Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations

Publication date: 2 May 2017
Source:Cell Reports, Volume 19, Issue 5
Author(s): Ping Zhong, Zhixing Hu, Houbo Jiang, Zhen Yan, Jian Feng
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.

Graphical abstract

Teaser

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.


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