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Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson's Disease
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Oramacell, F-75006 Paris, France..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology. Univ Melbourne, Dept Anat & Neurosci, Melbourne, Vic 3010, Australia..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 35203Article in journal (Refereed) Published
Abstract [en]

The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders.

Place, publisher, year, edition, pages
2016. Vol. 6, 35203
National Category
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-307529DOI: 10.1038/srep35203ISI: 000385768100001PubMedID: 27762319OAI: oai:DiVA.org:uu-307529DiVA: diva2:1047474
Funder
Swedish Research Council, 2013-4657 2014-3804The Swedish Brain FoundationÅke Wiberg Foundation
Available from: 2016-11-17 Created: 2016-11-17 Last updated: 2017-09-05Bibliographically approved
In thesis
1. United in Diversity: A Physiological and Molecular Characterization of Subpopulations in the Basal Ganglia Circuitry
Open this publication in new window or tab >>United in Diversity: A Physiological and Molecular Characterization of Subpopulations in the Basal Ganglia Circuitry
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Basal Ganglia consist of a number of different nuclei that form a diverse circuitry of GABAergic, dopaminergic and glutamatergic neurons. This complex network is further organized in subcircuits that govern limbic and motor functions in humans and other vertebrates. Due to the interconnection of the individual structures, dysfunction in one area or cell population can affect the entire network, leading to synaptic and molecular alterations in the circuitry as a whole. The studies in this doctoral thesis aimed at characterizing restricted subpopulations of neurons in the Basal Ganglia circuitry and their importance in the wider function of the network. To this end, we identified subpopulations of neurons in the subthalamic nucleus (STN), substantia nigra (SN) and ventral tegmental area (VTA), characterized their molecular profile and investigated their physiological role in the circuitry.

Within the mouse STN, reduction of glutamatergic neurotransmission in a subpopulation expressing Paired-like homeodomain transcription factor 2 (Pitx2) led to structural alterations in the nucleus as well as biochemical alterations of the dopaminergic system in the Nucleus accumbens (NAc) and changes in reward-related behavior. In the ventral midbrain, we identified and characterized novel marker genes selective to the VTA or SN. Of these, transient receptor potential cation channel subfamily V member 1 (TrpV1) marks a population of mainly glutamatergic neurons in the VTA which project to the NAc, while gastrin releasing peptide (Grp) is expressed in a population of dopaminergic neurons neuroprotected in Parkinson's disease. Furthermore, we discovered that disruption of glutamatergic co-release of dopaminergic neurons expressing dopamine transporter (DAT), diminishes fast EPSCs and glutamate release but does not affect the acquisition of reward-related behavioral tasks. To selectively quantify glutamate release from specific subpopulations, we devised a technique combining glutamate-amperometry and optogenetics. This was used to measure glutamate released from Pitx2-expressing synaptic terminals in the Globus pallidus as well as DAT- or TrpV1-expressing terminals in the NAc.

In summary, this doctoral thesis has furthered understanding of the function and importance of specific subpopulations within the Basal Ganglia circuitry and provides a novel means to investigate glutamate in the intact rodent brain within clearly defined, restricted cell populations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1369
Keyword
Glutamate, Optogenetics, Amperometry, Histology, Midbrain, Subthalamic Nucleus, Parkinson's disease, Ventral Tegmental Area, Substantia Nigra, Co-release
National Category
Neurosciences Physiology Medical Laboratory and Measurements Technologies
Identifiers
urn:nbn:se:uu:diva-328038 (URN)978-91-513-0063-4 (ISBN)
Public defence
2017-10-23, Zootissalen, Norbyvägen 14-18, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-09-29 Created: 2017-09-05 Last updated: 2017-10-18

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Viereckel, ThomasVlcek, BiancaBimpisidis, ZisisLagerström, Malin C.Konradsson-Geuken, ÅsaWallén-Mackenzie, Åsa
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