title: Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice.
abstract: Central arginine vasopressin receptor 1A (AVPR1A) modulates a wide range of behaviors, including stress management and territorial aggression, as well as social bonding and recognition. Inter- and intra-species variations in the expression pattern of AVPR1A in the brain and downstream differential behavioral phenotypes have been attributed to differences in the non-coding regions of the AVPR1A gene, including polymorphic elements within upstream regulatory areas. Gene association studies have suggested a link between AVPR1A polymorphisms and autism, and AVPR1A has emerged as a potential pharmacological target for treatment of social cognitive impairments and mood and anxiety disorders. To further investigate the genetic mechanism giving rise to species differences in AVPR1A expression patterns and associated social behaviors, and to create a preclinical mouse model useful for screening drugs targeting AVPR1A, we engineered and extensively characterized bacterial artificial chromosome (BAC) transgenic mice harboring the entire human AVPR1A locus with the surrounding regulatory elements. Compared with wild-type animals, the humanized mice displayed a more widely distributed ligand-AVPR1A binding pattern, which overlapped with that of primates. Furthermore, humanized AVPR1A mice displayed increased reciprocal social interactions compared with wild-type animals, but no differences in social approach and preference for social novelty were observed. Aspects of learning and memory, specifically novel object recognition and spatial relocation recognition, were unaffected. The biological alterations in humanized AVPR1A mice resulted in the rescue of the prepulse inhibition impairments that were observed in knockout mice, indicating conserved functionality. Although further behavioral paradigms and additional cohorts need to be examined in humanized AVPR1A mice, the results demonstrate that species-specific variations in the genomic content of regulatory regions surrounding the AVPR1A locus are responsible for differential receptor protein expression patterns across species and that they are likely to contribute to species-specific behavioral variation. The humanized AVPR1A mouse is a potential preclinical model for further understanding the regulation of receptor gene expression and the impact of variation in receptor expression on behaviors, and should be useful for screening drugs targeting human AVPR1A, taking advantage of the expression of human AVPR1A in human-relevant brain regions.
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Charles
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Nagahide
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Neurology Service, James J. Peters VA Medical Center, Bronx, NY 10468, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Elder
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Research and Development Service, James J. Peters VA Medical Center, Bronx, NY 10468, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gama Sosa
authors.affiliation: Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Young
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Friedman Brain Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA joseph.buxbaum@mssm.edu.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
mesh_terms: D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism*; D022202:Chromosomes, Artificial, Bacterial / Q000378:metabolism; D006801:Humans; D008822:Mice, Transgenic; D009928:Organ Specificity; D065808:Prepulse Inhibition / Q000502:physiology; D017483:Receptors, Vasopressin / Q000235:genetics* / Q000378:metabolism; D013216:Reflex, Startle / Q000502:physiology; D055139:Sensory Gating; D012919:Social Behavior; D013647:Task Performance and Analysis
chemical_list: D017483:Receptors, Vasopressin
keywords: AVPR1A; Autism; Humanized mouse; Microsatellite; Social behavior; Species-specific