Analysis of RAB39B role in X-linked Intellectual Disability: AMPA receptors as possible therapeutic targets

Human intellectual disability (ID), also referred to as Mental Retardation (MR), is a common and highly heterogeneous paediatric disorder with a frequency of 2 to 3%, with a very severe social impact. Family studies have identified 215 X-linked different ID conditions, but only 90 mutated genes have been found until now. These genes encode for several proteins with a variety of functions: chromatin remodelling, pre/post synaptic activity, intracellular trafficking, etc.; and the general idea is that ID phenotype could emerge as abnormal cellular processing leading to pre- and/or post-synaptic neuronal terminals dysfunction. In our laboratory, we identified loss of function mutations in GDI1 and RAB39B genes that cause ID. Our research will focus on the identification of the molecular pathways altered in the absence of RAB39B gene. It is known that αGDI controls the activity of RAB proteins involved in intracellular trafficking, one of the pathways important for development of cognitive functions. The proposed programme encompasses a large variety of techniques, spanning from molecular and cell biology and behavioural studies and the data generated, will carry out new insights in neuronal cell biology and development. Moreover, investigation of the neurobiological mechanisms underlying ID is a prerequisite for the development of therapies for the affected population.