Yun Zhou

• Albertini, Giulia; Deneyer, L.; Hansen, Sigrid Ottestad; Zhou, Yun; Ates, G; Walrave, L; Demuyser, Thomas; Bentea, Eduard; Sato, Hideyo; De Bundel, D; Danbolt, Niels Christian; Massie, Ann & Smolders, Ilse (2018). Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS-induced sickness and depressive-like behavior in mice. Glia.  ISSN 0894-1491.  66(9), s 1845- 1861 . doi: 10.1002/glia.23343 Show summary

  The communication between the immune and central nervous system (CNS) is affected in many neurological disorders. Peripheral injections of the endotoxin lipopolysaccharide (LPS) are widely used to study this communication: an LPS challenge leads to a biphasic syndrome that starts with acute sickness and is followed by persistent brain inflammation and chronic behavioral alterations such as depressive-like symptoms. In vitro, the response to LPS treatment has been shown to involve enhanced expression of system. This cystine-glutamate antiporter, with xCT as specific subunit, represents the main glial provider of extracellular glutamate in mouse hippocampus. Here we injected male xCT knockout and wildtype mice with a single intraperitoneal dose of 5 mg/kg LPS. LPS-injection increased hippocampal xCT expression but did not alter the mainly astroglial localization of the xCT protein. Peripheral and central inflammation (as defined by cytokine levels and morphological activation of microglia) as well as LPS-induced sickness and depressive-like behavior were significantly attenuated in xCT-deficient mice compared with wildtype mice. Our study is the first to demonstrate the involvement of system in peripheral and central inflammation in vivo and the potential therapeutic relevance of its inhibition in brain disorders characterized by peripheral and central inflammation, such as depression.

• Hansen, Sigrid Ottestad; Hu, Qiu Xiang; Follin-Arbelet, Virginie; Bentea, Eduard; Sato, Hideyo; Massie, Ann; Zhou, Yun & Danbolt, Niels Christian (2018). The cystine-glutamate exchanger (xCT, Slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain.. Glia.  ISSN 0894-1491.  66(5), s 951- 970 . doi: 10.1002/glia.23294 Show summary

  The cystine-glutamate exchanger (xCT) promotes glutathione synthesis by catalyzing cystine uptake and glutamate release. The released glutamate may modulate normal neural signaling and contribute to excitotoxicity in pathological situations. Uncertainty, however, remains as neither the expression levels nor the distribution of xCT have been unambiguously determined. In fact, xCT has been reported in astrocytes, neurons, oligodendrocytes and microglia, but most of the information derives from cell cultures. Here, we show by immunohistochemistry and by Western blotting that xCT is widely expressed in the central nervous system of both sexes. The labeling specificity was validated using tissue from xCT knockout mice as controls. Astrocytes were selectively labeled, but showed greatly varying labeling intensities. This astroglial heterogeneity resulted in an astrocyte domain-like labeling pattern. Strong xCT labeling was also found in the leptomeninges, along some blood vessels, in selected circumventricular organs and in a subpopulation of tanycytes residing the lateral walls of the ventral third ventricle. Neurons, oligodendrocytes and resting microglia, as well as reactive microglia induced by glutamine synthetase deficiency, were unlabeled. The concentration of xCT protein in hippocampus was compared with that of the EAAT3 glutamate transporter by immunoblotting using a chimeric xCT-EAAT3 protein to normalize xCT and EAAT3 labeling intensities. The immunoblots suggested an xCT/EAAT3 ratio close to one (0.75 ± 0.07; average ± SEM; n = 4) in adult C57BL6 mice. CONCLUSIONS: xCT is present in select blood/brain/CSF interface areas and in an astrocyte subpopulation, in sufficient quantities to support the notion that system xc- provides physiologically relevant transport activity.

