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Chronic maternal interleukin-17 and autism-related cortical gene expression, neurobiology, and behavior.

ABSTRACT: Chronic inflammation during pregnancy (e.g., preeclampsia, diabetes) is linked to increased risk for offspring neurodevelopmental disorders such as autism spectrum disorder (ASD). However, mediators of such exposures that could be targeted with maternal intervention are unclear, as few chronic gestational inflammation models have been tested. One potential mediator is interleukin-17 (IL-17), a pro-inflammatory cytokine implicated in neurodevelopmental disorders and gestational disease. To test chronic maternal IL-17 impacts on offspring, C57BL/6J dams were administered IL-17A continuously throughout pregnancy. Offspring were assessed for body weight; cortical volume, gene expression, and cellular composition; and adult behavior. IL-17A-condition offspring exhibited decreased somatic and cortical size at embryonic day 18 (E18) and as adults. mRNA sequencing of E18 cortex revealed 320 differentially expressed genes in males, but none in females. These were significantly enriched for ASD (Simons Foundation Autism Research Initiative), synaptic, and cell cycle genes. By adulthood, neocortical glial cell density and gene expression were decreased, while GABAergic synaptic gene expression was increased in males. Furthermore, IL-17A-condition male but not female offspring exhibited reduced anxiety-like behavior. Social approach deficits in males were negatively correlated with neocortical GABAergic synaptic gene expression. Chronic gestational IL-17A was sufficient to cause ASD-like phenotypes early and persistently in male offspring. This echoes the male bias, altered cortical development, and behavioral findings in ASD, suggesting that chronic maternal IL-17 contributes to offspring ASD pathogenesis. Furthermore, the trajectory from embryonically dysregulated synaptic and cell cycle genes to disrupted adult glia, inhibitory synapses, and behavior suggests a mechanism for chronic maternal IL-17 effects on offspring.

SUBMITTER: Gumusoglu SB

PROVIDER: S-EPMC7162858 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In autism, heterogeneity is the rule rather than the exception. One obvious source of heterogeneity is biological sex. Since autism was first recognized, males with autism have disproportionately skewed research. Females with autism have thus been relatively overlooked, and have generally been assumed to have the same underlying neurobiology as males with autism. Growing evidence, however, suggests that this is an oversimplification that risks obscuring the biological base of autism. This study seeks to answer two questions about how autism is modulated by biological sex at the level of the brain: (i) is the neuroanatomy of autism different in males and females? and (ii) does the neuroanatomy of autism fit predictions from the 'extreme male brain' theory of autism, in males and/or in females? Neuroanatomical features derived from voxel-based morphometry were compared in a sample of equal-sized high-functioning male and female adults with and without autism (n = 120, n = 30/group). The first question was investigated using a 2 × 2 factorial design, and by spatial overlap analyses of the neuroanatomy of autism in males and females. The second question was tested through spatial overlap analyses of specific patterns predicted by the extreme male brain theory. We found that the neuroanatomy of autism differed between adult males and females, evidenced by minimal spatial overlap (not different from that occurred under random condition) in both grey and white matter, and substantially large white matter regions showing significant sex × diagnosis interactions in the 2 × 2 factorial design. These suggest that autism manifests differently by biological sex. Furthermore, atypical brain areas in females with autism substantially and non-randomly (P < 0.001) overlapped with areas that were sexually dimorphic in neurotypical controls, in both grey and white matter, suggesting neural 'masculinization'. This was not seen in males with autism. How differences in neuroanatomy relate to the similarities in cognition between males and females with autism remains to be understood. Future research should stratify by biological sex to reduce heterogeneity and to provide greater insight into the neurobiology of autism.

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Chronic maternal interleukin-17 and autism-related cortical gene expression, neurobiology, and behavior.

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