits still present in adulthood. 61 These findings are consistent with the current view of chronic inflammation in which the proinflammatory-phase response (mainly fueled by ATP generated in glycolysis 13 ) predominates and persists unless external changes are implemented.…”

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

“…Repetitive behaviors in mice include unusually long bouts of self-grooming, digging, and burying foreign objects such as marbles. High levels of stereotyped or repetitive behaviors have been reported in mice with mutations in genes including Shank3 [15], 16p11.2 deletion [28,54], Cntnap2 [17], and Ephrin-A [27] in the inbred strains of BTBR [6,[55][56][57], C58/J [58], and in deer mice [59].…”

Induction of Maternal Immune Activation in Mice at Mid-gestation Stage with Viral Mimic Poly(I:C)

“…So far, the effect of MIA is mostly replicated in wild-type C57BL/6N mice 8,10,13,16 . Others have also observed the MIA effect in BTBR mouse strain 19 . It has been shown that poly(I:C) could elicit different immune responses in genetically engineered mice 13,[22][23][24] , which may introduce additional confounding effects to the offspring.…”

“…Furthermore, therapeutic and prophylactic strategies are also developed from this model system 13,16,17 . By inducing MIA at E12.5, others have shown that MIA produces fetal microglial activation and cholinergic developmental alteration in basal forebrain 18 , strain specific interaction 19 , brain cerebral synaptosomal ultrastructural abnormalities, cerebral mitochondrial respiratory chain hyperfunction abnormalties, downregulation of cerebral synaptosomal molecules 17 , depressive-like behaviors, impairment in cognition and hippocampal longterm potentiation (LTP), and deficit of adult hippocampal neurogenesis 1. Weigh the mouse on the scale and put it back into the cage.…”