Fractalkine/CX 3 CL 1 modulates GABAA currents in human temporal lobe epilepsy
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Summary: Purpose: The chemokine fractalkine/CX 3 CL 1 and its receptor CX 3 CR 1 are widely expressed in the central nervous system (CNS). Recent evidence showed that CX 3 CL 1 participates in inflammatory responses that are common features of CNS disorders, such as epilepsy. Mesial temporal lobe epilepsy (MTLE) is the prevalent form of focal epilepsy in adults, and hippocampal sclerosis (HS) represents the most common underlying pathologic abnormality, as demonstrated at autopsy and postresection studies. Relevant features of MTLE are a characteristic pattern of neuronal loss, as are astrogliosis and microglia activation. Several factors affect epileptogenesis in patients with MTLE, including a lack of γ‐aminobutyric acid (GABA)ergic inhibitory efficacy. Therefore, experiments were designed to investigate whether, in MTLE brain tissues, CX 3 CL 1 may influence GABA A receptor (GABA A R) mediatedtransmission, with a particular focus on the action of CX 3 CL 1 on the use‐dependent decrease (rundown) of the GABA‐evoked currents (I GABA), a feature underlying the reduction of GABA ergic function in epileptic tissue. Methods: Patch‐clamp recordings were obtained from cortical pyramidal neurons in slices from six MTLE patients after surgery. Alternatively, the cell membranes from epileptic brain tissues of 17 MTLE patients or from surgical samples and autopsies of nonepileptic patients were microtransplanted into Xenopus oocytes, and I GABA were recorded using the standard two‐microelectrode voltage‐clamp technique. Immunohistochemical staining and double‐labeling studies were carried out on the same brain tissues to analyze CX 3 CR 1 expression. Key Findings: In native pyramidal neurons from cortical slices of patients with MTLE, CX 3 CL 1 reduced I GABA rundown and affected the recovery of I GABA amplitude from rundown. These same effects were confirmed in oocytes injected with cortical and hippocampal MTLE membranes, whereas CX 3 CL 1 did not influence I GABA in oocytes injected with nonepileptic tissues. Consistent with a specific effect of CX 3 CL 1 on tissues from patients with MTLE, CX 3 CR 1 immunoreactivity was higher in MTLE sclerotic hippocampi than in control tissues, with a prominent expression in activated microglial cells. Significance: These findings indicate a role for CX 3 CL 1 in MTLE, supporting recent evidence on the relevance of brain inflammation in human epilepsies. Our data demonstrate that in MTLE tissues the reduced GABA ergic function can be modulated by CX 3 CL 1. The increased CX 3 CR 1 expression in microglia and the modulation by CX 3 CL 1 of GABA ergic currents in human epileptic brain suggests new therapeutic approaches for drug‐resistant epilepsies based on the evidence that the propagation of seizures can be influenced by inflammatory processes.
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An increase in CX3CR1 expression in activated microglia suppresses GABAA receptor signaling in excitatory neurons.
“and an increase in CX3CR1 expression in activated microglia suppresses GABAA receptor signaling in excitatory neurons [155]”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [155]
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Cites
The role of inflammation in epilepsy
Vezzani, A., French, J., Bartfai, T., & Baram, T. Z. (2011) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.178 · Cited by 1,876 · see citing works
Control of microglial neurotoxicity by the fractalkine receptor
Cardona, A. E., Pioro, E. P., Sasse, M. E., Kostenko, V., Cardona, S. M., Dijkstra, I. M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1715 · Cited by 1,531 · see citing works
Harrison, J. K., Jiang, Y., Chen, S., Xia, Y., Maciejewski, D., McNamara, R. K., Streit, W. J., Salafranca, M. N., Adhikari, S., Thompson, D. A., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10896 · Cited by 1,176 · see citing works
Stell, B. M., Brickley, S. G., Tang, C., Farrant, M., & Módy, I. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2435457100 · Cited by 799 · see citing works
