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Functional Analysis of the Vesicular Glutamate Transporter 2 in Specific Neuronal Circuits of the Brain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 748
Keyword [en]
Addiction, amphetamine, affective behaviour, cocaine, cognitive behaviour, conditional knockout mouse, dopamine, operant self-administration, reward system, schizophrenia
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-170046ISBN: 978-91-554-8297-8 (print)OAI: oai:DiVA.org:uu-170046DiVA: diva2:508423
Public defence
2012-04-20, B22, BMC, Husargatan 3, 751 24 Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-03-30 Created: 2012-03-07 Last updated: 2012-04-19Bibliographically approved
List of papers
1. Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function
Open this publication in new window or tab >>Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function
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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.

Keyword
neuronal network, physiology, CNS, transmitter, behavior, schizophrenia
National Category
Pharmaceutical Sciences Medical and Health Sciences Neurosciences
Identifiers
urn:nbn:se:uu:diva-102149 (URN)10.1523/JNEUROSCI.5851-08.2009 (DOI)000263558900028 ()19228977 (PubMedID)
Available from: 2009-05-05 Created: 2009-05-05 Last updated: 2017-12-13Bibliographically approved
2. VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioural activation
Open this publication in new window or tab >>VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioural activation
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2010 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 1, 389-394 p.Article in journal (Refereed) Published
Abstract [en]

The “One neuron-one neurotransmitter” concept has been challenged frequently during the last three decades, and the coexistence of neurotransmitters in individual neurons is now regarded as a common phenomenon. The functional significance of neurotransmitter coexistence is, however, less well understood. Several studies have shown that a subpopulation of dopamine (DA) neurons in the ventral tegmental area (VTA) expresses the vesicular glutamate transporter 2 (VGLUT2) and has been suggested to use glutamate as a cotransmitter. The VTA dopamine neurons project to limbic structures including the nucleus accumbens, and are involved in mediating the motivational and locomotor activating effects of psychostimulants. To determine the functional role of glutamate cotransmission by these neurons, we deleted VGLUT2 in DA neurons by using a conditional gene-targeting approach in mice. A DAT-Cre/Vglut2Lox mouse line (Vglut2f/f;DAT-Cre mice) was produced and analyzed by in vivo amperometry as well as by several behavioral paradigms. Although basal motor function was normal in the Vglut2f/f;DAT-Cre mice, their risk-taking behavior was altered. Interestingly, in both home-cage and novel environments, the gene targeted mice showed a greatly blunted locomotor response to the psychostimulant amphetamine, which acts via the midbrain DA system. Our results show that VGLUT2 expression in DA neurons is required for normal emotional reactivity as well as for psychostimulant-mediated behavioral activation.

Keyword
amphetamine, midbrain, neurotransmission, reward, striatum
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-169996 (URN)10.1073/pnas.0910986107 (DOI)000273559200068 ()20018672 (PubMedID)
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2017-12-07Bibliographically approved
3. Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice
Open this publication in new window or tab >>Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice
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2011 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 35, 12593-12603 p.Article in journal (Refereed) Published
Abstract [en]

The mesostriatal dopamine (DA) system contributes to several aspects of responses to rewarding substances and is implicated in conditions such as drug addiction and eating disorders. A subset of DA neurons has been shown to express the type 2 Vesicular glutamate transporter (Vglut2) and may therefore corelease glutamate. In the present study, we analyzed mice with a conditional deletion of Vglut2 in DA neurons (Vglut2(f/f;DAT-Cre)) to address the functional significance of the glutamate-DA cophenotype for responses to cocaine and food reinforcement. Biochemical parameters of striatal DA function were also examined by using DA receptor autoradiography, immediate-early gene quantitative in situ hybridization after cocaine challenge, and DA-selective in vivo chronoamperometry. Mice in which Vglut2 expression had been abrogated in DA neurons displayed enhanced operant self-administration of both high-sucrose food and intravenous cocaine. Furthermore, cocaine seeking maintained by drug-paired cues was increased by 76%, showing that reward-dependent plasticity is perturbed in these mice. In addition, several lines of evidence suggest that adaptive changes occurred in both the ventral and dorsal striatum in the absence of VGLUT2: DA receptor binding was increased, and basal mRNA levels of the DA-induced early genes Nur77 and c-fos were elevated as after cocaine induction. Furthermore, in vivo challenge of the DA system by potassium-evoked depolarization revealed less DA release in both striatal areas. This study demonstrates that absence of VGLUT2 in DA neurons leads to perturbations of reward consumption as well as reward-associated memory, features of particular relevance for addictive-like behavior.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-158895 (URN)10.1523/JNEUROSCI.2397-11.2011 (DOI)000294451900022 ()
Available from: 2011-09-19 Created: 2011-09-19 Last updated: 2017-12-08Bibliographically approved
4. Altered expression of Vglut2 affects behavior in a gender-dependent manner
Open this publication in new window or tab >>Altered expression of Vglut2 affects behavior in a gender-dependent manner
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(English)Manuscript (preprint) (Other academic)
Keyword
neuronal circuitry, transmitter, glutamate, dopamine, behavior, pre-pulse inhibition, amphetamine, human microarray
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-170048 (URN)
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2016-05-11
5. Targeted Prenatal Deletion of Vglut2 Expression in the Forebrain Decreases Anxiety-Related Behaviour of the Adult Mouse
Open this publication in new window or tab >>Targeted Prenatal Deletion of Vglut2 Expression in the Forebrain Decreases Anxiety-Related Behaviour of the Adult Mouse
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(English)Manuscript (preprint) (Other academic)
Keyword
cortex, amygdala, neurotransmission, development, memory, affective behaviour
National Category
Basic Medicine
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-169993 (URN)
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2016-05-11

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