title: Structure and function of neonatal social communication in a genetic mouse model of autism.
abstract: A critical step toward understanding autism spectrum disorder (ASD) is to identify both genetic and environmental risk factors. A number of rare copy number variants (CNVs) have emerged as robust genetic risk factors for ASD, but not all CNV carriers exhibit ASD and the severity of ASD symptoms varies among CNV carriers. Although evidence exists that various environmental factors modulate symptomatic severity, the precise mechanisms by which these factors determine the ultimate severity of ASD are still poorly understood. Here, using a mouse heterozygous for Tbx1 (a gene encoded in 22q11.2 CNV), we demonstrate that a genetically triggered neonatal phenotype in vocalization generates a negative environmental loop in pup-mother social communication. Wild-type pups used individually diverse sequences of simple and complicated call types, but heterozygous pups used individually invariable call sequences with less complicated call types. When played back, representative wild-type call sequences elicited maternal approach, but heterozygous call sequences were ineffective. When the representative wild-type call sequences were randomized, they were ineffective in eliciting vigorous maternal approach behavior. These data demonstrate that an ASD risk gene alters the neonatal call sequence of its carriers and this pup phenotype in turn diminishes maternal care through atypical social communication. Thus, an ASD risk gene induces, through atypical neonatal call sequences, less than optimal maternal care as a negative neonatal environmental factor.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Animal Science and Biotechnology, Azabu University, Sagamihara, Kanagawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Okabe
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: P Ó
authors.initials: PÓ
authors.lastname: Broin
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.|Department of Psychiatry, Course of Integrated Brain Sciences and Medical Informatics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nishi
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ye
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Beckert
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.|Department of Neuropharmacology, Graduate School of Hokkaido University College of Medicine, Sapporo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Department of Animal Science and Biotechnology, Azabu University, Sagamihara, Kanagawa, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Machida
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Kang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Abe
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Pena
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.|Department of Mathematical Sciences, Yeshiva University, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Golden
authors.affiliation: Department of Animal Science and Biotechnology, Azabu University, Sagamihara, Kanagawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kikusui
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.|Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Hiroi
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics*; D003142:Communication; D056915:DNA Copy Number Variations / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D008297:Male; D008425:Maternal Behavior; D051379:Mice; D010641:Phenotype; D012307:Risk Factors; D012919:Social Behavior; D013329:Structure-Activity Relationship; D020825:T-Box Domain Proteins / Q000235:genetics / Q000502:physiology*; D014828:Vocalization, Animal
chemical_list: D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse