Synaptic signalling in a network of dopamine neurons: What prevents proper inter-cellular crosstalk?

Human embryonic stem cell (hESC) – derived midbrain dopamine (DA) neurons stand out as a cell source for transplantation with their sustainability and consistency superior to the formerly used fetal tissues. However, multiple studies of DA neurons in culture failed to register action potential (AP) generation in response to synaptic input. To test, whether this is due to deficiency of NMDA receptor (NMDAR) co-agonists Glycine and D-Serine released from astroglia in living tissue, we studied the functional properties of neural receptors in hESC-derived DA neuronal cultures. We find that, apart of insufficient amount of co-agonists, lack of interneuronal crosstalk is caused by hypofunction of synaptic NMDARs due to their direct inhibition by synaptically released dopamine. This inhibitory tone is independent from DA receptors and affects NMDARs via the modulation of co-agonist binding site.