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Schweizer, Nadine
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Perland, E., Hellsten, S. V., Schweizer, N., Arapi, V., Rezayee, F., Bushra, M. & Fredriksson, R. (2017). Structural prediction of two novel human atypical SLC transporters, MFSD4A and MFSD9, and their neuroanatomical distribution in mice. PLoS ONE, 12(10), Article ID e0186325.
Öppna denna publikation i ny flik eller fönster >>Structural prediction of two novel human atypical SLC transporters, MFSD4A and MFSD9, and their neuroanatomical distribution in mice
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2017 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 10, artikel-id e0186325Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Out of the 430 known solute carriers (SLC) in humans, 30% are still orphan transporters regarding structure, distribution or function. Approximately one third of all SLCs belong to the evolutionary conserved and functionally diverse Major Facilitator Superfamily (MFS). Here, we studied the orphan proteins, MFSD4A and MFSD9, which are atypical SLCs of MFS type. Hidden Markov Models were used to identify orthologues in several vertebrates, and human MFSD4A and MFSD9 share high sequence identity with their identified orthologues. MFSD4A and MFSD9 also shared more than 20% sequence identity with other phylogenetically related SLC and MFSD proteins, allowing new family clustering. Homology models displayed 12 transmembrane segments for both proteins, which were predicted to fold into a transporter-shaped structure. Furthermore, we analysed the location of MFSD4A and MFSD9 in adult mouse brain using immunohistochemistry, showing abundant neuronal protein staining. As MFSD4A and MFSD9 are plausible transporters expressed in food regulatory brain areas, we monitored transcriptional changes in several mouse brain areas after 24 hours food-deprivation and eight weeks of high-fat diet, showing that both genes were affected by altered food intake in vivo. In conclusion, we propose MFSD4A and MFSD9 to be novel transporters, belonging to disparate SLC families. Both proteins were located to neurons in mouse brain, and their mRNA expression levels were affected by the diet.

Nyckelord
MFSD4A, MFSD9, solute carrier, major facilitator superfamily, transporter, homology models, protein expression, nutrition.
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-326695 (URN)10.1371/journal.pone.0186325 (DOI)000413195900057 ()
Tillgänglig från: 2017-08-01 Skapad: 2017-08-01 Senast uppdaterad: 2018-02-08Bibliografiskt granskad
Schweizer, N. (2016). Across Borders: A Histological and Physiological Study of the Subthalamic Nucleus in Reward and Movement. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Öppna denna publikation i ny flik eller fönster >>Across Borders: A Histological and Physiological Study of the Subthalamic Nucleus in Reward and Movement
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 73
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1177
Nyckelord
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
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-275165 (URN)978-91-554-9469-8 (ISBN)
Disputation
2016-03-18, Zootissalen, Norbyvägen 14-18, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-02-26 Skapad: 2016-01-31 Senast uppdaterad: 2018-01-10
Schweizer, N., Viereckel, T., Smith-Anttila, C. J. A., Nordenankar, K., Arvidsson, E., Mahmoudi, S., . . . Wallén-Mackenzie, Å. (2016). 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. ENEURO, 3(5), Article ID UNSP e0264.
Öppna denna publikation i ny flik eller fönster >>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
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2016 (Engelska)Ingår i: ENEURO, ISSN 2373-2822, Vol. 3, nr 5, artikel-id UNSP e0264Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
dopamine, dynorphin, glutamate, rearing, reward, self-administration
Nationell ämneskategori
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-315932 (URN)10.1523/ENEURO.0264-16.2016 (DOI)000391930400042 ()
Forskningsfinansiär
Vetenskapsrådet, Vetenskapsradet 2013-4657 2014-3804 2011-4423 2015-4870 2012-2304HjärnfondenÅke Wibergs Stiftelse
Tillgänglig från: 2017-02-22 Skapad: 2017-02-22 Senast uppdaterad: 2017-09-05Bibliografiskt granskad
Nordenankar, K., Smith-Anttila, C. J., Schweizer, N., Viereckel, T., Birgner, C., Mejia-Toiber, J., . . . Wallén-Mackenzie, Å. (2015). Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity. Brain Structure and Function, 220(4), 2171-2190
Öppna denna publikation i ny flik eller fönster >>Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity
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2015 (Engelska)Ingår i: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 220, nr 4, s. 2171-2190Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-239640 (URN)10.1007/s00429-014-0778-9 (DOI)000356874700020 ()24802380 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2007-5742, 2011-4747
Tillgänglig från: 2014-12-29 Skapad: 2014-12-29 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Pupe, S., Schweizer, N. & Wallen-Mackenzie, Å. (2015). Reply to Konsolaki and Skaliora: Habituation, hyperlocomotion, and "genuine hyperlocomotion" [Letter to the editor]. Proceedings of the National Academy of Sciences of the United States of America, 112(1), E5-E5
Öppna denna publikation i ny flik eller fönster >>Reply to Konsolaki and Skaliora: Habituation, hyperlocomotion, and "genuine hyperlocomotion"
2015 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 1, s. E5-E5Artikel i tidskrift, Letter (Refereegranskat) Published
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-246836 (URN)10.1073/pnas.1417574112 (DOI)000347447100004 ()
Tillgänglig från: 2015-03-11 Skapad: 2015-03-10 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
Schweizer, N., Pupe, S., Arvidsson, E., Nordenankar, K., Smith-Anttila, C. J. A., Mahmoudi, S., . . . Wallén-Mackenzie, Å. (2014). Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion. Proceedings of the National Academy of Sciences of the United States of America, 111(21), 7837-7842
Öppna denna publikation i ny flik eller fönster >>Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion
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2014 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 21, s. 7837-7842Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knockout mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.

