Hyperactivity and Abnormal Social and Vocal Behaviours in ProSAP1/Shank2 -/- Mice, a Model of Autism Spectrum Disorders

Background: Mutations in genes coding for synaptic proteins were shown to increase susceptibility to autism spectrum disorders (ASD). Among the causative proteins, the cell adhesion molecules neuroligins and neurexins as well as the scaffolding protein PROSAP2/SHANK3 were repeatedly associated in independent patients with ASD. Recently the scaffolding protein PROSAP1/SHANK2 has also been associated with ASD and we recently confirmed these results by the identification of novel mutations in patients with ASD and the ascertainment of the functional impact of these mutations on synaptic density (Leblond et al. PLoS Genetics, 2012).

Objectives: Following these studies, animal models were developed to better characterise the role of susceptibility genes in ASD. In a collaborative study, we recently analysed transgenic knockout mice lacking ProSAP1/Shank2 (see accompanying abstract by Schmeisser et al.). These mice display abnormal glutamatergic receptor expression and neurotransmission. Our group investigated the development and the adult behaviour of ProSAP1/Shank2 ^-/- mice to understand the contribution of ProSAP1/Shank2deletion to symptoms in social, communicative or stereotyped behaviours.

Methods: Comparisons were drawn between ProSAP1/Shank2 ^-/-, ProSAP1/Shank2 ^+/-and wild-type littermates. Pups and adults were tested to examine the developmental trajectory of abnormalities. We conducted social interactions tests recordings of ultrasonic vocalisations, self-grooming and digging measures, as well as general activity and anxiety measures.

Results: Abnormalities in body weight as well as in vocal behaviour emerged in the first two weeks of life of ProSAP1/Shank2 ^-/- pups, and persisted during adulthood. Adult ProSAP1/Shank2 ^-/- males and females were hyperactive. Only ProSAP1/Shank2 ^-/-females groomed themselves for longer time in comparison with their littermates. Impairments in social interactions emerged mostly in free social interactions, and appeared together with abnormalities in usage and structure of ultrasonic vocalisations.

Conclusions: All together, this collaborative study suggests that mutations in genes causing ASD in humans can alter glutamatergic neurotransmission and cause alterations in social interactions and communication in mice. Together with other mouse models of ASD, the ProSAP1/Shank2 ^-/- mice may provide a comprehensive framework to identify new knowledge-based treatments of ASD.