RT Journal Article SR Electronic T1 Excessive self-grooming of Shank3 mutant mice is associated with gene dysregulation and imbalance between the striosome and matrix compartments in the striatum JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.01.19.476922 DO 10.1101/2022.01.19.476922 A1 Allain-Thibeault Ferhat A1 Anne Biton A1 Elisabeth Verpy A1 Benoit Forget A1 Fabrice de Chaumont A1 Florian Mueller A1 Anne-Marie Le Sourd A1 Sabrina Coqueran A1 Julien Schmitt A1 Christelle Rochefort A1 Laure Rondi-Reig A1 Aziliz Leboucher A1 Anne Boland A1 Bertrand Fin A1 Jean François Deleuze A1 Tobias M. Boeckers A1 Elodie Ey A1 Thomas Bourgeron YR 2022 UL http://biorxiv.org/content/early/2022/01/21/2022.01.19.476922.abstract AB Autism spectrum disorders (ASD) are characterised by atypical social communication and stereotyped behaviours. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are detected in 1-2% of patients with ASD and intellectual disability (ID), but the mechanisms underpinning the symptoms remain largely unknown. Here, we characterized the behaviour of Shank3 mutant mice deleted for exon 11 (Shank3Δ11/Δ11) from three to twelve months of age. We observed decreased locomotor activity, increased stereotyped self-grooming and atypical 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 (DEG). DEGs were identified mainly in the striatum and were associated with synaptic transmission (e.g. Grm2, Dlgap1), G-protein-signalling pathways (e.g. Gnal, Prkcg1, and Camk2g), as well as excitation/inhibition balance (e.g. Gad2). Downregulated and upregulated genes were respectively enriched in the gene clusters of medium-sized spiny neurons expressing the dopamine 1 (D1-MSN) and the dopamine 2 receptor (D2-MSN). Moreover, expression of DEGs reported as striosome markers within the striatum (Cnr1, Gnal1, Gad2, and Drd4) were positively correlated with excessive self-grooming. Finally, we showed that the striosome compartment of Shank3Δ11/Δ11 mice was enlarged and displayed higher expression of GAD65 compared to wild-type mice. Altogether, these results shed light on a possible role of the striosomes/matrix imbalance in excessive self-grooming in Shank3Δ11/Δ11 mice. Such striatal alterations could be present in a subgroup of patients with ASD and ID and could open the way to new therapeutic approaches.Competing Interest StatementThe authors have declared no competing interest.