Modulation of NMDA Receptors by G-protein-coupled receptors: Role in Synaptic Transmission, Plasticity and Beyond

NMDA receptors (NMDARs) play a critical role in excitatory synaptic transmission, plasticity and in several forms of learning and memory. In addition, NMDAR dysfunction is believed to underlie a number of neuropsychiatric conditions. Growing evidence has demonstrated that NMDARs are tightly regulated by several G-protein-coupled receptors (GPCRs). Ligands that bind to GPCRs, such as neurotransmitters and neuromodulators, activate intracellular pathways that modulate NMDAR expression, subcellular localization and/or functional properties in a short- or a long-term manner across many synapses throughout the central nervous system. In this review article we summarize current knowledge on the molecular and cellular mechanisms underlying NMDAR modulation by GPCRs, and we discuss the implications of this modulation spanning from synaptic transmission and plasticity to circuit function and brain disease.