• Hu, Qiu Xiang; Hansen, Sigrid Ottestad; Holmseth, Silvia; Hassel, Bjørnar; Danbolt, Niels Christian & Zhou, Yun (2018). Expression of glutamate transporters in mouse liver, kidney, and intestine. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  66(3), s 189- 202 . doi: 10.1369/0022155417749828 Show summary

  Glutamate transport activities have been identified not only in the brain, but also in the liver, kidney, and intestine. Although glutamate transporter distributions in the central nervous system are fairly well known, there are still uncertainties with respect to the distribution of these transporters in peripheral organs. Quantitative information is mostly lacking, and few of the studies have included genetically modified animals as specificity controls. The present study provides validated qualitative and semi-quantitative data on the excitatory amino acid transporter (EAAT)1-3 subtypes in the mouse liver, kidney, and intestine. In agreement with the current view, we found high EAAT3 protein levels in the brush borders of both the distal small intestine and the renal proximal tubules. Neither EAAT1 nor EAAT2 was detected at significant levels in murine kidney or intestine. In contrast, the liver only expressed EAAT2 (but 2 C-terminal splice variants). EAAT2 was detected in the plasma membranes of perivenous hepatocytes. These cells also expressed glutamine synthetase. Conditional deletion of hepatic EAAT2 did neither lead to overt neurological disturbances nor development of fatty liver.

• Zhou, Yun; Dhaher, Roni; Parent, Maxime; Hu, Qiu Xiang; Hassel, Bjørnar; Yee, Siu-Pok; Hyder, Fahmeed; Gruenbaum, Shaun E.; Eid, Tore & Danbolt, Niels Christian (2018). Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration. Neurochemistry International.  ISSN 0197-0186.  s 1- 12 . doi: 10.1016/j.neuint.2018.07.009
• Zhou, Yun; Hassel, Bjørnar; Eid, Tore & Danbolt, Niels Christian (2018). Axon-terminals expressing EAAT2 (GLT-1; Slc1a2) are common in the forebrain and not limited to the hippocampus. Neurochemistry International.  ISSN 0197-0186.  123, s 101- 113 . doi: 10.1016/j.neuint.2018.03.006
• Danbolt, Niels Christian; Furness, David N & Zhou, Yun (2016). Neuronal vs glial glutamate uptake: Resolving the conundrum. Neurochemistry International.  ISSN 0197-0186.  98, s 29- 45 . doi: 10.1016/j.neuint.2016.05.009 Show summary

  Neither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that both astrocytes and neurons express glutamate transporters. However the relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) a hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox.

• Danbolt, Niels Christian; Zhou, Yun; Furness, David N & Holmseth, Silvia (2016). Strategies for immunohistochemical protein localization using antibodies: What did we learn from neurotransmitter transporters in glial cells and neurons. Glia.  ISSN 0894-1491.  64(12), s 2045- 2064 . doi: 10.1002/glia.23027 Show summary

  Immunocytochemistry and Western blotting are still major methods for protein localization, but they rely on the specificity of the antibodies. Validation of antibody specificity remains challenging mostly because ideal negative controls are often unavailable. Further, immunochemical labeling patterns are also influenced by a number of other factors such as postmortem changes, fixation procedures and blocking agents as well as the general assay conditions (e.g., buffers, temperature, etc.). Western blotting similarly depends on tissue collection and sample preparation as well as the electrophoretic separation, transfer to blotting membranes and the immunochemical probing of immobilized molecules. Publication of inaccurate information on protein distribution has downstream consequences for other researchers because the interpretation of physiological and pharmacological observations depends on information on where ion channels, receptors, enzymes or transporters are located. Despite numerous reports, some of which are strongly worded, erroneous localization data are being published. Here we describe the extent of the problem and illustrate the nature of the pitfalls with examples from studies of neurotransmitter transporters. We explain the importance of supplementing immunochemical observations with other measurements (e.g., mRNA levels and distribution, protein activity, mass spectrometry, electrophysiological recordings, etc.) and why quantitative considerations are integral parts of the quality control. Further, we propose a practical strategy for researchers who plan to embark on a localization study. We also share our thoughts about guidelines for quality control.

