URGENT : Unveiling the Role of Glutamate in dopaminE traNspoTer deficiency syndrome

Dopamine Transporter Deficiency Syndrome (DTDS) is a rare genetic disease affecting children with a deficit in the Dopamine Transporter (DAT), which regulates dopamine homeostasis and motor control. These children show severe motor symptoms from early infancy and worsening throughout childhood. At present, no effective treatments exist. Animal models allow to reveal mechanisms in depth using invasive methods that ethically cannot be applied to humans. Our consortium has multi-year experience in the study of rats lacking, totally or partially, the DAT, which is defective in DTDS patients. Strikingly, mutant animals replicate major symptoms found in children with DTDS, providing an excellent tool to identify novel pathophysiological pathways. To this end, by using these animals, as well as in vitro stem cell-based models reproducing DTDS mutations, we will study pathological mechanisms related to the glutamate system, the major excitatory neurotransmitter. We hypothesize that alteration of glutamate homeostasis, as shown by our preliminary data, could be rescued by memantine or bupropion. Since these drugs are commercially available, this would speed up the potential benefit for DTDS patients. Notably, our results could benefit other diseases characterized by altered dopamine-glutamate interactions such as Schizophrenia, Attention Deficit Hyperactive Disorder and Parkinson’s Disease. In the end, URGENT, via its well-integrated translational approach, holds the potential to identify meaningful markers of DTDS that could serve as guidance for more effective DTDS treatments.