About this item:

178 Views | 286 Downloads

Author Notes:

Author for correspondence (joseph.buxbaum@mssm.edu)

T.S., G.A.E., M.A.G.S. and J.D.B. performed BAC transgenesis and R.C. performed subsequent breeding to generate the mice.

J.D.B., R.C., T.S. and N.T. designed the experiments.

R.C. performed the biochemical and behavioral experiments and analysis.

L.J.Y. assisted with ligand binding assay performance and analysis, interpreting the results and editing the manuscript.

The manuscript was written by R.C., L.J.Y. and J.D.B., and all authors reviewed the manuscript before submission.

We thank Meera Modi and Nate Dorr for help at early stages of the project.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by the Seaver Foundation and a predoctoral fellowship from the Autism Science Foundation to R.C.

Additional support was provided by National Institutes of Health grants [MH056897 and MH064692 to L.J.Y. and P51OD11132 to Yerkes National Primate Research Center].

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Pathology
  • AVPR1A
  • Humanized mouse
  • Social behavior
  • Species-specific
  • Microsatellite
  • Autism
  • ANXIETY-RELATED BEHAVIOR
  • VASOPRESSIN RECEPTOR
  • KNOCKOUT MICE
  • PREPULSE INHIBITION
  • PROMOTER REGION
  • PSYCHIATRIC-DISORDERS
  • MONOGAMOUS VOLE
  • BINDING-SITES
  • MESSENGER-RNA
  • V-1A RECEPTOR

Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice

Tools:

Journal Title:

Disease Models and Mechanisms

Volume:

Volume 7, Number 8

Publisher:

, Pages 1013-1022

Type of Work:

Article | Final Publisher PDF

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 speciesspecific 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.

Copyright information:

© 2014. Published by The Company of Biologists Ltd

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

Creative Commons License

Export to EndNote