Mesencephalic dopaminergic neurons express a repertoire of olfactory receptors and respond to odorant-like molecules
- Equal contributors
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
BMC Genomics 2014, 15:729 doi:10.1186/1471-2164-15-729Published: 27 August 2014
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.
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.
Our study indicates that mDA neurons express ORs and respond to odor-like molecules providing new opportunities for pharmacological intervention in disease.