Brooks‐Kayal, A. R., Shumate, M. D., Jin, H., Rikhter, T. Y., & Coulter, D. A. (1998) · Nature Medicine · doi:10.1038/2661 · Cited by 746 · see citing works
Perturbed Chloride Homeostasis and GABAergic Signaling in Human Temporal Lobe Epilepsy
Huberfeld, G., Wittner, L., Clémenceau, S., Baulac, M., Kaila, K., Miles, R., & Rivera, C. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2761-07.2007 · Cited by 634 · see citing works
Chemokines, neuronal–glial interactions, and central processing of neuropathic pain
Gao, Y., & Ji, R. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.01.002 · Cited by 629 · see citing works
Lee, S., Varvel, N. H., Konerth, M. E., Xu, G., Cardona, A. E., Ransohoff, R. M., & Lamb, B. T. (2010) · The American Journal of Pathology · doi:10.2353/ajpath.2010.100265 · Cited by 539 · cited 1× · see citing works
“chemokine in several neuropathologies (Cardona et al., 2006; Lee et al., 2010; Cipriani et al., 2011), and with the”
BackgroundEpilepsy and brain inflammation
Vezzani, A., Aronica, E., Mazarati, A., & Pittman, Q. J. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2011.09.033 · Cited by 508 · see citing works
Self-citationChemokines and Chemokine Receptors: Standing at the Crossroads of Immunobiology and Neurobiology
Ransohoff, R. M. (2009) · Immunity · doi:10.1016/j.immuni.2009.09.010 · Cited by 372 · see citing works
A new clinico-pathological classification system for mesial temporal sclerosis
Blümcke, I., Pauli, E., Clusmann, H., et al. (2007) · Acta Neuropathologica · doi:10.1007/s00401-006-0187-0 · Cited by 350 · see citing works
Palma, E., Amici, M., Sobrero, F., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602979103 · Cited by 311 · see citing works
Self-citationAronica, E., Fluiter, K., Iyer, A. M., Zurolo, E., Vreijling, J. P., van Vliet, E. A., Baayen, J. C., & Gorter, J. A. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07122.x · Cited by 311 · see citing works
Self-citationMutations in GABAAreceptor subunits associated with genetic epilepsies
Macdonald, R. L., Kang, J., & Gallagher, M. J. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.186999 · Cited by 263 · see citing works
Spontaneous sharp waves in human neocortical slices excised from epileptic patients
Köhling, R. (1998) · Brain · doi:10.1093/brain/121.6.1073 · Cited by 201 · see citing works
Blümcke, I., Coras, R., Miyata, H., & Özkara, Ç. (2012) · Brain Pathology · doi:10.1111/j.1750-3639.2012.00583.x · Cited by 190 · see citing works
CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents
Cipriani, R., Villa, P., Chece, G., Lauro, C., Paladini, A., Micotti, E., Perego, C., Simoni, M. G. D., Fredholm, B. B., Eusebi, F., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3611-11.2011 · Cited by 189 · see citing works
Self-citationRavizza, T., Noè, F. M., Zardoni, D., Vaghi, V., Sifringer, M., & Vezzani, A. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.05.007 · Cited by 178 · see citing works
Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias
Iyer, A. M., Zurolo, E., Spliet, W. G. M., van Rijen, P. C., Baayen, J. C., Gorter, J. A., & Aronica, E. (2010) · Epilepsia · doi:10.1111/j.1528-1167.2010.02547.x · Cited by 178 · see citing works
Self-citationExtrasynaptic αβ subunit GABA A receptors on rat hippocampal pyramidal neurons
Mortensen, M., & Smart, T. G. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.117952 · Cited by 167 · see citing works
Chemokine CX3CL1 protects rat hippocampal neurons against glutamate-mediated excitotoxicity
Limatola, C., Lauro, C., Catalano, M., Ciotti, M. T., Bertollini, C., Di Angelantonio, S., Ragozzino, D., & Eusebi, F. (2005) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2005.03.023 · Cited by 153 · see citing works
Self-citationThe emerging role for chemokines in epilepsy
Fabene, P. F., Bramanti, P., & Constantin, G. (2010) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.05.016 · Cited by 152 · see citing works
Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy
Aronica, E., Zurolo, E., Iyer, A. M., et al. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.03115.x · Cited by 151 · see citing works
Self-citationPernot, F., Heinrich, C., Barbier, L., Peinnequin, A., Carpentier, P., Dhote, F., Baille, V., Beaup, C., Depaulis, A., & Dorandeu, F. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.03273.x · Cited by 134 · see citing works
