Neuronal dysfunctions underlying Phelan-McDermid syndrome and theirs rescue by genetic and pharmacological modulation of mGlu5 signaling

Phelan McDermid syndrome (PMS) is a genetic disorder, as of yet without cure, characterized by intellectual disability and autistic features, hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech and minor dysmorphic features. The increasing number of patients being reported supports the hypothesis that this syndrome may be a common source of autism and intellectual disability. Lack of one copy of Shank3 gene is very likely the cause of the major neurological features associated with PMS. Shank3 gene is encoding a structural protein located in the synapses of the human nervous system and involved in dendritic spines formation (small neuronal protrusions that are the contact point to receive input from the other neuronal cells). Our preliminary data suggest that the signaling pathways of a specific glutamate receptor protein expressed on the dendritic spines, called mGlu5, is altered in Shank3 KO mice, due to disassembly of the mGlu5-Homer-Shank protein complex in specific brain areas. The main goal of this project is to understand if therapeutic strategies based on mGlu5 positive modulators might ameliorate cognitive defects caused by Shank 3 genetic mutations. In this project we will use two complementary models. The use of Shank3 KO mice will allow to clarify, in vivo, how and in which brain areas Shank3 absence affects mGlu5 signaling and if treatment with mGlu5 positive modulators is able to ameliorate the functional and behavioral defects found in these mice. The use of hiPSC-derived neurons from PMS patients will provide the opportunity to test if the cellular and molecular phenotypes found in mice are present also in human neurons and might be rescued by increasing mGlu5 activity. The proposed project represents a preclinical step toward the development of potentially specific and effective therapies, based on mGlu5 positive modulators, to ameliorate neurological symptoms caused by Shank3 deletion.