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Autism is characterized by atypical social communication and stereotyped behaviors. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are detected in 1–2% of patients with autism and intellectual disability, but the mechanisms underpinning the symptoms remain largely unknown. Here, we characterized the behavior of Shank3Δ11/Δ11 mice from 3 to 12 months of age. We observed decreased locomotor activity, increased stereotyped self-grooming and modification of socio-sexual interaction compared to wild-type littermates. We then used RNAseq on four brain regions of the same animals to identify differentially expressed genes (DEGs). DEGs were identified mainly in the striatum and were associated with synaptic transmission (e.g., Grm2, Dlgap1), G-protein-signaling pathways (e.g., Gnal, Prkcg1, and Camk2g), as well as excitation/inhibition balance (e.g., Gad2). Downregulated and upregulated genes were enriched in the gene clusters of medium-sized spiny neurons expressing the dopamine 1 (D1-MSN) and the dopamine 2 receptor (D2-MSN), respectively. Several DEGs (Cnr1, Gnal, Gad2, and Drd4) were reported as striosome markers. By studying the distribution of the glutamate decarboxylase GAD65, encoded by Gad2, we showed that the striosome compartment of Shank3Δ11/Δ11 mice was enlarged and displayed much higher expression of GAD65 compared to wild-type mice. Altogether, these results indicate altered gene expression in the striatum of Shank3-deficient mice and strongly suggest, for the first time, that the excessive self-grooming of these mice is related to an imbalance in the striatal striosome and matrix compartments.

Mice are increasingly used as models of human-acquired neurological or neurodevelopmental conditions, such as autism, schizophrenia, and Alzheimer’s disease. All these conditions involve central auditory processing disorders, which have been little investigated despite their potential for providing interesting insights into the mechanisms behind such disorders. Alterations of the auditory steady-state response to 40 Hz click trains are associated with an imbalance between neuronal excitation and inhibition, a mechanism thought to be common to many neurological disorders. Here, we demonstrate the value of presenting click trains at various rates to mice with chronically implanted pins above the inferior colliculus and the auditory cortex for obtaining easy, reliable, and long-lasting access to subcortical and cortical complex auditory processing in awake mice. Using this protocol on a mutant mouse model of autism with a defect of the Shank3 gene, we show that the neural response is impaired at high click rates (above 60 Hz) and that this impairment is visible subcortically—two results that cannot be obtained with classical protocols for cortical EEG recordings in response to stimulation at 40 Hz. These results demonstrate the value and necessity of a more complete investigation of central auditory processing disorders in mouse models of neurological or neurodevelopmental disorders.