Ragozzino, D., Angelantonio, S. D., Trettel, F., Bertollini, C., Maggi, L., Gross, C. T., Charo, I. F., Limatola, C., & Eusebi, F. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3192-06.2006 · Cited by 128 · see citing works
Self-citationConti, L., Palma, E., Roseti, C., Lauro, C., Cipriani, R., de Groot, M., Aronica, E., & Limatola, C. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.03111.x · Cited by 121 · see citing works
Self-citationLauro, C., Di Angelantonio, S., Cipriani, R., Sobrero, F., Antonilli, L., Brusadin, V., Ragozzino, D., & Limatola, C. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.11.7590 · Cited by 110 · see citing works
Self-citationActivity‐dependent phosphorylation of GABAA receptors regulates receptor insertion and tonic current
Saliba, R. S., Kretschmannova, K., & Moss, S. (2012) · EMBO Journal · doi:10.1038/emboj.2012.109 · Cited by 102 · see citing works
Hulshof, S. C. J., van Haastert, E. S., Kuipers, H. F., van den Elsen, P. J., Groot, C. J. A. D., van der Valk, P., Ravid, R., & Biber, K. P. H. (2003) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/62.9.899 · Cited by 93 · see citing works
Miledi, R., Eusebi, F., Martínez‐Torres, A., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192445299 · Cited by 89 · see citing works
Pavlov, I., Kaila, K., Kullmann, D. M., et al. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.237958 · Cited by 85 · see citing works
Maggi, L., Trettel, F., Scianni, M., Bertollini, C., Eusebi, F., Fredholm, B. B., & Limatola, C. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.07.016 · Cited by 84 · see citing works
Self-citationYang, T., Zhou, D., & Stefan, H. (2010) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2010.06.002 · Cited by 81 · see citing works
Fractalkine/CX3CL1 depresses central synaptic transmission in mouse hippocampal slices
Bertollini, C., Ragozzino, D., Gross, C. T., Limatola, C., & Eusebi, F. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.05.027 · Cited by 80 · see citing works
Self-citationKan, A. A., de Jager, W., de Wit, M., Heijnen, C. J., van Zuiden, M., Ferrier, C. H., van Rijen, P. C., Gosselaar, P. H., Hessel, E. V. S., van Nieuwenhuizen, O., et al. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-207 · Cited by 78 · see citing works
Altered Expression of CX3CL1 in Patients with Epilepsy and in a Rat Model
Xu, Y., Zeng, K., Han, Y., Wang, L., Chen, D., Xi, Z., Wang, H., Wang, X., & Chen, G. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.01.024 · Cited by 78 · see citing works
Vezzani, A., Balosso, S., & Ravizza, T. (2012) · Handbook of clinical neurology · doi:10.1016/b978-0-444-52898-8.00010-0 · Cited by 76 · see citing works
Palma, E., Roseti, C., Maiolino, F., Fucile, S., Martinello, K., Mazzuferi, M., Aronica, E., Manfredi, M., Esposito, V., Cantore, G. P., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710522105 · Cited by 69 · see citing works
Self-citationThe mTOR pathway is activated in glial cells in mesial temporal sclerosis
Sosunov, A. A., Wu, X., McGovern, R. A., Coughlin, D. G., Mikell, C. B., Goodman, R. R., & McKhann, G. M. (2012) · Epilepsia · doi:10.1111/j.1528-1167.2012.03478.x · Cited by 68 · see citing works
Ragozzino, D., Palma, E., Angelantonio, S. D., Amici, M., Mascia, A., Arcella, A., Giangaspero, F., Cantore, G., Gennaro, G. D., Manfredi, M., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507339102 · Cited by 67 · see citing works
Self-citationScianni, M., Antonilli, L., Chece, G., Cristalli, G., Castro, M. A. D., Limatola, C., & Maggi, L. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-108 · Cited by 66 · see citing works
Self-citationBDNF modulates GABA A receptors microtransplanted from the human epileptic brain to Xenopus oocytes
Palma, E., Torchia, G., Limatola, C., Trettel, F., Arcella, A., Cantore, G. P., Gennaro, G. D., Manfredi, M., Esposito, V., Quarato, P. P., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409442102 · Cited by 65 · see citing works
Self-citationEusebi, F., Palma, E., Amici, M., et al. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.01.008 · Cited by 65 · see citing works
