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

Federica Bono, Paola Savoia, Adele Guglielmi, Massimo Gennarelli, Giovanna Piovani, Sandra Sigala, Damiana Leo, Stefano Espinoza, Raul R. Gainetdinov, Paola Devoto, Pier Franco Spano, Cristina Missale, Chiara Fiorentini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalMolecular Neurobiology
DOIs
Publication statusE-pub ahead of print - Jan 14 2017

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Keywords

  • Development
  • Dopamine D2/D3 receptor
  • hiPSC
  • Neurodegeneration
  • Neuroplasticity
  • Nicotine

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Bono, F., Savoia, P., Guglielmi, A., Gennarelli, M., Piovani, G., Sigala, S., Leo, D., Espinoza, S., Gainetdinov, R. R., Devoto, P., Spano, P. F., Missale, C., & Fiorentini, C. (2017). Role of Dopamine D2/D3 Receptors in Development, Plasticity, and Neuroprotection in Human iPSC-Derived Midbrain Dopaminergic Neurons. Molecular Neurobiology, 1-14. https://doi.org/10.1007/s12035-016-0376-3