Sex-dependent behavioral deficits and neuropathology in a maternal immune activation model of autism

Abstract

Infections during gestation and the consequent maternal immune activation (MIA) increase the risk of developing neuropsychiatric disorders in infants and throughout life, including autism spectrum disorders (ASD). ASD is a neurodevelopmental disorder that affects three times more males than females and is mainly characterized by deficits in social communication and restricted interests. Consistent findings also indicate that ASD patients suffer from movement disorders, although these symptoms are not yet considered as diagnosis criteria. Here we used the double-stranded RNA analog polyinosinic:polycytidylic acid (poly I:C) MIA animal model of ASD in mice and explored its effects in males and females on social and motor behavior. We then investigated brain areas implicated in controlling and coordinating movements, namely the nigro-striatal pathway, motor cortex and cerebellum. We show that male mice are more affected by this treatment than females as they show reduced social interactions as well as motor development and coordination deficits. Reduced numbers of Purkinje cells in the cerebellum was found more widespread and within distinct lobules in males than in females. Moreover, a reduced number of neurons was found in the motor cortex of males only. These results suggest that females are better protected against developmental insults leading to ASD symptoms in mice. They also point to brain areas that may be targeted to better manage social and motor consequences of ASD.

Maternal immune conditions are increased in males with autism spectrum disorders and are associated with behavioural and emotional but not cognitive co-morbidity

“…While previous studies have shown that maternal immune conditions are more prevalent in mothers of children with ASD [23][24][25] , our results suggest that this may be influenced by offspring sex, a finding not described previously. These results are consistent with animal research suggesting that males are more vulnerable to more neurodevelopmental abnormalities after MIA [48][49][50][51][52] . Maternal immune conditions and maternal asthma were associated with increased CBCL scores and more impairment in children, particularly on the Externalizing and Total scales.…”

“…In addition, offspring sex may contribute to the differential outcomes observed between male and female children in the maternal immune and maternal non-immune groups. Increasing evidence from preclinical models suggests that male offspring are more susceptible to adverse outcomes as a result of MIA compared to female offspring [48][49][50][51][52] . Although these models typically rely on short-term exposures to infections rather than potentially ongoing or episodic activation from chronic maternal immune conditions, the preclinical observations support findings seen in this study.…”

Lasting and Sex-Dependent Impact of Maternal Immune Activation on Molecular Pathways of the Amygdala

“…Moreover, our study identified sex-dependent molecular patterns that are consistent with the differential prevalence and symptoms of ASD, SSD, and MIA-related disorders between sexes reported in rodent and human studies (Wischhof et al, 2015). For example ASD tends to be more prevalent in young males (Kirsten et al, 2010;Haida et al, 2019), while SSD tends to be more prevalent in females (Bale et al, 2010;Bale, 2011). Similarly, lower sociability and preference for social novelty were observed in 2 weeks old pigs from gilts inoculated with PRRSV at GD 76 than from control gilts (Antonson et al, 2017).…”

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice

“…Thus, the prevalence of autism as well as characteristics of the autistic phenotypes are different in males vs. females [55][56][57][58] . Similarly, differences between males and females in the performance in ASD-associated behavioral tests were found in the Mthfr-deficient mice and in other autistic-like mouse models 18,[50][51][52]59,60 . Sex differences were also reported in the expression of several enzymes of the C1-metabolic pathway and in metabolite levels both regardless of the Mthfr genotype 23,61 and in Mthfr-deficient mice 23,62 .…”