Kainic Acid-Activated Microglia Mediate Increased Excitability of Rat Hippocampal Neurons in vitro and in vivo: Crucial Role of Interleukin-1beta
Abstract
Objective: It is known that highly activated microglia and the consequent production of inflammatory cytokines were associated with neuroexcitotoxic injuries. The present study was carried out to explore whether interleukin-1β (IL-1β), a proinflammatory cytokine produced in abundance by activated microglia, mediates increased excitability of hippocampal neurons and the related molecular mechanisms. Methods: Primary cultured microglia were activated by kainic acid (KA), and the KA-treated microglial conditioned medium (KA-MCM) was collected. KA-MCM with or without anti-rat IL-1β monoclonal neutralizing antibody was then injected into the rat in the right cerebral ventricle, or primary cultured hippocampal neurons were treated with the above-mentioned KA-MCM. The population spike amplitude changes in the CA3 region were assessed by electrophysiological recording in vivo. Western blot and RT-PCR assay were performed to investigate the expression changes of N-methyl-D-aspartate receptor subunit 1 (NMDAR1) and inducible nitric oxide synthase (iNOS) expression in hippocampal neurons. Results: Primary cultured microglia were significantly activated by KA with increased IL-1β levels. Interestingly, intracerebroventricular administration of KA-MCM to rats resulted in enhancement of population spike amplitude in the CA3 region and in upregulation of NMDAR1 and iNOS expression in the hippocampus, which was partially attenuated by anti-rat IL-1β antibody. Furthermore, the changes in NMDAR1 and iNOS expression in the rat hippocampus were verified by incubation of primary cultured hippocampal neurons with KA-MCM. Conclusion: This study provides evidence that KA-activated microglia mediate increased excitability of hippocampal neurons in vitro and in vivo and that IL-1β may be one of the main causes of this event.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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 animal models, seizures are associated with increased activation of microglia, especially the M1 subtype, and increased release of pro-inflammatory mediators.
“Studies in animal models have reported that seizures are associated with increased activation of microglia, especially of the M1 subtype [189], and an increased release of pro-inflammatory mediators [190, 191].”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [191]
Cites
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
Glutamate receptor ion channels
Mayer, M. L. (2005) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2005.05.004 · Cited by 3,645 · see citing works
NMDA receptor subunits: diversity, development and disease
Cull-Candy, S., Brickley, S., & Farrant, M. (2001) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(00)00215-4 · Cited by 1,694 · see citing works
Plasticity in the human central nervous system
Cooke, S. F. (2006) · Brain · doi:10.1093/brain/awl082 · Cited by 1,195 · see citing works
Liu, B., & Hong, J.-S. (2003) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.035048 · Cited by 1,095 · see citing works
Bright and dark sides of nitric oxide in ischemic brain injury
Iadecola, C. (1997) · Trends in Neurosciences · doi:10.1016/s0166-2236(96)10074-6 · Cited by 1,044 · see citing works
Interleukin-1 and neuronal injury
Allan, S. M., Tyrrell, P. J., & Rothwell, N. J. (2005) · Nature Reviews Immunology · doi:10.1038/nri1664 · Cited by 992 · see citing works
MICROGLIA AS MEDIATORS OF INFLAMMATORY AND DEGENERATIVE DISEASES
González-Scarano, F., & Baltuch, G. (1999) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.22.1.219 · Cited by 984 · see citing works
Tikka, T., Fiebich, B. L., Goldsteins, G., Keinänen, R., & Koistinaho, J. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-08-02580.2001 · Cited by 958 · see citing works
CNS immune privilege: hiding in plain sight
Carson, M. J., Doose, J. M., Melchior, B., Schmid, C. D., & Ploix, C. C. (2006) · Immunological Reviews · doi:10.1111/j.1600-065x.2006.00441.x · Cited by 797 · see citing works
Neurotransmitter receptors on microglia
Pocock, J. M., & Kettenmann, H. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.07.007 · Cited by 650 · see citing works
Microglia in degenerative neurological disease
McGeer, P. L., Kawamata, T., Walker, D. G., Akiyama, H., Tooyama, I., & McGeer, E. G. (1993) · Glia · doi:10.1002/glia.440070114 · Cited by 500 · see citing works
Emerging insights into the genesis of epilepsy
McNamara, J. O. (1999) · Nature · doi:10.1038/399a015 · Cited by 378 · see citing works