Nyckelord
Parkinson disease, deep brain stimulation, vesicular transporter, optogenetics, striatum
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-227717 (URN)10.1073/pnas.1323499111 (DOI)000336411300073 ()
Anmärkning

N.S. and S.P. contributed equally to this work.

Tillgänglig från: 2014-06-30 Skapad: 2014-06-30 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
Rajagopalan, A., Schweizer, N., Nordenankar, K., Jahan, S. N., Emilsson, L. & Wallen-Mackenzie, Å. (2014). Reduced Gene Expression Levels of Munc13-1 and Additional Components of the Presynaptic Exocytosis Machinery Upon Conditional Targeting of Vglut2 in the Adolescent Mouse. Synapse, 68(12), 624-633
Öppna denna publikation i ny flik eller fönster >>Reduced Gene Expression Levels of Munc13-1 and Additional Components of the Presynaptic Exocytosis Machinery Upon Conditional Targeting of Vglut2 in the Adolescent Mouse
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2014 (Engelska)Ingår i: Synapse, ISSN 0887-4476, E-ISSN 1098-2396, Vol. 68, nr 12, s. 624-633Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Presynaptic proteins orchestrate an intricate interplay of dynamic interactions in order to regulate quantal exocytosis of transmitter-filled vesicles, and their dysregulation might cause neurological and neuropsychiatric dysfunction. Mice carrying a spatiotemporal restriction in the expression of the Vesicular glutamate transporter 2 (Vglut2; aka Slc17a6) in the cortex, amygdala and hippocampal subiculum from the third postnatal week show a strong anxiolytic phenotype and certain behavioral correlates of schizophrenia. To further understand the molecular consequences of this targeted deletion of Vglut2, we performed an unbiased microarray analysis comparing gene expression levels in the subiculum of these conditional Vglut2 knockout mice (Vglut2(f/f;CamKII) cKO) to those in control littermates. Expression of Unc13C (Munc13-3), a member of the Unc/Munc family, previously shown to be important for glutamatergic transmission, was identified to be significantly down-regulated. Subsequent analysis by quantitative RT-PCR revealed a 50% down-regulation of Munc 13-1, the gene encoding the Unc/Munc subtype described as an essential component in the majority of glutamtergic synapses in the hippocampus. Genes encoding additional components of the presynaptic machinery were also found regulated, including Rab3A, RIM1, as well as Syntaxin1 and Synaptobrevin. Altered expression levels of these genes were further found in the amygdala and in the retrosplenial group of the cortex, additional regions in which Vglut2 was conditionally targeted. These findings suggest that expression levels of Vglut2 might be important for the maintenance of gene expression in the presynaptic machinery in the adult mouse brain. Synapse 68:624-633, 2014.

Nyckelord
amygdala, cortex, hippocampus, microarray, schizophrenia, Slc17a6, subiculum
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-237282 (URN)10.1002/syn.21776 (DOI)000343756900007 ()25139798 (PubMedID)
Tillgänglig från: 2014-12-03 Skapad: 2014-12-01 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
Lekholm, E., Eriksson, M., Klaesson, A., Perland, E., Schweizer, N. & Fredriksson, R.Glucose deprived mouse embryonal cortex cultures respond by altering MFS transporter expression and localization.
Öppna denna publikation i ny flik eller fönster >>Glucose deprived mouse embryonal cortex cultures respond by altering MFS transporter expression and localization
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-331327 (URN)
Tillgänglig från: 2017-10-12 Skapad: 2017-10-12 Senast uppdaterad: 2017-10-12
Schweizer, N. & Wallén-Mackenzie, Å.Identification of novel markers for the subthalamic nucleus in mice.
Öppna denna publikation i ny flik eller fönster >>Identification of novel markers for the subthalamic nucleus in mice
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord
vglut2, vesicular glutamate transporter 2, pitx2, paired-like homeodomain transcription factor 2, gria1, glutamate receptor ionotropic AMPA 1, foxA1, forkhead box transcription factor A1, lmx1a, LIM homeobox transcription factor 1a, lmx1b, LIM homeobox transcription factor 1b, calb2, calbindin 2, in situ hybridization, mRNA, embryonic, STN, subthalamic nucleus, screen
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-275162 (URN)
Tillgänglig från: 2016-01-31 Skapad: 2016-01-31 Senast uppdaterad: 2018-01-10
Schweizer, N., Viereckel, T., Smith-Anttila, C., Nordenankar, K., Arvidsson, E., Mahmoudi, S., . . . Wallén-Mackenzie, Å.Reduced consumption of sugar identifies a regulatory role for a Pitx2/Vglut2 co-expressing subpopulation in the structure and function of the mouse subthalamic nucleus.
Öppna denna publikation i ny flik eller fönster >>Reduced consumption of sugar identifies a regulatory role for a Pitx2/Vglut2 co-expressing subpopulation in the structure and function of the mouse subthalamic nucleus
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord
STN, deep brain stimulation, DBS, reward, Parkinson's disease, self-administration, conditional knock-out, Pitx2, Vglut2, in vivo chronoamperometry, dopamine, glutamate, globus pallidus, entopeduncular nucleus
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:uu:diva-274855 (URN)
Tillgänglig från: 2016-01-31 Skapad: 2016-01-26 Senast uppdaterad: 2018-01-10
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