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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function
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, Developmental Genetics.
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2009 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 7, 2238-2251 p.Article in journal (Refereed) Published
Abstract [en]

A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.

Place, publisher, year, edition, pages
2009. Vol. 29, no 7, 2238-2251 p.
Keyword [en]
neuronal network, physiology, CNS, transmitter, behavior, schizophrenia
National Category
Pharmaceutical Sciences Medical and Health Sciences Neurosciences
URN: urn:nbn:se:uu:diva-102149DOI: 10.1523/JNEUROSCI.5851-08.2009ISI: 000263558900028PubMedID: 19228977OAI: oai:DiVA.org:uu-102149DiVA: diva2:214466
Available from: 2009-05-05 Created: 2009-05-05 Last updated: 2016-05-11Bibliographically approved
In thesis
1. Functional Analysis of the Vesicular Glutamate Transporter 2 in Specific Neuronal Circuits of the Brain
Open this publication in new window or tab >>Functional Analysis of the Vesicular Glutamate Transporter 2 in Specific Neuronal Circuits of the Brain
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A key issue in neuroscience is to determine the connection between neuronal circuits and behaviour. In the adult brain, all neuronal circuits include a glutamatergic component. Three proteins designated Vesicular glutamate transporter 1-3 (VGLUT1-3) possess the capability of packaging glutamate into presynaptic vesicles for release of glutamate at the nerve terminal.

The present study aimed at determining the role of VGLUT2 in neuronal circuits of higher brain function, emotion, and reward-pocessing. A conditional knockout (cKO) strategy was utilised, and three different mouse lines were produced to delete VGLUT2 in specific neuronal circuits in a temporally and spatially controlled manner. First, we produced a cKO mouse in which Vglut2 was deleted in specific subpopulations of the cortex, amygdala and hippocampus from preadolescence. This resulted in blunted aspects in cognitive, emotional and social behaviour in a schizophrenia-related phenotype. Furthermore, we showed a downstream effect of the targeted deletion on the dopaminergic system. In a subsequent analysis of the same cKO mice, we showed that female cKO mice were more affected their male counterparts, and we also found that female schizophrenia patients, but not male patients, had increased Vglut2 levels in the cortex.  Second, we produced and analysed cKO mice in which Vglut2 was deleted in the cortex, amygdala and hippocampus already from midgestation, and could show that this deletion affected emotional, but not cognitive, function. Third, we addressed the role of VGLUT2 in midbrain dopamine neurons by targeting Vglut2 specifically in these neurons. These cKO mice showed a blunted activational response to the psychostimulant amphetamine and increased operant self-administration of both sugar and cocaine reinforcers. Further, the cKO mice displayed strongly enhanced cocaine-seeking in response to cocaine-associated cues, a behaviour of relevance for addiction in humans.

In summary, this thesis work has addressed the role of the presynaptic glutamatergic neuron in different neuronal circuits and shown that the temporal and spatial distribution of VGLUT2 is of great significance for normal brain function.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 53 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 748
Addiction, amphetamine, affective behaviour, cocaine, cognitive behaviour, conditional knockout mouse, dopamine, operant self-administration, reward system, schizophrenia
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Research subject
urn:nbn:se:uu:diva-170046 (URN)978-91-554-8297-8 (ISBN)
Public defence
2012-04-20, B22, BMC, Husargatan 3, 751 24 Uppsala, 09:15 (English)
Available from: 2012-03-30 Created: 2012-03-07 Last updated: 2012-04-19Bibliographically approved

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Wallén-Mackenzie, ÅsaNordenankar, KarinLagerström, Malin CEmilsson, LinaFredriksson, RobertSchiöth, Helgi BLångström, BengtFredriksson, AndersRoman, ErikaKullander, Klas
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Developmental GeneticsFunctional PharmacologyDepartment of Biochemistry and Organic ChemistryPsychiatry, University HospitalDepartment of Pharmaceutical Biosciences
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