AUTHOR=Ferhat Allain-Thibeault , Verpy Elisabeth , Biton Anne , Forget Benoît , De Chaumont Fabrice , Mueller Florian , Le Sourd Anne-Marie , Coqueran Sabrina , Schmitt Julien , Rochefort Christelle , Rondi-Reig Laure , Leboucher Aziliz , Boland Anne , Fin Bertrand , Deleuze Jean-François , Boeckers Tobias M. , Ey Elodie , Bourgeron Thomas 

TITLE=Excessive self-grooming, gene dysregulation and imbalance between the striosome and matrix compartments in the striatum of Shank3 mutant mice

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=16

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1139118

DOI=10.3389/fnmol.2023.1139118

ISSN=1662-5099

ABSTRACT=<p>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 <italic>Shank3</italic><sup>Δ11/Δ11</sup> 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., <italic>Grm2, Dlgap1</italic>), G-protein-signaling pathways (e.g., <italic>Gnal</italic>, <italic>Prkcg1</italic>, <italic>and Camk2g</italic>), as well as excitation/inhibition balance (e.g., <italic>Gad2</italic>). 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 (<italic>Cnr1</italic>, <italic>Gnal</italic>, <italic>Gad2</italic>, <italic>and Drd4</italic>) were reported as striosome markers. By studying the distribution of the glutamate decarboxylase GAD65, encoded by <italic>Gad2</italic>, we showed that the striosome compartment of <italic>Shank3</italic><sup>Δ11/Δ11</sup> 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 <italic>Shank3</italic>-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.</p>