• Eid, Tore; Gruenbaum, SE; Dhaher, R; Lee, T W; Zhou, Yun & Danbolt, Niels Christian (2016). The Glutamate-Glutamine Cycle in Epilepsy. Advances in neurobiology.  ISSN 2190-5215.  13, s 351- 400
• Petr, Geraldine T; Sun, Yan; Frederick, Natalie M; Zhou, Yun; Dhamne, Sameer C; Hameed, Mustafa Q; Miranda, Clive; Bedoya, Edward A; Fischer, Kathryn D; Armsen, Wencke; Wang, Jianlin; Danbolt, Niels Christian; Rotenberg, Alexander; Aoki, Chiye J & Rosenberg, Paul A (2015). Conditional deletion of the glutamate transporter GLT-1 reveals that astrocytic GLT-1 protects against fatal epilepsy while neuronal GLT-1 contributes significantly to glutamate uptake into synaptosomes. Journal of Neuroscience.  ISSN 0270-6474.  35(13), s 5187- 5201 . doi: 10.1523/JNEUROSCI.4255-14.2015
• Zhou, Yun; Kempson, S.A. & Danbolt, Niels Christian (2015). Betaine uptake with a focus on the betaine/GABA transporter. Food and Nutritional Components in Focus.  ISSN 2045-1695.  2015-January(7), s 76- 89
• Bjørnsen, Lars Petter; Hadera, Mussie Ghezu; Zhou, Yun; Danbolt, Niels Christian & Sonnewald, Ursula (2014). The GLT-1 (EAAT2; Slc1a2) glutamate transporter is essential for glutamate homeostasis in the neocortex of the mouse. Journal of Neurochemistry.  ISSN 0022-3042.  128(5), s 641- 649 . doi: 10.1111/jnc.12509
• Zhou, Yun & Danbolt, Niels Christian (2014). Glutamate as a neurotransmitter in the healthy brain. Journal of neural transmission.  ISSN 0300-9564.  121(8), s 799- 817 . doi: 10.1007/s00702-014-1180-8
• Zhou, Yun; Waanders, LF; Holmseth, Silvia; Guo, C; Berger, Urs V; Li, Yuchuan; Lehre, Anne- Catherine W G; Lehre, Knut Petter Dæhlin & Danbolt, Niels Christian (2014). Proteome analysis and conditional deletion of the EAAT2 glutamate transporter provide evidence against a role of EAAT2 in pancreatic insulin secretion in mice. Journal of Biological Chemistry.  ISSN 0021-9258.  289(3), s 1329- 1344 . doi: 10.1074/jbc.M113.529065
• Zhou, Yun; Wang, Xiaoyu; Tzingounis, Anastasios V; Danbolt, Niels Christian & Larsson, H Peter (2014). EAAT2 (GLT-1; slc1a2) glutamate transporters reconstituted in liposomes argues against heteroexchange being substantially faster than net uptake. Journal of Neuroscience.  ISSN 0270-6474.  34(40), s 13472- 13485 . doi: 10.1523/JNEUROSCI.2282-14.2014
• Zhou, Yun & Danbolt, Niels Christian (2013). GABA and Glutamate Transporters in Brain. Frontiers in Endocrinology.  ISSN 1664-2392.  4 . doi: 10.3389/fendo.2013.00165
• Zhou, Yun; Waanders, Leonie; Holmseth, Silvia; Guo, Caiying; Berger, Urs V; Li, Yuchuan; Lehre, Anne- Catherine W G; Lehre, Knut Petter Dæhlin & Danbolt, Niels Christian (2013). Proteome analysis and conditional deletion of the EAAT2 glutamate transporter provide evidence against a role of EAAT2 in pancreatic insulin secretion in mice. Journal of Biological Chemistry.  ISSN 0021-9258. . doi: 10.1074/jbc.M113.529065
