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.
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“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]
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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
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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
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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
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