Role of NMDA receptor nanoscale organization in normal brain development and GRIN disorders. – GRINTRACK

More than 1% of children are born with a neurodevelopmental disorder, including autism spectrum disorders and developmental delay. Whole-genome sequencing has revolutionized diagnostic assessment and has identified hundreds of genes that may cause intellectual disability and developmental delay via a point mutation or a gene truncation. Considerable genetic variation in the ionotropic glutamate receptor genes, N-methyl-d-aspartate (RNMDA) receptors (GRIN), has recently emerged, with several hundred variants identified. When specific mutations strongly affect RNMDA activity, patients present with extensive brain malformation, illustrating the critical role of this receptor in neuronal development. However, developmental delay can also be observed in patients with point mutations, especially in the intracellular part (CTD) of RNMDA, which controls their motilities at the neuronal surface without altering RNMDA activity. By combining molecular and cellular biology approaches, high-resolution microscopy techniques and mouse and human models of these pathologies, we will first characterize and manipulate the NMDAR nanoscale organization and mobility during the different steps of neuronal development. By studying a mutant lacking its DCT part, identified in a patient with an autistic-like syndrome, we want to determine if RNMDA mobility can contribute to neurodevelopmental diseases. Finally, we will develop a diagnostic platform dedicated to the characterization of GRIN disorders and evaluating the therapeutic potential of existing drugs or new molecules.