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Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. 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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
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2016 (English)In: ENEURO, ISSN 2373-2822, Vol. 3, no 5, article id UNSP e0264Article in journal (Refereed) Published
Abstract [en]

The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson's disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system.

Place, publisher, year, edition, pages
2016. Vol. 3, no 5, article id UNSP e0264
Keywords [en]
dopamine, dynorphin, glutamate, rearing, reward, self-administration
National Category
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-315932DOI: 10.1523/ENEURO.0264-16.2016ISI: 000391930400042OAI: oai:DiVA.org:uu-315932DiVA, id: diva2:1076460
Funder
Swedish Research Council, Vetenskapsradet 2013-4657 2014-3804 2011-4423 2015-4870 2012-2304The Swedish Brain FoundationÅke Wiberg FoundationAvailable from: 2017-02-22 Created: 2017-02-22 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. p. 57
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1369
Keywords
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)
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Supervisors
Available from: 2017-09-29 Created: 2017-09-05 Last updated: 2018-01-13

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Schweizer, NadineViereckel, ThomasNordenankar, KarinArvidsson, EmmaBergquist, JonasKonradsson-Geuken, ÅsaAndersson, MalinWallén-Mackenzie, Åsa

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Schweizer, NadineViereckel, ThomasNordenankar, KarinArvidsson, EmmaBergquist, JonasKonradsson-Geuken, ÅsaAndersson, MalinWallén-Mackenzie, Åsa
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Developmental GeneticsFunctional PharmacologyComparative PhysiologyDepartment of NeuroscienceDepartment of Pharmaceutical BiosciencesAnalytical Chemistry
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