Synaptic and behavioral dysfunctions in mice carrying the autism-risk Shank3 Q321R mutation

Abstract

Shank3 is a postsynaptic scaffolding protein involved in the regulation of synapse assembly and function. Mutation in Shank3 protein has been implicated in psychiatric disorders, including autism spectrum disorders (ASD) and Phelan-McDermid Syndrome. In the present study, we generated and characterized a knock-in mouse line carrying the Shank3 Q321R mutation (Shank3 Q321R mice) identified in a human individual with ASD. Shank3 Q321R mutation located in the ankyrin repeat region (ARR) of the Shank3 protein (exon 8 of the Shank3 gene) cause a selective decrease in the expression level of Shank3a, an ARR-containing protein variant, but not other variants. Shank3 Q321R mice show normal excitatory synaptic transmission but decreased intrinsic neuronal excitability in the hippocampal pyramidal neurons. Behaviorally, these mice show anxiolytic-like behaviors and enhanced self-grooming, but normal locomotion, social interaction, and object recognition memory. In addition, these mice display abnormal electroencephalography (EEG) patterns and decreased susceptibility to induced seizures. These results indicate that the Q321R human mutation alters Shank3 protein stability, neuronal excitability, repetitive and anxiety-like behavior, EEG patterns, and seizure susceptibility in mice.