Shank3 deficits in the anteromedial bed nucleus of the stria terminalis trigger an anxiety phenotype in mice

• Published in: The European journal of neuroscience Vol. 57; no. 12; pp. 1966 - 1979
• Main Authors: Contestabile, Alessandro, Casarotto, Giulia, Musardo, Stefano, Espinosa, Pedro, Maltese, Federica, Jiang, Yong‐hui, Bellone, Camilla, Glangetas, Christelle
• Format: Journal Article
• Language: English
• Published: France Wiley Subscription Services, Inc 01.06.2023
• Subjects: Animals; anteromedial bed nucleus of the stria terminalis (amBNST); Anxiety; Anxiety - metabolism; Anxiety disorders; Anxiety Disorders - metabolism; Autism; Genotype & phenotype; Glutamatergic transmission; Longitudinal studies; longitudinal study; Medicin och hälsovetenskap; Mice; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Morbidity; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Phelan–McDermid syndrome; Phenotype; Phenotypes; Septal Nuclei - metabolism; Shank3; Social Behavior; Social interactions; Stria terminalis; anteromedial bed nucleus of the stria terminalis (amBNST); anxiety; longitudinal study; Phelan-McDermid syndrome; Shank3
• ISSN: 0953-816X; 1460-9568; 1460-9568
• DOI: 10.1111/ejn.16043

Anxiety disorders are the most prevalent co‐morbidity factor associated with the core domains of autism spectrum disorders (ASD). Investigations on potential common neuronal mechanisms that may explain the co‐occurrence of ASD and anxiety disorders are still poorly explored. One of the key questions that remained unsolved is the role of Shank3 protein in anxiety behaviours. Firstly, we characterize the developmental trajectories of locomotor, social behaviour and anxiety traits in a mouse model of ASD. We highlight that the anxiety phenotype is a late‐onset emerging phenotype in mice with a Shank3Δe4‐22 mutation. Consequently, we used an shRNA strategy to model Shank3 insufficiency in the bed nucleus of the stria terminalis (BNST), a brain region exerting a powerful control on anxiety level. We found that Shank3 downregulation in the anteromedial BNST (amBNST) induced anxiogenic effects and enhanced social avoidance after aversive social defeat. Associated with these behavioural defects, we showed alteration of glutamatergic synaptic functions in the amBNST induced by Shank3 insufficiency during adolescence. Our data strongly support the role of Shank3 in the maturation of amBNST, and its key role in anxiety control. Our results may further help to pave the road on a better understanding of the neuronal mechanisms underlying anxiety disorders implicated in ASDs. Shank3Δe4‐22 mutated adult mice present anxiety traits. In order to fully understand the role of Shank3 protein in anxiety behaviours, it is important to identify when the behavioural deficits appear and which brain regions are implicated. In this study, we highlight that the anxiety phenotype is emerging 36 days after birth in Shank3‐deficient mice. Moreover, using an shRNA strategy to model Shank3 insufficiency, we demonstrated that perturbation of the anteromedial BNST (amBNST) induced anxiogenic effects.