Chronic microglial activation and progressive dopaminergic neurotoxicity
Block, M. L., & Hong, J. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351127 · Cited by 324 · see citing works
New Roles for Interleukin-1 Beta in the Mechanisms of Epilepsy
Vezzani, A., & Baram, T. (2007) · Epilepsy Currents · doi:10.1111/j.1535-7511.2007.00165.x · Cited by 266 · see citing works
Narita, M., Miyatake, M., Narita, M., Shibasaki, M., Shindo, K., Nakamura, A., Kuzumaki, N., Nagumo, Y., & Suzuki, T. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301007 · Cited by 218 · see citing works
Giulian, D., Li, J., Leara, B., & Keenen, C. (1994) · Neurochemistry International · doi:10.1016/0197-0186(94)90066-3 · Cited by 181 · see citing works
Nuclear calcium transport and the role of calcium in apoptosis
Nicotera, P., Zhivotovsky, B., & Orrenius, S. (1994) · Cell Calcium · doi:10.1016/0143-4160(94)90091-4 · Cited by 179 · see citing works
Minocycline inhibits LPS-induced retinal microglia activation
Wang, A., Yu, A. C., Lau, L. T., LEE, C., WU, L., ZHU, X., & Tso, M. O. M. (2005) · Neurochemistry International · doi:10.1016/j.neuint.2005.04.018 · Cited by 178 · see citing works
Kingham, P. J., Cuzner, M. L., & Pocock, J. M. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0730538.x · Cited by 138 · see citing works
Molecular Mechanisms Underlying Specificity of Excitotoxic Signaling in Neurons
Aarts, M. M., & Tymianski, M. (2004) · Current Molecular Medicine · doi:10.2174/1566524043479202 · Cited by 127 · see citing works
The role of glial membrane ion channels in seizures and epileptogenesis
D’Ambrosio, R. (2004) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2004.05.004 · Cited by 75 · see citing works
Role and Mechanisms of Interleukin-1 in the Modulation of Neurotoxicity
Ma, X. C., Gottschall, P. E., Chen, L. T., Wiranowska, M., & Phelps, C. P. (2002) · NeuroImmunoModulation · doi:10.1159/000068322 · Cited by 72 · see citing works
Berzhanskaya, J., Urban, N. N., & Barrionuevo, G. (1998) · Journal of Neurophysiology · doi:10.1152/jn.1998.79.4.2111 · Cited by 63 · see citing works
He, Z., Huang, L., Wu, Y., et al. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.03.060 · Cited by 36 · see citing works
Cell cycle-dependent regulation of kainate-induced inward currents in microglia
Yamada, J., Sawada, M., & Nakanishi, H. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.08.126 · Cited by 20 · see citing works
Retinoic acid enhances the secretion of plasminogen from cultured rat microglia
Nakajima, K., Takemoto, N., & Kohsaka, S. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)80966-k · Cited by 19 · see citing works
Interleukin-1 and β-Cell Function: More Than One Second Messenger?*
Argilés, J. M. A., López‐Soriano, J., Ortiz, M. A., Pou, J. M., & López-Soriano, F. J. (1992) · Endocrine Reviews · doi:10.1210/edrv-13-3-515 · Cited by 15 · see citing works
Wang, X., Zheng, H., Liu, C., Zhu, C., Wang, W., & Zheng-li, L. (2007) · Neurochemical Research · doi:10.1007/s11064-007-9514-7 · Cited by 14 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation
Lima Giacobbo, B., Doorduin, J., Klein, H. C., Dierckx, R. A. J. O., Bromberg, E., & de Vries, E. F. J. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1283-6 · Cited by 750 · see citing works
- Authors
- Zheng, H., Zhu, W., Zhao, H., Wang, X., Wang, W., & Li, Z.
- Affiliations
- Tongji University (CN)
- Tongji Hospital (CN)
- Venue
- Neuroimmunomodulation
- Publisher
- S. Karger AG
- Published
- 2009-10-05
- Volume
- 17
- Issue
- 1
- Pages
- 31-38
- ISSN
- 1021-7401 (ISSN-L)
- 1423-0216
- OpenAlex
- W1998279824
- Cited by
- 39
- References
- 29
- Citations by year
- 2026: 1 · 2025: 2 · 2022: 2 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 1 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 3
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- NeuroImmunoModulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- kainic acid, microglial activation, IL-1β, hippocampal neurons, neuronal excitability, NMDA receptor 1, inducible nitric oxide synthase, neuroinflammation, neuroexcitotoxicity, CA3 region, conditioned medium
- MeSH terms
- Action Potentials, Animals, Animals, Newborn, Cells, Cultured, Encephalitis, Epilepsy, Hippocampus, Kainic Acid, Male, Nerve Degeneration, Neurons, Neurotoxins, Up-Regulation, Receptors, N-Methyl-D-Aspartate, Culture Media, Conditioned, Rats, Sprague-Dawley, Microglia, Excitatory Amino Acid Agonists, Rats, Nitric Oxide Synthase Type II, Interleukin-1beta, Antibodies, Neutralizing
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
