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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
Author(s) -
Sala M.,
Braida D.,
Donzelli A.,
Martucci R.,
Busnelli M.,
Bulgheroni E.,
Rubino T.,
Parolaro D.,
Nishimori K.,
Chini B.
Publication year - 2013
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/j.1365-2826.2012.02385.x
Subject(s) - oxytocin receptor , haploinsufficiency , psychology , oxytocin , biology , genetics , neuroscience , gene , phenotype
We characterised the behavioural phenotype of mice heterozygous ( O xtr +/− ) for the oxytocin receptor gene ( O xtr ) and compared it with that of O xtr null mice ( O xtr −/− ), which display autistic‐like behaviours, including impaired sociability and preference for social novelty, impaired cognitive flexibility, and increased aggression. Similar to O xtr −/− mice, the O xtr +/− showed impaired sociability and preference for social novelty but, unlike the null genotype, their cognitive flexibility and aggression were normal. By autoradiography, O xtr +/− mice were found to have approximately 50% fewer oxytocin receptors ( OXTR s) in all of the examined brain regions. Thus, because a partial reduction in O xtr gene expression is sufficient to compromise social behaviour, the O xtr acts as a haploinsufficient gene. Furthermore, the inactivation of the O xtr gene affects specific behaviours in a dose‐dependent manner: social behaviour is sensitive to even a partial reduction in O xtr gene expression, whereas defects in aggression and cognitive flexibility require the complete inactivation of the O xtr gene to emerge. We then investigated the rescue of the O xtr +/− social deficits by oxytocin ( OT ) and T hr 4 G ly 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 O xtr −/− , thus suggesting that the rescue effect is mediated by OXTR in O xtr +/− and by other receptors (presumably vasopressin V 1a receptors) in O xtr −/− . In line with this, a low dose of the selective oxytocin antagonist desGly DT yr OVT blocks the rescue effect of TGOT only in the O xtr +/− genotype, whereas the less selective antagonist SR 49059 blocks rescue in both genotypes. In conclusion, the O xtr +/− mouse is a unique animal model for investigating how partial loss of the O xtr gene impair social interactions, and for designing pharmacological rescue strategies.