BEHAVIOR PHENOTYPING OF A MOUSE MODEL OF PHELAN MCDERMID SYNDROME WITH A FULL DELETION OF SHANK3 GENE

Background Phelan-McDermid Syndrome (PMS) is a rare genetic syndrome in which one copy of the q13 portion of chromosome 22 is missing or mutated leading to a global developmental delay, hypotonia, delayed or absent speech, intellectual disability, and autistic behaviors. SHANK3, a gene coding for a key structural part of the post-synaptic density, is the critical gene for the core neurological and behavioral symptoms in this syndrome, and the loss of one copy of SHANK3, occurring through intragenic deletion or point mutation, is sufficient to cause Phelan-McDermid syndrome. However, the size of the region affected can be highly variable, from point mutation to up to 8 Mb deletions and the deletion size seems to be correlated with the syndrome severity. Due to multiple intragenic promoters and alternatively spliced coding exons within the gene, several Shank3 isoforms have been identified in human and mouse brains. Methods Numerous mouse models have been generated but most target only some of those isoforms while the vast majority of SHANK3 mutations found in PMS patients are deletions of the entire gene. Our aim is based on a novel mouse model, in which all Shank3 isoforms are disrupted and which more closely mirrors the most common genetic mutations found in PMS and our goal was to investigate the behavioral consequences of a disruption of all isoforms of Shank3. Results Our laboratory had previously created a mouse model with a deletion of exons 4 to 9 leading to the disruption of the full length Shank3 protein. We used a Cre-LoxP strategy to add an additional LoxP site flanking exon 22 and disrupt all isoforms. We carried an extensive behavioral phenotyping of neonate, young and adult wild-type, heterozygote and homozygote mice with a battery of test designed to assess the main feature of PMS including neurodevelopmental milestones, sensory and motor functions, sociability, stereotypies and cognitive functioning. Discussion Mice with a full deletion of Shank3 are more severely affected than previously published mouse model with a partial deletion. Abnormal Mendelian ratios at the time of weaning were observed showing a significant deficit for homozygote mice that can be partially explained by an increase of early postnatal lethality. Both sensory and motor disabilities were detected in neonate and adult mice. While social performances and interest for social stimuli were not impaired, the homozygote mice displayed a strong object avoidance and escape behavior. Additionally, we observed a deficit in both initial training and reversal of Barnes maze, a spatial memory task involving hippocampal-prefrontal circuits. Electrophysiological recording showed that both long-term potentiation and long-term depression are impaired in Shank3 deficient mice. Our new mouse model of PMS recapitulates the core symptoms of PMS providing an improvement of both construction and face validity compared to previous model. Ongoing experiments will identify neural mechanisms and brain circuitry involved in PMS and will use this model to screen potential treatments for Shank3-haploinsufficiency.