title: Sex-specific gene-environment interactions underlying ASD-like behaviors.
abstract: The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a "three-hit" (genetic load × environmental factor × sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three "hits" had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic-pituitary-adrenal/stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.
authors.affiliation: Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065 S.M.Schaafsma@umcutrecht.nl pfaff@rockefeller.edu.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Schaafsma
authors.affiliation: Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065.
authors.forename: Khatuna
authors.initials: K
authors.lastname: Gagnidze
authors.affiliation: Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065.
authors.forename: Anny
authors.initials: A
authors.lastname: Reyes
authors.affiliation: Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065.
authors.forename: Natalie
authors.initials: N
authors.lastname: Norstedt
authors.affiliation: Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065.
authors.forename: Karl
authors.initials: K
authors.lastname: Månsson
authors.affiliation: Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065.
authors.forename: Kerel
authors.initials: K
authors.lastname: Francis
authors.affiliation: Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065 S.M.Schaafsma@umcutrecht.nl pfaff@rockefeller.edu.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Pfaff
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D012919:Social Behavior; D000099052:CRF Receptor, Type 1
chemical_list: C568163:CNTNAP2 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
keywords: Cntnap2; autism; maternal immune activation; prenatal stress; sex differences