Behavioral phenotyping of an improved mouse model of Phelan-McDermid Syndrome with a complete deletion of the Shank3 gene

Phelan-McDermid Syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability, and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms. Here, we report the production and thorough behavioral characterization of a new mouse model in which all Shank3 isoforms are disrupted. Our mice are more severely affected than previously published models. While the deficits were typically more pronounced in homozygotes, an intermediate phenotype was observed for heterozygotes in many paradigms. As in other Shank3 mouse models, stereotypies, including increased grooming, were observed. Additionally, both sensory and motor deficits were detected in neonatal and adult mice. While social behaviors were not strongly impacted, Shank3 -deficient mice displayed a strong escape behavior and avoidance of inanimate objects indicating increased novelty-induced anxiety. Similarly, increased freezing was observed during fear conditioning training and amygdala-dependent cued retrieval. Finally, deficits were observed in both initial training and reversal in the Barnes maze and in contextual fear memory that are memory tasks involving hippocampal-prefrontal circuits. This new mouse model of PMS, engineered to most closely represent human mutations, recapitulates core symptoms of PMS providing improvements for both construct and face validity, compared to previous models. Significant statement Phelan-McDermid syndrome, caused by happloinsufficiency of Shank3 , is a severe and complex neurodevelopmental disorder. This study investigates the behavioral consequences of a disruption of all Shank3 isoforms in neonatal and adult mice using a detailed battery of tests tailored to investigate core symptoms and usual comorbidities of PMS. We found that our new model is more severely affected than previously published mouse models with only partial deletions of Shank3 and more closely recapitulates symptoms of PMS thus providing improvements for both construct and face validity. Our results highlight the significance of using a mouse model with a complete deletion of Shank3 for studying mechanisms underlying autism spectrum disorder and PMS, carrying preclinical studies and testing test novel therapeutic approaches.