Molecular Neurobiology

, Volume 55, Issue 2, pp 1054–1067 | Cite as

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

  • Federica BonoEmail author
  • Paola Savoia
  • Adele Guglielmi
  • Massimo Gennarelli
  • Giovanna Piovani
  • Sandra Sigala
  • Damiana Leo
  • Stefano Espinoza
  • Raul R. Gainetdinov
  • Paola Devoto
  • PierFranco Spano
  • Cristina Missale
  • Chiara Fiorentini


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.


hiPSC Dopamine D2/D3 receptor Neuroplasticity Nicotine Neurodegeneration Development 



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.

Compliance with Ethical Standards


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

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Approval

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.

Supplementary material

12035_2016_376_MOESM1_ESM.docx (428 kb)
ESM 1 (DOCX 428 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Federica Bono
    • 1
    Email author
  • Paola Savoia
    • 1
  • Adele Guglielmi
    • 1
  • Massimo Gennarelli
    • 2
    • 3
  • Giovanna Piovani
    • 2
  • Sandra Sigala
    • 1
  • Damiana Leo
    • 4
  • Stefano Espinoza
    • 4
  • Raul R. Gainetdinov
    • 4
    • 5
    • 6
  • Paola Devoto
    • 7
  • PierFranco Spano
    • 1
    • 8
  • Cristina Missale
    • 1
    • 8
  • Chiara Fiorentini
    • 1
  1. 1.Division of Pharmacology, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  2. 2.Section of Biology and Genetic, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  3. 3.Section of Genetics, IRCCS “Centro S. Giovanni di Dio” FatebenefratelliBresciaItaly
  4. 4.Department of Neuroscience and Brain TechnologiesItalian Institute of Technology (IIT)GenovaItaly
  5. 5.Institute of Translational BiomedicineSt. Petersburg State UniversitySt. PetersburgRussia
  6. 6.Skolkovo Institute of Science and Technology (Skoltech) SkolkovoMoscow RegionRussia
  7. 7.Section of Neuroscience and Clinical Pharmacology, Department of Biomedical SciencesUniversity of CagliariCagliariItaly
  8. 8.“C. Golgi” Women Health CenterUniversity of BresciaBresciaItaly

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