Mice Heterozygous for the Oxytocin Receptor Gene (Oxtr^+/−) Show Impaired Social Behaviour but not Increased Aggression or Cognitive Inflexibility: Evidence of a Selective Haploinsufficiency Gene Effect

Abstract

We characterised the behavioural phenotype of mice heterozygous (Oxtr(+/-)) for the oxytocin receptor gene (Oxtr) and compared it with that of Oxtr null mice (Oxtr(-/-)), which display autistic-like behaviours, including impaired sociability and preference for social novelty, impaired cognitive flexibility, and increased aggression. Similar to Oxtr(-/-) mice, the Oxtr(+/-) showed impaired sociability and preference for social novelty but, unlike the null genotype, their cognitive flexibility and aggression were normal. By autoradiography, Oxtr(+/-) mice were found to have approximately 50% fewer oxytocin receptors (OXTRs) in all of the examined brain regions. Thus, because a partial reduction in Oxtr gene expression is sufficient to compromise social behaviour, the Oxtr acts as a haploinsufficient gene. Furthermore, the inactivation of the Oxtr gene affects specific behaviours in a dose-dependent manner: social behaviour is sensitive to even a partial reduction in Oxtr gene expression, whereas defects in aggression and cognitive flexibility require the complete inactivation of the Oxtr gene to emerge. We then investigated the rescue of the Oxtr(+/-) social deficits by oxytocin (OT) and Thr(4)Gly(7)OT (TGOT) administered i.c.v. at different doses. TGOT was more potent than OT in rescuing sociability and social novelty in both genotypes. Furthermore, the TGOT doses that reverted impaired sociability and preference for social novelty in Oxtr(+/-) were lower than those required in Oxtr(-/-), thus suggesting that the rescue effect is mediated by OXTR in Oxtr(+/-) and by other receptors (presumably vasopressin V1a receptors) in Oxtr(-/-). In line with this, a low dose of the selective oxytocin antagonist desGlyDTyrOVT blocks the rescue effect of TGOT only in the Oxtr(+/-) genotype, whereas the less selective antagonist SR49059 blocks rescue in both genotypes. In conclusion, the Oxtr(+/-) mouse is a unique animal model for investigating how partial loss of the Oxtr gene impair social interactions, and for designing pharmacological rescue strategies.

Selective and Potent Agonists and Antagonists for Investigating the Role of Mouse Oxytocin Receptors

“…However, in slices, the effective dose was very similar to the OT doses used, and the half-maximally effective concentration was only slightly more potent than OT (Huber et al, 2005). A similar discrepancy between in vitro and in vivo potencies of TGOT was also observed in social behavioral rescue experiments recently performed in OTRnull mice (Sala et al, 2011(Sala et al, , 2013. TGOT rescued the social deficit at a dose of 0.0005 ng/animal in Oxtr 1/2 mice, which is consistent with a selective action of TGOT through OTRs.…”

“…However, as we used transfected cells, one major issue is to verify whether the selectivity profile observed in transfected cells is maintained in vivo. In this regard, when used in mice at a dose of 0.0008 ng/animal, OTA3 specifically blocked the mOTR-mediated rescue of sociability defects in heterozygous Oxtr 1/2 animals, suggesting the validity of this approach to identify mOTR antagonists (Sala et al, 2013). TGOT has been previously used in mice mainly in electrophysiology experiments, which found evidence of its selectivity for OTR-versus V1a-mediated responses (Huber et al, 2005;Gozzi et al, 2010).…”

“…TGOT rescued the social deficit at a dose of 0.0005 ng/animal in Oxtr 1/2 mice, which is consistent with a selective action of TGOT through OTRs. However, at a dose of 0.05 ng/animal, TGOT also rescued the social deficit of Oxtr 2/2 mice, suggesting that despite its very low affinity for the V1a and V1b receptors in vitro, TGOT was still active on these receptors in vivo (Sala et al, 2013). Several factors may be responsible for the discrepancy in TGOT potency observed in vitro and in vivo.…”

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

“…27 Alteration of Oxytocin-Vasopressin levels is indeed associated to impaired social interaction and a role for these genes in autistic behavior has been reported. 26,28 The presence of autistic features, like poor eye contact, is evident in patients affected by the congenital variant of RTT, caused by FOXG1 mutations, as well as in classic RTT, thus suggesting a potential contribution for these genes to the behavioral phenotype of RTT.…”

Learning About Oxytocin: Pharmacologic and Behavioral Issues

“…The U-shaped, biphasic, or even more complex doseresponse curves may be due to various factors. High doses of OT may activate AVP V1a and/or V1b receptors, as observed in Oxtr À/À and Oxtr ϩ/À mice (36,37), and the release of other neurotransmitter/hormone systems may be modulated. When given before extinction, OT delays fear conditioning extinction in rats in a bimodal manner, depending on the levels of corticosterone released (16), whereas AVP has no significant effect on the corticosterone response to noise stress (38).…”