Maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppression

• Published in: Translational psychiatry Vol. 11; no. 1; p. 348
• Main Authors: Jaini, Ritika, Wolf, Matthew R., Yu, Qi, King, Alexander T., Frazier, Thomas W., Eng, Charis
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.06.2021; Nature Publishing Group
• Subjects: 13/21; 13/51; 38/39; 38/91; 631/208; 64/60; 692/699/476/1373; 82/51; Autism; Behavioral Sciences; Biological Psychology; Gene expression; Genetics; Genotype & phenotype; Medicine; Medicine & Public Health; Neurosciences; Pharmacotherapy; Psychiatry
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-021-01472-x

Genetic studies in ASD have mostly focused on the proband, with no clear understanding of parental genetic contributions to fetal neurodevelopment. Among parental etiological factors, perinatal maternal inflammation secondary to autoimmunity, infections, and toxins is associated with ASD. However, the inherent impact of maternal genetics on in-utero inflammation and fetal neurodevelopment in the absence of strong external inflammatory exposures is not known. We used the Pten WT/m3m4 mouse model for ASD to demonstrate the impact of maternal genetics on the penetrance of ASD-like phenotypes in the offspring. Pten WT/m3m4 (Mom m3m4 ) or Pten WT/WT (Mom WT ) females, their offspring, and placental interface were analyzed for inflammatory markers, gene expression, and cellular phenotypes at E17.5. Postnatal behavior was tested by comparing pups from Mom m3m4 vs. Mom WT . Mothers of the Pten WT/m3m4 genotype (Mom m3m4 ) showed inadequate induction of IL-10 mediated immunosuppression during pregnancy. Low IL-10 in the mother was directly correlated with decreased complement expression in the fetal liver. Fetuses from Mom m3m4 had increased breakdown of the blood–brain–barrier, neuronal loss, and lack of glial cell maturation during in-utero stages. This impact of maternal genotype translated to a postnatal increase in the risk of newborn mortality, visible macrocephaly and ASD-like repetitive and social behaviors. Depending on maternal genotype, non-predisposed (wildtype) offspring showed ASD-like phenotypes, and phenotypic penetrance was decreased in predisposed pups from Mom WT . Our study introduces the concept that maternal genetics alone, without any added external inflammatory insults, can modulate fetal neurodevelopment and ASD-related phenotypes in the offspring via alteration of IL-10 mediated materno-fetal immunosuppression.