Abstract
Dysregulated TSC/mTOR signaling may play a pathogenetic role in forms of syndromic autism, such as autism associated with tuberous sclerosis, a genetic disorder caused by heterozygous TSC1 or TSC2 mutations. Environmental risk factors, such as gestational viral infections, may, in some cases, also contribute to the pathogenesis of autism and related neuropsychiatric disorders. We have recently found that a heterozygous Tsc2 mutation and the poly I:C model of maternal immune activation (MIA) interactively perturb fetal development and adult social behavior in mice, suggesting that these factors converge on shared pathways. TSC/mTOR signaling plays an important role in the modulation of immune responses, raising the possibility that the damage caused by MIA was greater in Tsc2+/− than in wildtype fetuses because of an exacerbated immune response in the mutants. Here, cytokine antibody arrays were employed to measure relative cytokine abundances in the fetal brain and the placenta during MIA. Cytokines were induced by gestational poly I:C but there was no obvious modulatory effect of Tsc2 haploinsufficiency. The data indicate that cytokine exposure during MIA is comparable in Tsc2 haploinsufficient and wildtype control fetuses, suggesting that downstream molecular and cellular processes may account for the interactive effects of Tsc2 haploinsufficiency and MIA.
Highlights
Dysregulated mTOR signaling and altered protein synthesis are emerging as common themes in the biology of autism [1,2,3]
Dysregulated TSC/mTOR signaling may play a pathogenetic role in forms of syndromic autism, such as autism associated with tuberous sclerosis, a genetic disorder caused by heterozygous TSC1 or TSC2 mutations
We have recently found that a heterozygous Tsc2 mutation and the poly I:C model of maternal immune activation (MIA) interactively perturb fetal development and adult social behavior in mice, suggesting that these factors converge on shared pathways
Summary
Dysregulated mTOR signaling and altered protein synthesis are emerging as common themes in the biology of autism [1,2,3]. Heterozygous mutations in the TSC1 or TSC2 gene cause tuberous sclerosis, a multisystem disorder, which is associated with autism in 20–60% of cases [4,5,6]. Fragile X syndrome, another single gene disorder, in which the regulation of mRNA translation is perturbed [1], is associated with autism [11]. These data collectively highlight the mTOR pathway and protein synthesis as one important theme in the pathogenesis of autism-related disorders. In addition to genetic factors, environmental risk factors may contribute to the pathogenesis of autism spectrum disorders. There is a growing literature suggesting the presence of inflammatory or immunological changes in the brains of at least a subset of individuals affected by autism [17,18,19,20,21], suggesting that immune activation/inflammatory processes may play a role (primary and/or secondary) in the pathogenesis of some cases of autism
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