Excitatory GluN1/GluN3A glycine receptors (eGlyRs) in brain signaling

Association of the NMDA receptor (NMDAR) subunit GluN3A with GluN1 leads to the formation of GluN1/GluN3A excitatory glycine receptors (eGlyRs), the properties of which differ strikingly from those of ‘conventional’ GluN1/GluN2 NMDARs.eGlyRs are bona fide brain receptors that are functionally expressed in several brain regions, including the medial habenula, basolateral amygdala, and neocortex.eGlyRs have been found in both excitatory and inhibitory neurons, being particularly enriched in somatostatin interneurons.By generating tonic excitatory currents, eGlyRs operate through glycine volume transmission.eGlyRs mediate a novel signaling modality by which extracellular ambient glycine controls neuronal excitability, circuit function, and behavior.GluN3A is highly expressed in brain regions controlling emotional and motivational states, making eGlyRs potential therapeutic targets for neuropsychiatric disorders. GluN3A is a glycine-binding subunit belonging to the NMDA receptor (NMDAR) family that can assemble with GluN1 subunits to form unconventional NMDARs insensitive to glutamate and activated by glycine only. The existence of such excitatory glycine receptors (eGlyRs) in the central nervous system (CNS) has long remained elusive. Recently, eGlyRs have been identified in specific brain regions, where they represent a novel neuronal signaling modality by which extracellular glycine tunes neuronal excitability, circuit function, and behavior. In this review, we summarize the emerging knowledge regarding these underappreciated receptors. The existence of eGlyRs reshapes current understanding of NMDAR diversity and of glycinergic signaling, previously thought to be primarily inhibitory. Given that GluN3A expression is concentrated in brain regions regulating emotional responses, eGlyRs are potential new targets of therapeutic interest in neuropsychiatry.