Electrochemical measurements at human iPSC-derived FOXA2 dopaminergic neurons suggest a role for partial release in presynaptic plasticity.

During the past decade, emerging studies using electrochemistry and nanoscale imaging have demonstrated that partial exocytotic release is prevailing in neuroendocrine cell models. However, due to complicated structure and culture process, few studies have been carried out using neurons, especially human neurons. Here, dopamine (DA) release from individual vesicles and DA content stored within vesicles were quantified from induced pluripotent stem cell-derived DA neurons with electrochemical techniques. The results indicate that around 61% of the total vesicular DA content is released from these neurons during exocytosis. The vesicular content quantified in DA neurons is significantly higher than that in undifferentiated neural progenitor cells, owing to the increased appearance of dense-core vesicles that are able to store more DA molecules than the clear vesicles. When the neurons are differentiated with BAY-K8644, which stimulates neuronal maturation as well as DA release, the release fraction rises to 91%. The use of BAY-K8644 can be considered as chronic stimulation and leads to similar effects on exocytosis as repetitive stimulation, which triggers short-term plasticity. This study demonstrates partial release in DA transmission in human neurons and provides a link between neuronal maturation and the formation of plasticity. Furthermore, this work suggests that the fraction of release in exocytosis at human neurons may be a factor in determining plasticity.