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

Abstract

Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks 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. 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-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.

Shank mutant mice as an animal model of autism

“…In contrast, the Shank2 e6 -7 mutation showed decreased NMDAR-EPSC/AMPAR-EPSC ratio, together with impaired NMDAR-LTP and NMDAR-LTD. In other words, the results of Schmeisser et al [68] are consistent with increased NMDAR-mediated synaptic function, and the results of Won et al [67] are consistent with decreased NMDAR-mediated synaptic function. The distinct findings of both enhanced and reduced NMDAR function in mice that display similar autistic-like behaviours suggest that maintaining normal levels of NMDAR function could be the critical factor.…”

“…And these discrepancies are, to some extent, likely due to the laboratory environment and the genetic background of the transgenic mice [78,79]. For instance, can we claim the same phenotype for the Shank2 mice that show repetitive jumping behaviour in one line and repetitive self-grooming in another [67,68]?…”

“…In a three-chamber test, Shank2 e6 -7 mice showed less preference to a novel animal over a novel object [67]. In a resident-intruder social interaction test, both male and female Shank2 e7 could not maintain social contact with novel mice for as long as WT mice did [68].…”

“…There have been pioneering studies using genetic constructs of Shank2 mimicking human Shank2 microdeletions (table 2). One group tested mice with a deletion of exons 6 and 7 (Shank2 e6 -7 ) [67], while another group tested mice with a deletion of exon 7 only (Shank2 e7 ) [68]. Although the exons targeted by the two studies differ slightly, both target the PDZ region and should knock out all known Shank2 isoforms.…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Shank2 -/-mice, which exhibit almost all the core features of ASD such as increased stereotypic behavior, impairment in social interaction, hyperactivity and anxiety show a similar reduction in the number of dendritic spines and a decrease basal synaptic transmission with depletion of NMDA receptors 183 . Several mouse models have been generated to investigate the role of Shank3 and its splice variants in ASD.…”