The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
Interleukin-6 Mediates the Increase in NADPH-Oxidase in the Ketamine Model of Schizophrenia
Open accessAbstract
Adult exposure to NMDA receptor antagonists, such as ketamine, produces psychosis in humans, and exacerbates symptoms in schizophrenic patients. We recently showed that ketamine activates the innate immune enzyme NADPH-oxidase in brain, and that the superoxide produced leads to dysfunction of a subset of fast-spiking inhibitory interneurons expressing the calcium-binding protein parvalbumin (PV). Here we show that neuronal production of interleukin-6 (IL-6) is necessary and sufficient for ketamine-mediated activation of NADPH-oxidase in brain. Removal of IL-6 in neuronal cultures by anti-IL-6 blocking antibodies, or in vivo by use of IL-6-deficient mice, prevented the increase in superoxide by ketamine and rescued the interneurons. Accumulating evidence suggests that schizophrenia patients suffer from diminished antioxidant defenses, and a recent clinical trial showed that enhancing these defenses may ameliorate symptoms of the disease. Our results showing that ketamine-induced IL-6 is responsible for the activation of NADPH-oxidase in brain suggest that reducing brain levels of this cytokine may protect the GABAergic phenotype of fast-spiking PV-interneurons and thus attenuate the propsychotic effects of ketamine.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“For example, the NMDA receptor antagonist ketamine, a pro-inflammatory stimulus, injures PV-INs in vitro and in vivo [16,95].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [95]
In the citing paper
“This injury is connected to IL-6mediated Nox2-dependent NADPH oxidase activation and production of superoxide [16,95].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [95]
In the citing paper
“Noncompeting NMDA antagonists affect inhibitory interneuron function by altering redox mechanisms, 74 an effect that depends on interleukin 6 and other cytokines.75”
From Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models (2011) · cites this paper as [75]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Bedard, K., & Krause, K.-H. (2007) · Physiological Reviews · doi:10.1152/physrev.00044.2005 · Cited by 6,989
Cortical inhibitory neurons and schizophrenia
Lewis, D. A., Hashimoto, T., & Volk, D. W. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1648 · Cited by 2,297
Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6
Smith, S. E. P., Li, J., Garbett, K., Mirnics, K., & Patterson, P. H. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2178-07.2007 · Cited by 1,605
Jentsch, J. D. (1999) · Neuropsychopharmacology · doi:10.1016/s0893-133x(98)00060-8 · Cited by 1,329
Homayoun, H., & Moghaddam, B. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2213-07.2007 · Cited by 1,231
Kawasaki, Y., Zhang, L., Cheng, J.-K., & Ji, R.-R. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3338-07.2008 · Cited by 1,162
NMDA receptor hypofunction model of schizophrenia
Olney, J. W., Newcomer, J. W., & Farber, N. B. (1999) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(99)00029-1 · Cited by 1,020
Akbarian, S. (1995) · Archives of General Psychiatry · doi:10.1001/archpsyc.1995.03950160008002 · Cited by 1,002
Hashimoto, T., Volk, D. W., Eggan, S. M., Mirnics, K., Pierri, J. N., Sun, Z., Sampson, A. R., & Lewis, D. A. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-15-06315.2003 · Cited by 938
Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase
Behrens, M. M., Ali, S. S., Dao, D. N., Lucero, J., Shekhtman, G., Quick, K. L., & Dugan, L. L. (2007) · Science · doi:10.1126/science.1148045 · Cited by 585
Self-citationJavitt, D. C. (2007) · International review of neurobiology · doi:10.1016/s0074-7742(06)78003-5 · Cited by 568
Berk, M., Copolov, D., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M., Judd, F., Katz, F., Katz, P., et al. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.03.004 · Cited by 552
Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo
Do, K. Q., Trabesinger, A. H., Kirsten‐Krüger, M., Lauer, C. J., Dydak, U., Hell, D., Holsboer, F., Boesiger, P., & Cuénod, M. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00229.x · Cited by 540
Prenatal Infection as a Risk Factor for Schizophrenia
Brown, A. S. (2006) · Schizophrenia Bulletin · doi:10.1093/schbul/sbj052 · Cited by 540
Interleukin-6 (IL-6)—A molecule with both beneficial and destructive potentials
Gadient, R. A., & Otten, U. (1997) · Progress in Neurobiology · doi:10.1016/s0301-0082(97)00021-x · Cited by 481
Meyer, U., Nyffeler, M., Yee, B. K., Knuesel, I., & Feldon, J. (2008) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2007.09.012 · Cited by 457
Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics
BEASLEY, C., & REYNOLDS, G. (1997) · Schizophrenia Research · doi:10.1016/s0920-9964(96)00122-3 · Cited by 426
Byrne, J., Grieve, D., Bendall, J. K., Li, J., Gove, C. D., Lambeth, J. D., Cave, A. C., & Shah, A. M. (2003) · Circulation Research · doi:10.1161/01.res.0000099504.30207.f5 · Cited by 412
Cysteine regulation of protein function – as exemplified by NMDA-receptor modulation
Lipton, S. A., Choi, Y.-B., Takahashi, H., Zhang, D., Li, W., Godzik, A., & Bankston, L. A. (2002) · Trends in Neurosciences · doi:10.1016/s0166-2236(02)02245-2 · Cited by 375
Chattopadhyaya, B., Cristo, G. D., Wu, C. Z., Knott, G. W., Kuhlman, S. J., Fu, Y., Palmiter, R. D., & Huang, Z. J. (2007) · Neuron · doi:10.1016/j.neuron.2007.05.015 · Cited by 337
Kinney, J. W., Davis, C. N., Tabarean, I., Conti, B., Bartfai, T., & Behrens, M. M. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4722-05.2006 · Cited by 329
Self-citationA Review of the Fetal Brain Cytokine Imbalance Hypothesis of Schizophrenia
Meyer, U., Feldon, J., & Yee, B. K. (2008) · Schizophrenia Bulletin · doi:10.1093/schbul/sbn022 · Cited by 324
Altered glutathione redox state in schizophrenia.