• Holmseth, Silvia; Dehnes, Yvette; Huang, YHH; Follin-Arbelet, Virginie; Verket, Nina Julie; Mylonakou, Maria-Niki; Plachez, C; Zhou, Yun; Furness, DN; Bergles, DE; Lehre, Knut Petter Dæhlin & Danbolt, Niels Christian (2012). The Density of EAAC1 (EAAT3) Glutamate Transporters Expressed by Neurons in the Mammalian CNS. Journal of Neuroscience.  ISSN 0270-6474.  32(17), s 6000- 6013 . doi: 10.1523/JNEUROSCI.5347-11.2012
• Holmseth, Silvia; Zhou, Yun; Follin-Arbelet, Virginie; Lehre, Knut Petter Dæhlin; Bergles, Dwight E. & Danbolt, Niels Christian (2012). Specificity Controls for Immunocytochemistry: The Antigen Preadsorption Test Can Lead to Inaccurate Assessment of Antibody Specificity. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  60(3), s 174- 187 . doi: 10.1369/0022155411434828
• Li, Yuchuan; Zhou, Yun & Danbolt, Niels Christian (2012). The Rates of Postmortem Proteolysis of Glutamate Transporters Differ Dramatically between Cells and between Transporter Subtypes. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  60(11), s 811- 821 . doi: 10.1369/0022155412458589
• Zhou, Yun; Holmseth, Silvia; Guo, C; Hassel, Bjørnar; Höfner, G; Huitfeldt, Henrik; Wanner, KT & Danbolt, Niels Christian (2012). Deletion of the γ-aminobutyric acid transporter 2 (GAT2 and SLC6A13) gene in mice leads to changes in liver and brain taurine contents. Journal of Biological Chemistry.  ISSN 0021-9258.  287(42), s 35733- 35746 . doi: 10.1074/jbc.M112.368175
• Zhou, Yun; Holmseth, Silvia; Hua, Rui; Lehre, Anne- Catherine W G; Olofsson, Anna Maria; Poblete-Naredo, Irais; Kempson, S.A. & Danbolt, Niels Christian (2012). The betaine-GABA transporter (BGT1, slc6a12) is predominantly expressed in the liver and at lower levels in the kidneys and at the brain surface. American Journal of Physiology - Renal, fluid and electrolyte physiology.  ISSN 0363-6127.  302(3), s F316- F328 . doi: 10.1152/ajprenal.00464.2011
• Lehre, Anne- Catherine W G; Rowley, Nicole; Zhou, Yun; Holmseth, Silvia; Guo, Chungang; Holen, Torgeir; Hua, Rui; Laake, Petter; Olofsson, Anna Maria; Poblete-Naredo, Irais; Rusakov, Dimitri A.; Madsen, Karsten K.; Clausen, Rasmus P.; Schousboe, Arne; White, H. Steve & Danbolt, Niels Christian (2011). Deletion of the betaine-GABA transporter (BGT1; slc6a12) gene does not affect seizure thresholds of adult mice. Epilepsy Research.  ISSN 0920-1211.  95(1-2), s 70- 81 . doi: 10.1016/j.eplepsyres.2011.02.014
• Furness, DN; Dehnes, Yvette; Akhtar, Aisha Qureshi; Rossi, DJ; Hamann, M; Grutle, Nina J.; Gundersen, Vidar; Holmseth, Silvia; Lehre, Knut Petter Dæhlin; Ullensvang, Kyrre; Wojewodzic, Marcin; Zhou, Yun; Attwell, D & Danbolt, Niels Christian (2008). A QUANTITATIVE ASSESSMENT OF GLUTAMATE UPTAKE INTO HIPPOCAMPAL SYNAPTIC TERMINALS AND ASTROCYTES: NEW INSIGHTS INTO A NEURONAL ROLE FOR EXCITATORY AMINO ACID TRANSPORTER 2 (EAAT2). Neuroscience.  ISSN 0306-4522.  157(1), s 80- 94 . doi: 10.1016/j.neuroscience.2008.08.043

