Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations

Ping Zhong,Zhixing Hu,Houbo Jiang,Zhen Yan,Jian Feng

doi:10.1016/j.celrep.2017.04.023

Abstract

Locomotor symptoms in Parkinson's disease (PD) are accompanied by widespread oscillatory neuronal activities in basal ganglia. Here, we show that activation of dopamine D1-class receptors elicits a large rhythmic bursting of spontaneous excitatory postsynaptic currents (sEPSCs) in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations, but not normal subjects. Overexpression of wild-type parkin, but not its PD-causing mutant, abolishes the oscillatory activities in patient neurons. Dopamine induces a delayed enhancement in the amplitude of spontaneous, but not miniature, EPSCs, thus increasing quantal content. The results suggest that presynaptic regulation of glutamatergic transmission by dopamine D1-class receptors is significantly potentiated by parkin mutations. The aberrant dopaminergic regulation of presynaptic glutamatergic transmission in patient-specific iPSC-derived midbrain neurons provides a mechanistic clue to PD pathophysiology, and it demonstrates the usefulness of this model system in understanding how mutations of parkin cause movement symptoms in Parkinson's disease.

Highlights

Parkinson’s disease (PD) is a movement disorder characterized by the loss of nigral dopaminergic (DA) neurons
We found that dopamine induced a delayed increase in the amplitude of spontaneous excitatory postsynaptic currents in induced pluripotent stem cells (iPSCs)-derived midbrain neurons from PD patients with parkin mutations, but not from normal subjects
The patient-specific iPSC-derived midbrain DA neurons provide a novel platform to study the molecular mechanism of the abnormal rhythmic bursting of neuronal activities in basal ganglia, which has long been associated with movement symptoms of PD

Summary

Graphical Abstract

In midbrain neurons derived from induced pluripotent stem cells of Parkinson’s disease patients with parkin mutations, Zhong et al find that activation of dopamine D1-class receptors induces oscillatory activities reminiscent of synchronized and rhythmic neuronal activities seen uniquely in the brains of Parkinson’s disease patients. Highlights d Dopamine D1 receptors elicit oscillatory activities in neurons from parkin patients d No oscillatory activity is found in iPSC-derived neurons from normal subjects d Wild-type parkin rescues oscillatory activities in neurons from parkin patients d Mutant parkin fails to rescue oscillatory activities in Parkinson’s patient neurons. 2017, Cell Reports 19, 1033–1044 May 2, 2017 a 2017 The Author(s).

SUMMARY

INTRODUCTION

RESULTS

DISCUSSION

EXPERIMENTAL PROCEDURES