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

Frontiers in Molecular Neuroscience

Molecular Neuroscience

Anne Biton¹  Bertrand Fin²  Anne Boland²  Jean-François Deleuze³  Christelle Rochefort⁴  Julien Schmitt⁴  Laure Rondi-Reig⁴  Benoît Forget⁵  Anne-Marie Le Sourd⁵  Aziliz Leboucher⁵  Elisabeth Verpy⁵  Fabrice De Chaumont⁵  Thomas Bourgeron⁵  Sabrina Coqueran⁵  Allain-Thibeault Ferhat⁶  Elodie Ey⁷  Florian Mueller⁸  Tobias M. Boeckers⁹ 

[1] Bioinformatics and Biostatistics Hub, Institut Pasteur, Université Paris Cité, Paris, France;Centre National de Recherche en Génomique Humaine, CEA, Université Paris-Saclay, Evry, France;Centre National de Recherche en Génomique Humaine, CEA, Université Paris-Saclay, Evry, France;Centre d’Étude du Polymorphisme Humain, Paris, France;Cerebellum Navigation and Memory Team, Institut de Biologie Paris Seine, Neurosciences Paris Seine, CNRS UMR 8246, Inserm UMR-S 1130, Sorbonne Université, Paris, France;Génétique Humaine et Fonctions Cognitives, Institut Pasteur, CNRS UMR 3571, IUF, Université Paris Cité, Paris, France;Génétique Humaine et Fonctions Cognitives, Institut Pasteur, CNRS UMR 3571, IUF, Université Paris Cité, Paris, France;Department of Neuroscience, Columbia University Irving Medical Center, New York, NY, United States;Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States;Génétique Humaine et Fonctions Cognitives, Institut Pasteur, CNRS UMR 3571, IUF, Université Paris Cité, Paris, France;Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, Inserm UMR-S 1258, Université de Strasbourg, Illkirch-Graffenstaden, France;Imagerie et Modélisation, Institut Pasteur, CNRS UMR 3691, Paris, France;Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany;Deutsches Zentrum für Neurodegenerative Erkrankungen, Ulm, Germany;

关键词: autism;    Shank3;    mouse model;    stereotyped behavior;    striatum compartmentation;    GAD65;    striosomes;    matrix;   

DOI  :  10.3389/fnmol.2023.1139118

 received in 2023-01-06, accepted in 2023-02-16,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Ferhat, Verpy, Biton, Forget, De Chaumont, Mueller, Le Sourd, Coqueran, Schmitt, Rochefort, Rondi-Reig, Leboucher, Boland, Fin, Deleuze, Boekers, Ey and Bourgeron.