Co-agonist glycine controls the occurrence of bursts by activating extrasynaptic NMDARs in nigral dopamine neurons

Dopamine control of movement initiation is correlated in time to the phasic activity of substantia nigra pars compacta neurons. The participation of NMDARs to the generation of bursts is essential but the mechanisms regulating their level of activation are unknown. Here, we reveal that triheteromeric NMDARs composed of GluN2B and GluN2D subunits are expressed both at synaptic and extrasynaptic sites but are activated by distinct co-agonists. D-serine is predominant for the activation of synaptic NMDARs whereas glycine is for extrasynaptic NMDARs. The pattern of bursts is insensitive to enzymatic depletion of either D-serine or glycine but the latter controls their occurrence. The co-agonist glycine through the activation of extrasynaptic NMDARs plays a central role in the generation of bursts responsible for the enhanced release of dopamine in postsynaptic areas initiating downstream motor-related behavior.