Synaptic signalling in a network of dopamine neurons: what prevents proper intercellular crosstalk?

Yixi Chen,Joanna Simpson,Tilo Kunath,Natalie Homer,Sergiy Sylantyev

doi:10.1002/1873-3468.13910

Yixi Chen, Joanna Simpson + Show 3 more

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https://doi.org/10.1002/1873-3468.13910

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Abstract

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 upon synaptic input. To test whether this is due to deficiency of NMDA receptor (NMDAR) coagonists released from astroglia, we studied the functional properties of neural receptors in hESC-derived DA neuronal cultures. We find that, apart from an insufficient amount of coagonists, lack of interneuronal crosstalk is caused by hypofunction of synaptic NMDARs due to their direct inhibition by synaptically released DA. This inhibitory tone is independent of DA receptors and affects the NMDAR coagonist binding site.

Highlights

Human embryonic stem cell-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
Multiple studies of DA neurons in culture failed to register action potential (AP) generation upon synaptic input. To test whether this is due to deficiency of NMDA receptor (NMDAR) coagonists released from astroglia, we studied the functional properties of neural receptors in Human embryonic stem cell (hESC)-derived DA neuronal cultures
This signature includes the presence of functional NMDARs and AMPA receptors (AMPARs) [27,71], GABAA receptors [36,72], glycine receptors (GlyRs) [37,73] and DA corelease with GABA [38] and glutamate [39]

Summary

Introduction

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. Multiple studies of DA neurons in culture failed to register action potential (AP) generation upon synaptic input To test whether this is due to deficiency of NMDA receptor (NMDAR) coagonists released from astroglia, we studied the functional properties of neural receptors in hESC-derived DA neuronal cultures. Morphological studies provide the most detailed description of human neural development, outlining a multicomponent process of neurogenesis, where early neuroepithelial cells form neural networks and major CNS elements [1] These studies, do not answer the question of how a naїve stem cell becomes a functionally mature neuron, since they do not monitor electrophysiological properties, which are critical for neuronal function, at the cellular and molecular level.

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