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Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. 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, Developmental Genetics.
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.
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2015 (English)In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 220, no 4, 2171-2190 p.Article in journal (Refereed) Published
Abstract [en]

Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations ("TH-Vglut2 Class1") also expressed the dopamine transporter (DAT) gene while one did not ("TH-Vglut2 Class2"), and the remaining population did not express TH at all ("Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area.

Place, publisher, year, edition, pages
2015. Vol. 220, no 4, 2171-2190 p.
National Category
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-239640DOI: 10.1007/s00429-014-0778-9ISI: 000356874700020PubMedID: 24802380OAI: oai:DiVA.org:uu-239640DiVA: diva2:774902
Funder
Swedish Research Council, 2007-5742, 2011-4747
Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Across Borders: A Histological and Physiological Study of the Subthalamic Nucleus in Reward and Movement
Open this publication in new window or tab >>Across Borders: A Histological and Physiological Study of the Subthalamic Nucleus in Reward and Movement
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The basal ganglia are the key circuitry controlling movement and reward behavior. Both locomotion and reward-related behavior are also modified by dopaminergic input from the substantia nigra and the ventral tegmental area (VTA). If the basal ganglia are severed by lesion or in disease, such as in Parkinson’s disease, the affected individuals suffer from severe motor impairments and often of affective and reward-related symptoms. The subthalamic nucleus (STN) is a glutamatergic key area of the basal ganglia and a common target for deep brain stimulation in Parkinson’s disease to alleviate motor symptoms. The STN serves not only motoric, but also limbic and cognitive functions, which is often attributed to a tripartite anatomical subdivision. However, the functional output of both VTA and STN may rely more on intermingled subpopulations than on a strictly anatomical subdivision. In this doctoral thesis, the role of subpopulations within and associated with the basal ganglia is addressed from both a genetic and a behavioral angle. The identification of a genetically defined subpopulation within the STN, co-expressing Paired-like homeodomain transcription factor 2 (Pitx2) and Vesicular glutamate transport 2 (Vglut2), made it possible to conditionally reduce glutamatergic transmission from this subgroup of neurons and to investigate its influence on locomotion and motivational behavior, giving interesting insights into the mechanisms possibly underlying deep brain stimulation therapy and its side-effects. We address the strong influence of the Pitx2-Vglut2 subpopulation on movement, as well as the more subtle changes in reward-related behavior and the impact of the alterations on the reward-related dopaminergic circuitry. We also further elucidate the genetic composition of the STN by finding new markers for putative STN subpopulations, thereby opening up new possibilities to target those cells genetically and optogenetically. This will help in future to examine both STN development, function in the adult central nervous system and defects caused by specific deletion. Eventually identifying and characterizing subpopulations of the STN can contribute to the optimization of deep brain stimulation and help to reduce its side-effects, or even open up possibilities for genetic or optogenetic therapy approaches.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1177
Keyword
subthalamic nucleus, STN, basal ganglia, locomotion, hyperlocomotion, rearing, ventral tegmental area, VTA, dopamine, glutamate, vesicular glutamate transporter 2, Vglut2, Parkinson's disease, deep brain stimulation, subpopulation, conditional knock-out, optogenetic, co-expression, in situ hybridization, self-administration, reward behavior, mouse genetics
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-275165 (URN)978-91-554-9469-8 (ISBN)
Public defence
2016-03-18, Zootissalen, Norbyvägen 14-18, Uppsala, 09:15 (English)
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Supervisors
Available from: 2016-02-26 Created: 2016-01-31 Last updated: 2016-03-09

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Nordenankar, KarinSchweizer, NadineViereckel, ThomasLeao, Richardson NavesWallén-Mackenzie, Åsa
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