Synaptic Dysfunction in Intellectual Disability Caused by SYNGAP1. Translational Research to Develop Human Models and Advance Pharmacological Treatments.
SYNGAP1 is a GTPase activating protein highly specific to excitatory synapses, where it is a major constituent of the postsynaptic density. De novo mutations in SYNGAP1 represent one of the most prevalent monogenic forms of intellectual disability (ID), possibly explaining up to 1% of all ID cases. Syngap1+/- mice present cognitive and behavioural alterations related to ID and have many synaptic properties compromised. Syngap1 animal models indicate that synapse dysfunction is a major contributor to ID. Despite our substantial understanding of Syngap1 protein function, pharmacological strategies devised in mice have failed to recover cognitive and behavioural phenotypes. Indicating that our knowledge of the underlying molecular pathology is still insufficient. Moreover, human research models of SYNGAP1 ID are lacking, which also difficult the formulation of better pharmacological strategies. TREAT-SNGAP will develop human neuronal models of SYNGAP1 haploinsufficiency from patients, which will be used to investigate this condition in human neurons for the first time. Mouse models will also be investigated to put human findings in context with previous data. An unpublished proteomics dataset identifying the main signalling pathways altered in Syngap1+/- mice has been used to select four drugs. These will be tested in human and mouse to look for rescue of synaptic phenotypes relevant to SYNGAP1 ID. The ultimate goal of TREAT-SNGAP is to identify new strategies to treat ID.
Imaging techniques, Gene targeting in the brain, Stem cells and neural differentiation/cell therapy, schizophrenia, Imaging techniques, Pharmacology, Electrophisiological approaches, Behavioural methodologies, Clinical trial, Intellectual disability, omics approaches, anti-NMDA receptor encephalitis, psychosis, cognitive impairment, motor symptoms, Translational, Multidisciplinary, Synaptopathy, iPSC, Organoid, human brain models, SYNGAP1
2018 - 2021
Alex Bayes (Coordinator)