Yao, J. K., Leonard, S., & Reddy, R. (2006) · Disease Markers · doi:10.1155/2006/248387 · Cited by 321
Interleukin‐6: a cytokine to forget
Balschun, D., Wetzel, W., del Rey, A., Pitossi, F. J., Schneider, H., Zuschratter, W., & Besedovsky, H. O. (2004) · The FASEB Journal · doi:10.1096/fj.04-1625fje · Cited by 317
Impaired glutathione synthesis in schizophrenia: Convergent genetic and functional evidence
Gysin, R., Kraftsik, R., Sandell, J., Bovet, P., Chappuis, C., Conus, P., Deppen, P., Preisig, M., Ruiz, V., Steullet, P., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706778104 · Cited by 309
Sparkman, N. L., Buchanan, J. B., Heyen, J. R. R., Chen, J., Beverly, J. L., & Johnson, R. W. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3376-06.2006 · Cited by 307
NMDA receptor channels: Subunit-specific potentiation by reducing agents
Köhr, G., Eckardt, S., Lüddens, H., Monyer, H., & Seeburg, P. H. (1994) · Neuron · doi:10.1016/0896-6273(94)90311-5 · Cited by 256
Rujescu, D., Bender, A., Keck, M. E., Hartmann, A. M., Ohl, F., Ræder, H., Giegling, I., Genius, J., McCarley, R. W., Möller, H., et al. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.08.029 · Cited by 241
Cochran, S. M., Kennedy, M., McKerchar, C. E., Steward, L. J., Pratt, J. A., & MORRIS, B. J. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300031 · Cited by 236
Schizophrenia and Oxidative Stress: Glutamate Cysteine Ligase Modifier as a Susceptibility Gene
Tosic, M., Ott, J., Barral, S., Bovet, P., Deppen, P., Gheorghita, F., Matthey, M.-L., Parnas, J., Preisig, M., Saraga, M., et al. (2006) · The American Journal of Human Genetics · doi:10.1086/507566 · Cited by 234
Keilhoff, G., Becker, A., Grecksch, G., Wolf, G. L., & Bernstein, H. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.03.039 · Cited by 206
A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice
Quick, K. L., Ali, S. S., Arch, R. H., Xiong, C., Wozniak, D. F., & Dugan, L. L. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.09.014 · Cited by 185
Self-citationSamland, H., Huitrón‐Reséndiz, S., Masliah, E., Criado, J. R., Henriksen, S. J., & Campbell, I. L. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10635 · Cited by 178
Wang, C. Z., Yang, S. F., Xia, Y., & Johnson, K. M. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301647 · Cited by 161
The effects of maternal inflammation on neuronal development: possible mechanisms
Jonakait, G. M. (2007) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2007.08.017 · Cited by 145
Nitric oxide S -nitrosylates serine racemase, mediating feedback inhibition of d -serine formation
Mustafa, A. K., Kumar, M., Selvakumar, B., Ho, G. P. H., Ehmsen, J. T., Barrow, R. K., Amzel, L. M., & Snyder, S. H. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611620104 · Cited by 136
Induction of Interleukin-6 by Depolarization of Neurons
Sallmann, S., Jüttler, E., Prinz, S., Petersen, N., Knopf, U., Weiser, T., & Schwaninger, M. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-23-08637.2000 · Cited by 122
D’Arcangelo, G., Tancredi, V., Onofri, F., D’Antuono, M., Giovedı̀, S., & Benfenati, F. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00011.x · Cited by 117
Holcomb, H. H., Lahti, A. C., Medoff, D. R., Cullen, T. J., & Tamminga, C. A. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300824 · Cited by 108
Zhang, Y., Behrens, M. M., & Lisman, J. E. (2008) · Journal of Neurophysiology · doi:10.1152/jn.00079.2008 · Cited by 107
Self-citationCochran, S. M., Fujimura, M., MORRIS, B. J., & Pratt, J. A. (2002) · Synapse · doi:10.1002/syn.10126 · Cited by 85
Cabungcal, J.-H., Preissmann, D., Delseth, C., Cuénod, M., Kim, Q., & Schenk, F. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.03.001 · Cited by 83
The Risk for Schizophrenia From Childhood and Adult Infections
Brown, A. S. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2007.07101637 · Cited by 80
