Neuropharmacology

Biography

Biography: Jean-Pierre Mothet

Abstract

The N-Methyl D-Aspartic acid (NMDA) receptors (NMDARs) are key glutamate-gated ionotropic receptors that are central for synaptic plasticity across lifespan but also engaged in the pathogenesis of many brain diseases that affect our societies. For this reasons NMDARs are prime targets for drug development. Activation of NMDARs always requires the binding of a co-agonist that has long been thought to be glycine. However, intense research over the last two decades has have shown that D-serine, an atypical amino acid metabolized by brain cells is the preferential co-agonist for a large proportion of synaptic NMDARs in many areas of the adult brain. Nowadays, a totally new picture of glutamatergic synapses at work is emerging where both glycine and D-serine are involved in a complex orchestration of NMDAR functions in the CNS following temporal and spatial constraints. During my lecture, I will highlight the particular role of each co-agonist in modulating NMDAR at developing and mature central synapses of different brain regions and show how the functions of D-serine and glycine at NMDARs can be pressured by specific neuromodulatory systems. Then, I will show how the discovery of D-serine metabolism and functions have opened new avenues for the development of new drug-based therapies of cognitive deficits during normal aging, for those associated to psychiatric disorders such as schizophrenia but also to prevent cellular damages associated to NMDARs overactivation as observed in early phases of Alzheimer’s disease.