The Timing and Specificity of Prenatal Immune Risk Factors for Autism Modeled in the Mouse and Relevance to Schizophrenia

Abstract

Autism is a highly heritable condition, but there is strong epidemiological evidence that environmental factors, especially prenatal exposure to immune challenge, contribute to it. This evidence is largely indirect, and experimental testing is necessary to directly examine causal mechanisms. Mouse models reveal that prenatal immune perturbation disrupts postnatal brain maturation with alterations in gene and protein expression, neurotransmitter function, brain structure and behavioral indices reminiscent of, but not specific to, autism. This likely reflects a neurodevelopmental spectrum in which autism and schizophrenia share numerous genetic and environmental risk factors for difficulties in social interaction, communication, emotion processing and executive function. Recent epidemiological studies find that early rather than late pregnancy infection confers the greater risk of schizophrenia. The autism literature is more limited, but exposures in the 2nd half of pregnancy may be important. Mouse models of prenatal immune challenge help dissect these observations and show some common consequences of early and late gestational exposures, as well as distinct ramifications potentially relevant to schizophrenia and autism. Although nonspecificity of immune-stimulated mouse models could be considered a disadvantage, we propose a broadened perspective, exploiting the possibility that advances made investigating a target condition can contribute towards the understanding of related conditions.

Fractone-associated N-sulfated heparan sulfate shows reduced quantity in BTBR T+tf/J mice: A strong model of autism

“…The link of altered expression of certain growth factors with autistic-like behaviors is further strengthened by studies using a prenatal immune challenge (Poly I:C; given on E9), such as has been hypothesized to model an environmental condition influencing autism [61,62] reported an enhancement of FGF-8 in treated fetuses two days after treatment followed by a precipitous drop later, as well as a significant reduction in dopamine levels. FGF-8 hypomorphic mice also show alterations of the epithalamus, including the habenula and the pineal gland [63] providing a potential link to the sleep disturbances that are very common in autism [64,65].…”

Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders

“…Studies on prenatal exposure of rodents and primates to maternal infection or inflammation have shown that challenged offspring demonstrate altered behavioral phenotypes relevant to ASD and SZ (Borrell et al, 2002; Fatemi et al, 2002; Shi et al, 2003; McAlonan et al, 2010; Ehninger et al, 2012; Malkova et al, 2012; Bauman et al, 2014). While some studies failed to detect signs of inflammation in offspring born to immune-challenged mothers (Willi et al, 2013; Missault et al, 2014) and even showed reduction in inflammatory cytokines in the periphery (Pacheco-Lopez et al, 2013), others have reported increased cytokine levels in the periphery and in the brain (Borrell et al, 2002; Garay et al, 2012; Krstic et al, 2012), immune dysregulation (Hsiao et al, 2012), as well as neuropathological features such as activated microglia (Borrell et al, 2002; Krstic et al, 2012 but see Garay et al 2012) and astrocyte activation (Borrell et al, 2002; Fatemi et al, 2002) in juvenile or adult animals.…”

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

“…Although PPI deficits have been reported in higher functioning adults with ASD [68] or Asperger"s Disorder [69], equivocal PPI findings have been reported in lower functioning children and adolescents [70] and in a cohort of individuals with both high-and low functioning individuals with ASD [71]. A higher dose of VPA in late gestation has been reported to alter PPI [67], however other late gestation exposures which may increase risk of ASD -specifically maternal immune activation -do not disrupt PPI either [28][29][30]. Thus, a PPI impairment is not always a consequence of exposure to ASD risks.…”

“…For example, we and others have reported that exposure to maternal immune activation (MIA) in early or late gestation precipitates a distinct phenotype in terms of both nature and severity [28][29][30]. In the VPA model, the embryotoxicity of VPA initially came to light because it induced neural tube defects.…”