Volterra, A., Trotti, D., FLORIDI, S., & Racagni, G. (1994) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1994.tb21800.x · Cited by 73
Tomitaka, S., Tomitaka, M., Tolliver, B. K., & Sharp, F. R. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00018.x · Cited by 69
Xi, D., Keeler, B. E., Zhang, W., Houlé, J. D., & Gao, W. (2008) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2008.09.013 · Cited by 69
Zuo, D., Wu, Y., Yao, W.-X., Cao, Y., Wu, C., & Tanaka, M. (2006) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2006.05.010 · Cited by 61
Morrow, B. A., Elsworth, J. D., & Roth, R. H. (2007) · Psychopharmacology · doi:10.1007/s00213-007-0708-0 · Cited by 61
Amino terminal domain regulation of NMDA receptor function
Herin, G. A., & Aizenman, E. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.07.015 · Cited by 57
Pinteaux, E., Copin, J.-C., Ledig, M., & Tholey, G. (2009) · Developmental Neuroscience · doi:10.1159/000111433 · Cited by 51 · cited 1×
“Because the glutamatergic synapse is highly sensitive to oxidizing conditions (Kohr et al., 1994; Volterra et al., 1994; Pinteaux et al., 1996; Lipton et al., 2002; Herin 4 immunohistochemistry for PV and oxidized DHE fluorescence.”
Paterson, G., Ohashi, Y., Reynolds, G. P., Pratt, J. A., & MORRIS, B. J. (2006) · Journal of Psychopharmacology · doi:10.1177/0269881106062025 · Cited by 41
Oxidative Stress after Subarachnoid Hemorrhage in gp91phox Knockout Mice
Liu, S., Tang, J., Ostrowski, R. P., Titova, E., Monroe, C. E., Chen, W., Lo, W., Martin, R., & Zhang, J. H. (2007) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/s031716710000682x · Cited by 32
Cited by
Sorted by citations
Interneuron dysfunction in psychiatric disorders
Marín, O. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3155 · Cited by 1,190
Berk, M., Kapczinski, F., Andreazza, A. C., Dean, O. M., Giorlando, F., Maes, M., Yücel, M., Gama, C. S., Dodd, S., Dean, B., et al. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.10.001 · Cited by 1,178
Le Belle, J. E., Orozco, N. M., Paucar, A. A., Saxe, J. P., Mottahedeh, J., Pyle, A. D., Wu, H., & Kornblum, H. I. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2010.11.028 · Cited by 789
Fillman, S. G., Cloonan, N., Catts, V. S., Miller, L. C., Wong, J., McCrossin, T., Cairns, M., & Weickert, C. S. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.110 · Cited by 609
Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase
Behrens, M. M., Ali, S. S., Dao, D. N., Lucero, J., Shekhtman, G., Quick, K. L., & Dugan, L. L. (2007) · Science · doi:10.1126/science.1148045 · Cited by 585
Self-citation
Metadata
- Authors
- Behrens, M. M., Ali, S. S., & Dugan, L. L.
- Affiliations
- University of California San Diego (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-12-17
- Volume
- 28
- Issue
- 51
- Pages
- 13957-13966
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2752712
- OpenAlex
- W2062030838
- Cited by
- 241
- References
- 52
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 7 · 2023: 9 · 2022: 11 · 2021: 9 · 2020: 14 · 2019: 8 · 2018: 13 · 2017: 13 · 2016: 18 · 2015: 20 · 2014: 23 · 2013: 17 · 2012: 28
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hartford Foundation for Public Giving
- Larry L. Hillblom Foundation
- National Institute on Aging (K25AG026379, R21AG030320)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- interleukin-6, NADPH oxidase, ketamine, schizophrenia, NMDA receptor antagonists, superoxide, parvalbumin interneurons, fast-spiking interneurons, GABAergic interneurons, antioxidant defense, cytokine inhibition, IL-6-deficient mice
- MeSH terms
- Animals, Antibodies, Cells, Cultured, Disease Models, Animal, Enzyme Activation, gamma-Aminobutyric Acid, Interneurons, Ketamine, Male, Mice, Inbred C57BL, RNA, Messenger, Schizophrenia, Superoxides, Interleukin-6, Prefrontal Cortex, Mice, Knockout, NADPH Oxidases, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
