Location of NMDARs and co-agonist controls the generation of bursts in nigral dopamine neurons

Abstract

NMDA receptor activation in pars compacta substantia nigra dopamine neurons is central to the generation of bursting activity, a key signal temporally associated to movement initiation. The site of the NMDAR pool (synaptic and/or extrasynaptic) as well as the identity of the co-agonist involved in the ignition of this phasic activity remains unknown. Using ex vivo electrophysiological recordings, we demonstrate that NMDARs located outside synapses are preponderant for this firing. This pool of receptors is recruited during intense synaptic activity via spillover of glutamate and require the binding of NMDAR co-agonist glycine for their full activation. Synaptic NMDARs are not directly involved in bursting and are activated by D-serine, a distinct co-agonist. Location dependency of NMDARs and co-agonist underlying burst generation may serve as a guideline in understanding the physiological role of dopamine neurons in health and disease. TeaserExtrasynaptic NMDARs recruited by spillover and glycine allow the generation of bursts in dopamine neurons.