Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations

• Published in: Cell reports (Cambridge) Vol. 19; no. 5; pp. 1033 - 1044
• Main Authors: Zhong, Ping, Hu, Zhixing, Jiang, Houbo, Yan, Zhen, Feng, Jian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.05.2017; Elsevier
• Subjects: Aged; Case-Control Studies; Cells, Cultured; dopamine; Dopamine - pharmacology; dopaminergic neurons; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - physiology; excitatory postsynaptic currents; Excitatory Postsynaptic Potentials; Female; Humans; induced pluripotent stem cells; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - physiology; Male; Mesencephalon - cytology; Mesencephalon - metabolism; Mesencephalon - physiopathology; Middle Aged; Mutation; oscillation; parkin; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Parkinson’s disease; Receptors, Dopamine D1 - metabolism; Ubiquitin-Protein Ligases - genetics; parkin; dopaminergic neurons; oscillation; excitatory postsynaptic currents; induced pluripotent stem cells; dopamine; Parkinson’s disease
• ISSN: 2211-1247; 2639-1856; 2211-1247
• DOI: 10.1016/j.celrep.2017.04.023

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. [Display omitted] •Dopamine D1 receptors elicit oscillatory activities in neurons from parkin patients•No oscillatory activity is found in iPSC-derived neurons from normal subjects•Wild-type parkin rescues oscillatory activities in neurons from parkin patients•Mutant parkin fails to rescue oscillatory activities in Parkinson’s patient neurons 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.