Aix Marseille University
Jean-Pierre Mothet have been investigated the functions of astrocyte-neuron interactions and the novel brain messenger D-serine in synapse physiology in the central nervous system. He has 20 years of research experience with synaptic transmission and cell signalling. He received his MSc in Physiology at the University of Lyon in 1992 and then his PhD in Neuroscience from the University Pierre and Marie Curie, Paris, in 1996. During his PhD under the supervision of DR. Ladislav Tauc in Gif-sur-Yvette (France), he studied biophysics and neuropharmacology of synaptic transmission in the sea slug Aplysia. After his Ph.D, he moved to the USA to carry out postdoctoral research in the laboratory of Pr Solomon H. Snyder at The Johns Hopkins School of Medicine in Baltimore (USA). There he worked at exploring the functions and the synthesis pathway of brain D-amino acids a novel class of brain molecules with a special focus on D-serine. He discovered that D-serine rather than glycine is the endogenous coagonist of synaptic N-Methyl D-Aspartate subtype of glutamatergic receptors in the hippocampus, a breakthrough with profound lasting impact in the fields of synaptic physiology and neuropharmacology. He also helped to identify serine racemase the enzyme that synthesizes D-serine from L-serine in the brain. In 1999, he took a second postdoctoral position in the laboratory of Professor Jacopo Meldolesi In 1999 (Milano, Italy), one of the most eminent cell biologists in Europe where he got trained in the study of calcium-dependent exocytosis of transmitter release and membrane trafficking. Since 2000 as a CNRS scientist, he has been continuously developping an unique and very innovative project in France and EU on the neurobiology of D-serine. His team investigates the regulation of NMDA receptors by their co-agonists (D-serine and glycine) at synapses and circuits underlying memory formation, motivation and decision-making in the context of neuron-glia interactions of the healthy and diseased nervous system. He also explores the molecular and cellular events driving gliotransmission, i.e. the process by which glia releases chemical messengers, and the functional relevance of this process for synapses patterning and neuronal network functions. He was first to establish that astrocytes release D-serine through a calcium and SNARE protein-regulated exocytosis (PNAS 2005) of synaptobrevin2 positive secretory organelles (Glia 2008). More recently, he developed unique protocols for the purification of glial vesicles and found functional evidence for the existence of a vesicular transporter for D-serine (J Neurosci 2013). Growing on his expertise in the field, he has shown that in the hypothalamus D-serine released by astrocytes controls the direction and the amplitude of long-term synaptic plasticity (Cell 2006). Furthermore, his team has demonstrated that at mature synapses D-serine is the right co-agonist for synaptic GluN2A-containing NMDARs at glutamatergic neurons in the prefrontal cortex (Cereb Cortex 2012) and in the hippocampus (Cell 2012) while glycine is the co-agonist for extrasynaptic GluN2B-containing NMDARs. He has also shown that the identity of the co-agonist is synapse specific and developmentally regulated in the hippocampus paralleling the developmental switch of GluN2A/2B subunits (PNAS 2015). His team has also discovered that D-serine plays a central role in learning and memory and that a deficit in its synthesis is responsible for the cognitive and synaptic deficits associated to normal aging (Aging Cell 2006, 2012). He is currently leading the lab \'Gliotransmission and Synaptopathies\' at the Centre de Recherches en Neurobiologie et Neurophysiologie de Marseille (France) where his team is combining cell biology, biochemistry, and cellular electrophysiology with live cell imaging and the development of biosensors. In 2012, he was elected President of the French Club of Glial Cells an association aimed to ^romote and support research on glial cells. He is the member of the Editorial board of Frontiers in Synaptic Neuroscience and of PlosONE. His research is internationally recognized and has stimulated many research programs in academy and Industry in France and worldwide. His research have paved the ways for the development of new drug-based therapies of cognitive deficits during normal aging but also for those associated to psychiatric disorders such as schizophrenia.
Research Interests: 1. Regulation of NMDA receptors by their co-agonists in the healthy and diseased nervous system 2. Molecular and cellular mechanisms of gliotransmission and the functional impact of this process in synapse and neuronal network patterning and dynamics, 3. Development of technologies like biosensors.