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• Danbolt, Niels Christian; Ottestad-Hansen, Sigrid; Hu, Qiu Xiang; Follin-Arbelet, Virginie; Bentea, Eduard; Sato, Hideyo; Massie, Ann & Zhou, Yun (2018). The cysteine-glutamate exchanger (xCT, slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain.
• Gudmundsrud, Ruben; Ottestad-Hansen, Sigrid; Hu, Qiu Xiang; Danbolt, Niels Christian & Zhou, Yun (2018). The role of glutamate/cystine exchanger (slc7a11) in amyotrophic lateral sclerosis.
• Zhou, Yun (2018). Glutamate uptake in nerve terminals.
• Zhou, Yun (2018). Neuronal vs glial glutamate uptake: Resolving the conundrum.
• Zhou, Yun; Hassel, Bjørnar; Eid, Tore & Danbolt, Niels Christian (2018). Axon-terminals expressing EAAT2 (GLT-1; slc1a2) are common in the forebrain and not limited to the hippocampus.
• Danbolt, Niels Christian; Zhou, Yun; Dhaher, Roni; Parent, Maxime; Yee, Siu-Pok; Hyder, Fahmeed; Hu, Qiu Xiang & Eid, Tore (2017). Loss of glutamine synthetase initiates a sequence of neuropathological events that culminate in epilepsy and neurodegeneration.
• Hu, Qiu Xiang; Danbolt, Niels Christian; Eid, Tore & Zhou, Yun (2017). Phenotypic differences between brain- and liver-specific glutamine synthetase knockout mice.
• Ottestad-Hansen, Sigrid; Hu, Qiu Xiang; Follin-Arbelet, Virginie; Sato, Hideyo; Bentea, Eduard; Massie, Ann; Zhou, Yun & Danbolt, Niels Christian (2017). The cystine-glutamate exchanger (xCT, Slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain..
• Hu, Qiu Xiang; Ottestad-Hansen, Sigrid; Kavanaugh, M.; Danbolt, Niels Christian & Zhou, Yun (2016). Vizualization of the EAAT3 glutamate transporter EAAC1 in mouse kidney and intestine.
• Ottestad-Hansen, Sigrid; Zhou, Yun; Follin-Arbelet, Virginie; Sato, Hideyo; Massie, Ann & Danbolt, Niels Christian (2016). The localization of glutamate-cystine exchanger xCT (slc7a11) in mouse brain.
• Danbolt, Niels Christian; Zhou, Yun; Xu, Ji & Khakh, Baljit (2015). Generation and characterization of BAC transgenic GABA transporter 2 (GAT2; slc6a13) tdTomato reporter mice.
• Danbolt, Niels Christian; Zhou, Yun; Xu, Ji & Khakh, Baljit (2015). Generation and characterization of BAC transgenic GABA transporter 2 (GAT2; slc6a13) tdTomato reporter mice.
• Wang, Helen; Dhaher, Roni; Farina, M.; Zhou, Yun; Yee, Siu-Pok; Danbolt, Niels Christian & Eid, Tore (2015). Brain site specific suppression of glutamine synthetase in mice using an adenoassociated virus knockout approach.
• Wang, Helen; Dhaher, Roni; Farina, M.; Zhou, Yun; Yee, Siu-Pok; Danbolt, Niels Christian & Eid, Tore (2015). Brain site specific suppression of glutamine synthetase in mice using an adenoassociated virus knockout approach.
• Zhou, Yun; Corbin, Karen; Xiang, Yi-Kong; Eskild, Winnie; Zeisel, Steven H. & Danbolt, Niels Christian (2015). The betaine-GABA transporter (BGT1; slc6a12) is not involved in the inactivation of transmitter GABA, but plays a role in preserving the choline levels in the liver.
• Zhou, Yun; Corbin, Karen; Xiang, Yi-Kong; Eskild, Winnie; Zeisel, Steven H. & Danbolt, Niels Christian (2015). The betaine-GABA transporter (BGT1; slc6a12) may play its main roles in the liver rather than in the brain.
• Kempson, SA; Zhou, Yun & Danbolt, Niels Christian (2014). The betaine/GABA transporter and betaine: Roles in brain, kidney, and liver. Frontiers in Physiology.  ISSN 1664-042X.  5 APR . doi: 10.3389/fphys.2014.00159
• Zhou, Yun; Danbolt, Niels Christian & Kempson, S.A. (2014). The Betaine-GABA transporter, In Victor R. Preedy (ed.),  Betaine - Chemistry, Analysis, Function and Effects.  Royal Society of Chemistry.  ISBN 9781849738866.  The Betaine-GABA transporter.
• Hadera, Mussie Ghezu; Bjørnsen, Lars Petter; Zhou, Yun; Sonnewald, Ursula & Danbolt, Niels Christian (2013). Impairment of glial-neuronal interaction in GLT-1 knockout mice: an NMR spectroscopy study. Journal of Neurochemistry.  ISSN 0022-3042.  125, s 109- 109
• Hadera, Mussie Ghezu; Bjørnsen, Lars Petter; Zhou, Yun; Sonnewald, Ursula & Danbolt, Niels Christian (2013). Impairment of glial-neuronal interaction in GLT-1 knockout mice: an NMR spectroscopy study.
• Danbolt, Niels Christian; Holmseth, Silvia; Dehnes, Yvette; Huang, Y.; Follin-Arbelet, Virginie; Grutle, N; Plachez, C.; Furness, D.; Zhou, Yun; Bergles, D & Lehre, Knut Petter Dæhlin (2011). QUANTIFICATION AND LOCALIZATION OF THE EAAC1 GLUTAMATE TRANSPORTER IN BRAIN. Glia.  ISSN 0894-1491.  59, s S66- S66
• Zhou, Yun; Holmseth, Silvia; Holen, Torgeir & Danbolt, Niels Christian (2011). EVIDENCE AGAINST A ROLE OF THE BETAINE-GABA TRANSPORTER (BGT1, SLC6A12) IN THE CONTROL OF GABA RECEPTOR ACTIVATION. Glia.  ISSN 0894-1491.  59, s S69- S70

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