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.
Highlights
Introduction of the humanarginine vasopressin receptor 1A (AVPR1A) gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic miceRhonda Charles1,2, Takeshi Sakurai1,3, Nagahide Takahashi3, Gregory A
Received 25 April 2014; Accepted 5 June 2014 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
Comparison of quantitative realtime reverse-transcriptase-PCR results for mRNA extracts from the left hemisphere of brains of 6-month-old wild-type (m/m) and partially humanized (h,m/m) mice showed that the introduction of the human transgene did not affect the levels of mouse-specific Avpr1a mRNA (t-test, P=0.212; supplementary material Fig. S1A)
Summary
Introduction of the humanAVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic miceRhonda Charles, Takeshi Sakurai, Nagahide Takahashi, Gregory A. AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice. 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. Avpr1a knockout mice displayed reduced anxiety, impaired reciprocal social interaction and decreased social recognition (Bielsky et al, 2004; Egashira et al, 2007), indicating that the receptor is an important factor in mediating essential social behaviors. Animal models have provided insight into the function of AVPR1A in behavior modulation, these models have more limited usefulness in evaluating therapeutics for the treatment of abnormal behaviors associated with psychiatric diseases because of variability in receptor expression patterns and pharmacology between species. A humanized mouse model is likely to be more useful in elucidating the mechanisms of gene regulation and gene expression that leads to specific behavioral phenotypes and could provide a suitable in vivo model for novel drug screens
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