Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2

Altered glutamatergic neurotransmission can lead to the core symptoms of autism, and ProSAP1/Shank2 and ProSAP2/Shank3 proteins seem to serve different interrelated functions at excitatory synapses, especially in glutamate receptor targeting/assembly. Synapse defects linked to autism ProSAP/Shank scaffolding proteins are part of the complex protein machinery of the postsynaptic density region at excitatory synapses, and have been genetically linked to some forms of autism. Tobias Boeckers and colleagues generate a Shank2-knockout mouse that is extremely hyperactive, and displays autism-related behaviours such as increased anxiety and abnormal social behaviour. At the cellular level, glutamatergic activity is increased, which is the opposite effect of that seen in mice lacking a related protein, Shank3. These results suggest that balanced levels of individual ProSAP/Shank family members are essential to normal synaptic function, and highlight the fact that opposing cellular and molecular effects can lead to similar behavioural phenotypes. Eunjoon Kim and colleagues demonstrate that Shank2-mutant mice carrying a mutation identical to a microdeletion in the human SHANK2 gene that is associated with Autism spectrum disorder are hyperactive and exhibit autism-like behaviours, including disrupted social behaviours. The mice have decreased NMDA glutamate-receptor (NMDAR) function, and their social behaviour can be improved by restoring NMDAR function pharmacologically. Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour 1 . Mutations in synaptic proteins such as neuroligins 2 , 3 , neurexins 4 , GKAPs/SAPAPs 5 and ProSAPs/Shanks 6 , 7 , 8 , 9 , 10 were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion 11 , 12 . Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2 −/− mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N -methyl-