Social Behavior in Fmr1 Hemizygotic and SAPAP3 Knockout Mice

Background: Mounting evidence suggests that a number of psychiatric disorders such as schizophrenia, obessive-compulsive disorder, intellectual disability and autism spectrum disorder are associated with synaptic defects. Of its myriad of components, the translational repressor FMR1 and the cytoskeletal SAPAP3 proteins are two members of the intricate postsynaptic machinery. While a link between Fmr1 gene mutations and syndromic autism is well established, variations of the Sapap3 gene have been suggested to be associated with obsessive-compulsive disorder and not autism. Yet, a relationship between the SAPAP3 protein and autistic behaviour cannot be ruled out completely. SAPAP proteins belong to the postsynaptic scaffold arching from neurexins to Shank proteins that has also been implicated in autism and dendritic translation of SAPAP proteins is regulated by the FMR1 protein.  

Objectives: Earlier studies showed both impaired, unaltered or even higher than normal social behaviour in Fmr1 hemizygotic mice depending on the background strain, the behavioural assay used and the investigating site. One aim of the present study was to examine whether Fmr1 hemizygotic mice made on an FVB/AntJ background behaved in an asocial way that would support the notion of the use of these mice as a disease model of autism. The other objective of the study was to investigate whether the lack of the SAPAP3 protein resulted in any social behavioural defect. 

Methods:  Both Fmr1 hemizygotic and SAPAP3 knockout mice were made at the Institute of Experimental Medicine of the Hungarian Academy of Sciences on an FVB.129P2-Pde6b⁺ Tyr^c-ch/AntJ and C57Bl/6J background, respectively. In case of Fmr1 mice only males, while in case of SAPAP3 transgenics, both male and female mice were investigated. Social behaviour of the animals was assessed in three assays; the dyadic reciprocal social interaction, the 5-trial social memory and the 3-chamber social preference tests (at ages of 2.5-5 months and 4.5-7.5 months for Fmr1 and SAPAP mice, respectively).

Results:  Fmr1 knockout male mice made on an FVB background showed normal social behaviour in all three assays and were not different from their wild type littermates. Both male and female SAPAP3 knockout animals spent more time in active social interaction when compared with the wild type littermates of the same gender. In the 3-chamber sociability assay, both genders showed preference for a gender-matched target mouse. In the 5-trial social memory assay SAPAP knockout mice of both genders produced a typical pattern of habituation and dishabituation however, male knockouts were significantly less active than their wild type littermates.

Conclusions:  Social behaviour of Fmr1 knockout mice made on the FVB/AntJ background is not different from their wild type littermates in the assays applied in the present study. SAPAP3 KO mice showed a complex, nevertheless in general normal social behaviour. Notwithstanding the implication of the FMR1 protein in the pathomechanism of autism, the Fmr1 knockout mice on this particular genetic background cannot be used as a disease model of autism. Results of the present study also indicate that SAPAP3 knockouts are not suitable models of defective social behaviour.