title: Role of Dopamine D2/D3 Receptors in Development, Plasticity, and Neuroprotection in Human iPSC-Derived Midbrain Dopaminergic Neurons.
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.
authors.affiliation: Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy. federica.bono@unibs.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Bono
authors.affiliation: Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Savoia
authors.affiliation: Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Guglielmi
authors.affiliation: Section of Biology and Genetic, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.|Section of Genetics, IRCCS "Centro S. Giovanni di Dio" Fatebenefratelli, Brescia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
authors.affiliation: Section of Biology and Genetic, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Piovani
authors.affiliation: Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sigala
authors.affiliation: Department of Neuroscience and Brain Technologies, Italian Institute of Technology (IIT), 16163, Genova, Italy.
authors.forename: Damiana
authors.initials: D
authors.lastname: Leo
authors.affiliation: Department of Neuroscience and Brain Technologies, Italian Institute of Technology (IIT), 16163, Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Espinoza
authors.affiliation: Department of Neuroscience and Brain Technologies, Italian Institute of Technology (IIT), 16163, Genova, Italy.|Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, 199034, Russia.|Skolkovo Institute of Science and Technology (Skoltech) Skolkovo, Moscow Region, 143025, Russia.
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.affiliation: Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.|"C. Golgi" Women Health Center, University of Brescia, 25123, Brescia, Italy.
authors.forename: PierFranco
authors.initials: P
authors.lastname: Spano
authors.affiliation: Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.|"C. Golgi" Women Health Center, University of Brescia, 25123, Brescia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Missale
authors.affiliation: Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fiorentini
mesh_terms: D001552:Benzazepines / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004298:Dopamine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D000066829:Neuroprotection / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D007211:Indoles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C046649:ropinirole; D019257:Quinpirole; C067113:SK&F 81297; D004298:Dopamine
keywords: Development; Dopamine D2/D3 receptor; Neurodegeneration; Neuroplasticity; Nicotine; hiPSC