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Role of Dopamine D2/D3 Receptors in Development, Plasticity, and Neuroprotection in Human iPSC-Derived Midbrain Dopaminergic Neurons

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Abstract

The role of dopamine D2 and D3 receptors (D2R/D3R), located on midbrain dopaminergic (DA) neurons, in the regulation of DA synthesis and release and in DA neuron homeostasis has been extensively investigated in rodent animal models. By contrast, the properties of D2R/D3R in human DA neurons have not been elucidated yet. On this line, the use of human-induced pluripotent stem cells (hiPSCs) for producing any types of cells has offered the innovative opportunity for investigating the human neuronal phenotypes at the molecular levels. In the present study, hiPSCs generated from human dermal fibroblasts were used to produce midbrain DA (mDA) neurons, expressing the proper set of genes and proteins typical of authentic, terminally differentiated DA neurons. In this model, the expression and the functional properties of the human D2R/D3R were investigated with a combination of biochemical and functional techniques. We observed that in hiPSC-derived mDA neurons, the activation of D2R/D3R promotes the proliferation of neuronal progenitor cells. In addition, we found that D2R/D3R activation inhibits nicotine-stimulated DA release and exerts neurotrophic effects on mDA neurons that likely occur via the activation of PI3K-dependent mechanisms. Furthermore, D2R/D3R stimulation counteracts both the aggregation of alpha-synuclein induced by glucose deprivation and the associated neuronal damage affecting both the soma and the dendrites of mDA neurons. Taken together, these data point to the D2R/D3R-related signaling events as a biochemical pathway crucial for supporting both neuronal development and survival and protection of human DA neurons.

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Acknowledgements

We thank Ginetta Collo and Laura Cavalleri for their contribution in hiPSC generation, and Lee L. Rubin and Eunju Chung for helping in the development of midbrain DA neurons differentiation. We are also grateful to Konrad Hochedlinger for plasmids located in the Addgene depository.

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Authors and Affiliations

  1. Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy

    Federica Bono, Paola Savoia, Adele Guglielmi, Sandra Sigala, PierFranco Spano, Cristina Missale & Chiara Fiorentini

  2. Section of Biology and Genetic, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy

    Massimo Gennarelli & Giovanna Piovani

  3. Section of Genetics, IRCCS “Centro S. Giovanni di Dio” Fatebenefratelli, Brescia, Italy

    Massimo Gennarelli

  4. Department of Neuroscience and Brain Technologies, Italian Institute of Technology (IIT), 16163, Genova, Italy

    Damiana Leo, Stefano Espinoza & Raul R. Gainetdinov

  5. Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, 199034, Russia

    Raul R. Gainetdinov

  6. Skolkovo Institute of Science and Technology (Skoltech) Skolkovo, Moscow Region, 143025, Russia

    Raul R. Gainetdinov

  7. Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

    Paola Devoto

  8. “C. Golgi” Women Health Center, University of Brescia, 25123, Brescia, Italy

    PierFranco Spano & Cristina Missale

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  1. Federica Bono
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  2. Paola Savoia
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Correspondence to Federica Bono.

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This work was supported by “C. Golgi” Foundation, Brescia, Italy.

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The authors declare that they have no conflict of interest.

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Informed consent was obtained from a healthy donor prior to cell donation. The local ethics committee (CEIOC—Fatebenefratelli Hospital “San Giovanni di Dio” – Brescia, Italy, 44/2001 and 39/2005), previously approved this consent form.

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Bono, F., Savoia, P., Guglielmi, A. et al. Role of Dopamine D2/D3 Receptors in Development, Plasticity, and Neuroprotection in Human iPSC-Derived Midbrain Dopaminergic Neurons. Mol Neurobiol 55, 1054–1067 (2018). https://doi.org/10.1007/s12035-016-0376-3

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