Final Report Summary - MERE-GLU (Mental Retardation: Harnessing the Glutamate Hypofunction Hypothesis)
This research project is aimed at unravelling the molecular and cellular mechanisms underlying ID, by focusing on the synaptic deficits of the disease. Our hypothesis is that at the cellular level, most of the ID proteins impinge on signalling pathways that are important for the proper functioning of the synapse. More specifically we propose that those signalling pathways are involved in controlling the expression and/or trafficking of glutamate receptors at the synapse.
Our objectives are concentrated around three themes. First, by performing a functional screening of ID genes for synaptic function in rodent neuronal systems we will identify novel ‘hub’ signalling pathways implicated in ID. Second, we will investigate in detail how known ID genes lead to synaptic dysfunction in vivo. Third we will develop tools to rescue the synaptic deficits caused by ID genes.
Through the functional screening of novel identified ID genes we identified novel main ‘hub’ signalling pathways that are implicated in synaptic function and more specifically in glutamate receptor expression/trafficking. Genes linked to epigenetic regulation have emerged as an important signalling pathway involved in ID and related disorders such as autism and schizophrenia. We have performed in depth characterization of the gene cluster involved in Kleefstra syndrome (e.g. EHMT1, MBD5, MLL3, SMARCB1 and NR/3) and Koolen-de Vries syndrome. We were able to link epigenetic modifications to synaptic function and cognition. To this end we took advantage of human induced pluripotent stem cells, a state of the art technology that allowed us to make pluripotent stem cells from patient fibroblasts and subsequently derive them into neurons. By doing so we have identified key signalling mechanisms disturbed in Kleefstra syndrome. Together these results indicate that through the functional characterization of ID genes novel hub signalling pathways, which are important for synaptic function, can be uncovered. This will be critical in order to design detailed pharmacological strategies for ID.