Enhanced social behaviors and brain-region specific upregulation of oxytocin receptors in GABAB(1a) knockout mice: Implications for autism spectrum disorders

Impaired social behaviour is the most prominent symptom of autism. The neurobiology mediating sociability deficits in autistic patients is not well understood and there is no treatment that effectively improves social behaviours. There is evidence showing that the neuropeptide oxytocin is involved in the pathophysiology of autism and that oxytocin treatment can improve social avoidance seen in autistic individuals. Recent findings implicate a possible action of oxytocin through γ-aminobutyric acid (GABA) receptors to mediate several behaviors in rodents. Moreover, it has been shown that baclofen, a GABAB agonist, reverses social deficits and repetitive behaviours. GABA beta (GABAB) receptors are G protein-coupled receptors that regulate several neurotransmitter systems via its pre- and post- synaptic receptor subtypes, GABAB(1a) and GABAB(1b) respectively. Therefore, in the present study we aimed to assess the role of GABAB receptor subunits and the involvement of the oxytocin receptor system in male BALB/c mice, a strain that manifest sociability impairment. Social interaction was assessed using the Crawley’s three-chambered social approach paradigm in wild type (WT), GABAB(1a) (1a-/-) and GABAB(1b) (1b-/-) knockout mice (n=11-16). This consisted of three 10-min phases; (i) habituation: the subject mouse was allowed to explore all three empty chambers; (ii) sociability: a stranger mouse was placed in a small cage in one of the two end-chambers while the other cage was empty; (iii) social novelty: a novel mouse was placed in the previously empty cage while the previous stranger mouse was now a familiar conspecific. The time spent by the test mouse in each of the chambers was measured to determine the sociability and social novelty behaviors. To examine a possible role of oxytocin underlying the differential social responses of these mice we performed quantitative oxytocin receptor autoradiography using [125I] OVTA in brain sections (n=6/genotype). While all genotypes showed normal sociability behaviour by preferring spending their time in the chamber containing the stranger mouse (two-way ANOVA; social chamber effect: p<0.001), only 1a-/- mice displayed preference for the novel mouse (two-way ANOVA; p<0.01). These behavioral changes were concomitant with an increased oxytocin receptor binding specifically in 1a-/- mice in the nucleus accumbens (1a-/-, 0.652 ± 0.164; p<0.01 and p<0.05; compared to WT, 0.135 ± 0.056 and 1b-/-, 0.257 ± 0.080 respectively; one-way ANOVA), as well as in the ventral limb of the diagonal band of Broca (1a-/-, 1.561 ± 0.0.73; p<0.01 and p<0.05; compared to WT, 1.055 ± 0.136 and 1b-/-, 1.266 ± 0.110 respectively; one-way ANOVA). Our data show an enhanced response to social novelty of the 1a-/- mice when compared to WT and 1b-/-, which might have an association with a region-specific increase of oxytocin receptor density in the brain. In addition, these findings suggest a possible interaction of GABAB(1a) and oxytocin receptors to mediate social behaviors and point towards further investigation for these receptors as a novel target for autism treatment.