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. (24th January 2013)

• Record Type: Journal Article
• Authors: Sala, M.; Braida, D.; Donzelli, A.; Martucci, R.; Busnelli, M.; Bulgheroni, E.; Rubino, T.; Parolaro, D.; Nishimori, K.; Chini, B.
• Is Part Of: Journal of neuroendocrinology. Volume 25:Number 2(2013:Feb.)
• Page Start: 107
• Page End: 118
• Publication Date: 2013-01-24
• Subjects: Neuroendocrinology -- Periodicals; 616.4
• DOI: 10.1111/j.1365-2826.2012.02385.x
• Languages: English
• ISSNs: 0953-8194

Abstract

<abstract abstract-type="main" xml:lang="en" id="jne2385-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>We characterised the behavioural phenotype of mice heterozygous (O<italic>xtr</italic><sup><italic>+/−</italic></sup>) for the oxytocin receptor gene (O<italic>xtr</italic>) and compared it with that of O<italic>xtr</italic> null mice (O<italic>xtr</italic><sup><italic>−/−</italic></sup>), which display autistic‐like behaviours, including impaired sociability and preference for social novelty, impaired cognitive flexibility, and increased aggression. Similar to O<italic>xtr</italic><sup><italic>−/−</italic></sup> mice, the O<italic>xtr</italic><sup><italic>+/−</italic></sup> showed impaired sociability and preference for social novelty but, unlike the null genotype, their cognitive flexibility and aggression were normal. By autoradiography, O<italic>xtr</italic><sup><italic>+/−</italic></sup> mice were found to have approximately 50% fewer oxytocin receptors (OXTRs) in all of the examined brain regions. Thus, because a partial reduction in O<italic>xtr</italic> gene expression is sufficient to compromise social behaviour, the O<italic>xtr</italic> acts as a haploinsufficient gene. Furthermore, the inactivation of the O<italic>xtr</italic> gene affects specific behaviours in a dose‐dependent manner: social behaviour is sensitive to even a partial reduction in O<italic>xtr</italic> gene expression, whereas defects in aggression and cognitive flexibility require the complete inactivation of the O<italic>xtr</italic> gene to emerge. We then investigated the rescue of the O<italic>xtr</italic><sup><italic>+/−</italic></sup> social deficits by oxytocin (OT) and Thr<sup>4</sup>Gly<sup>7</sup>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 <italic>Oxtr</italic><sup><italic>+/−</italic></sup> were lower than those required in O<italic>xtr</italic><sup><italic>−/−</italic></sup>, thus suggesting that the rescue effect is mediated by OXTR in O<italic>xtr</italic><sup><italic>+/−</italic></sup> and by other receptors (presumably vasopressin V1a receptors) in O<italic>xtr</italic><sup><italic>−/−</italic></sup>. In line with this, a low dose of the selective oxytocin antagonist desGlyDTyrOVT blocks the rescue effect of TGOT only in the O<italic>xtr</italic><sup><italic>+/−</italic></sup> genotype, whereas the less selective antagonist SR49059 blocks rescue in both genotypes. In conclusion, the O<italic>xtr</italic><sup><italic>+/−</italic></sup> mouse is a unique animal model for investigating how partial loss of the O<italic>xtr</italic> gene impair social interactions, and for designing pharmacological rescue strategies.</p> </abstract>