Open Access Research article

Mesencephalic dopaminergic neurons express a repertoire of olfactory receptors and respond to odorant-like molecules

Alice Grison1, Silvia Zucchelli12, Alice Urzì1, Ilaria Zamparo3, Dejan Lazarevic14, Giovanni Pascarella156, Paola Roncaglia114, Alejandro Giorgetti78, Paula Garcia-Esparcia9, Christina Vlachouli1, Roberto Simone1, Francesca Persichetti2, Alistair RR Forrest56, Yoshihide Hayashizaki1056, Paolo Carloni11127, Isidro Ferrer9, Claudia Lodovichi3, Charles Plessy56, the FANTOM Consortium, Piero Carninci56* and Stefano Gustincich113*

Author Affiliations

1 SISSA, Area of Neuroscience, via Bonomea 265, 34136 Trieste, Italy

2 Department of Health Sciences, University of Eastern Piedmont “A. Avogadro”, via Solaroli 17, 28100 Novara, Italy

3 Venetian Institute of Molecular Medicine (VIMM), via Orus 2, 35129 Padua, Italy

4 CBM, AREA Science Park, s.s. 14, Km 163.5, Basovizza 34012 Trieste, Italy

5 RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan

6 RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan

7 Computational Biophysics, German Research School for Simulation Sciences (Joint venture of RWTH Aachen University and Forschungszentrum Jülich), Jülich, Germany

8 Department of Biotechnology, University of Verona, Ca’ Vignal 1, Strada Le Grazie 15, 37134 Verona, Italy

9 Institute of Neuropathology, IDIBELL-University Hospital of Bellvitge, Carrer Feixa Llarga sn, 08907 Hospitalet de Llobregat, Spain

10 RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan

11 Institute for Advanced Simulation IAS-5, Computational Biomedicine, Forschungszentrum Jülich, Jülich, Germany

12 Computational Biomedicine Section INM-9, Institute for Neuroscience and Medicine, Jülich, Germany

13 The Giovanni Armenise-Harvard Foundation Laboratory, SISSA, via Bonomea 265, 34136 Trieste, Italy

14 Current address: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hixton, Cambridge CB10 1SD, UK

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BMC Genomics 2014, 15:729  doi:10.1186/1471-2164-15-729

Published: 27 August 2014

Abstract

Background

The mesencephalic dopaminergic (mDA) cell system is composed of two major groups of projecting cells in the Substantia Nigra (SN) (A9 neurons) and the Ventral Tegmental Area (VTA) (A10 cells). Selective degeneration of A9 neurons occurs in Parkinson’s disease (PD) while abnormal function of A10 cells has been linked to schizophrenia, attention deficit and addiction. The molecular basis that underlies selective vulnerability of A9 and A10 neurons is presently unknown.

Results

By taking advantage of transgenic labeling, laser capture microdissection coupled to nano Cap-Analysis of Gene Expression (nanoCAGE) technology on isolated A9 and A10 cells, we found that a subset of Olfactory Receptors (OR)s is expressed in mDA neurons. Gene expression analysis was integrated with the FANTOM5 Helicos CAGE sequencing datasets, showing the presence of these ORs in selected tissues and brain areas outside of the olfactory epithelium. OR expression in the mesencephalon was validated by RT-PCR and in situ hybridization. By screening 16 potential ligands on 5 mDA ORs recombinantly expressed in an heterologous in vitro system, we identified carvone enantiomers as agonists at Olfr287 and able to evoke an intracellular Ca2+ increase in solitary mDA neurons. ORs were found expressed in human SN and down-regulated in PD post mortem brains.

Conclusions

Our study indicates that mDA neurons express ORs and respond to odor-like molecules providing new opportunities for pharmacological intervention in disease.

Keywords:
NanoCAGE; Odors; Odorant receptors; Dopaminergic neurons; Ventral midbrain