Self-citationMicrotransplantation of Neurotransmitter Receptors From Cells to Xenopus Oocyte Membranes
Miledi, R., Palma, E., & Eusebi, F. (2006) · Methods in molecular biology · doi:10.1007/978-1-59745-000-3_24 · Cited by 65 · see citing works
Self-citationMolecular pathways controlling inhibitory receptor expression
Grabenstatter, H. L., Russek, S. J., & Brooks‐Kayal, A. R. (2012) · Epilepsia · doi:10.1111/epi.12036 · Cited by 61 · see citing works
Heinisch, S., & Kirby, L. G. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.08.075 · Cited by 59 · see citing works
Wu, Y., Wang, X., Mo, X., et al. (2008) · Clinical Neuropathology · doi:10.5414/npp27055 · Cited by 59 · see citing works
Palma, E., Trettel, F., Fucile, S., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0438006100 · Cited by 56 · see citing works
Self-citationYeo, S.-I., Kim, J.-E., Ryu, H. J., Seo, C. H., Lee, B. C., Choi, I.-G., Kim, D.-S., & Kang, T.-C. (2011) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2011.03.005 · Cited by 55 · see citing works
Mazzuferi, M., Palma, E., Martinello, K., Maiolino, F., Roseti, C., Fucile, S., Fabene, P. F., Schio, F., Pellitteri, M., Sperk, G., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914710107 · Cited by 54 · see citing works
Self-citationAdenosine receptor antagonists alter the stability of human epileptic GABA A receptors
Roseti, C., Martinello, K., Fucile, S., Piccari, V., Mascia, A., Gennaro, G. D., Quarato, P. P., Manfredi, M., Esposito, V., Cantore, G. P., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807277105 · Cited by 51 · see citing works
Self-citationPalma, E., Ragozzino, D., Angelantonio, S. D., Spinelli, G., Trettel, F., Martínez‐Torres, A., Torchia, G., Arcella, A., Gennaro, G. D., Quarato, P. P., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403683101 · Cited by 50 · see citing works
Self-citationPiccinin, S., Angelantonio, S. D., Piccioni, A., Volpini, R., Cristalli, G., Fredholm, B. B., Limatola, C., Eusebi, F., & Ragozzino, D. (2010) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.05.012 · Cited by 45 · see citing works
Self-citationZhu, Y., Lu, S., & Gold, M. S. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.06.025 · Cited by 39 · see citing works
Functional rundown of gamma‐aminobutyric acidAreceptors in human hypothalamic hamartomas
Li, G., Yang, K., Zheng, C. J., Liu, Q., Chang, Y., Kerrigan, J., & Wu, J. (2010) · Annals of Neurology · doi:10.1002/ana.22298 · Cited by 31 · see citing works
Basic mechanisms of status epilepticus due to infection and inflammation
Vezzani, A., Balosso, S., Aronica, E., & Ravizza, T. (2009) · Epilepsia · doi:10.1111/j.1528-1167.2009.02370.x · Cited by 30 · see citing works
Self-citationBefore Epilepsy Unfolds: Finding the epileptogenesis switch
Vezzani, A. (2012) · Nature Medicine · doi:10.1038/nm.2982 · Cited by 26 · see citing works
Roseti, C., Palma, E., Martinello, K., Fucile, S., Morace, R., Esposito, V., Cantore, G. P., Arcella, A., Giangaspero, F., Aronica, E., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907324106 · Cited by 26 · see citing works
Self-citationGABAA receptor properties in catastrophic infantile epilepsy
Jansen, L. A., Peugh, L. D., & Ojemann, J. G. (2008) · Epilepsy Research · doi:10.1016/j.eplepsyres.2008.05.011 · Cited by 21 · see citing works
Caioli, S., Pieri, M., Antonini, A., Guglielmotti, A., Severini, C., & Zona, C. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.05.045 · Cited by 13 · see citing works
Inhibitory GABA Current Rundown in Epileptic Brain: Use-Dependent and Pathology-Specific Mechanisms
Janigro, D. (2006) · Epiliepsy currents/Epilepsy currents · doi:10.1111/j.1535-7511.2006.00124.x · Cited by 4 · see citing works
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Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
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- Authors
- Roseti, C., Fucile, S., Lauro, C., Martinello, K., Bertollini, C., Esposito, V., Mascia, A., Catalano, M., Aronica, E., Limatola, C., & Palma, E.
- Affiliations
- IRCCS San Raffaele Roma (IT)
- Istituto Neurologico Mediterraneo (IT)
- Istituto Pasteur (IT)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Palma, Eleonora
- ORCID
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2013-09-13
- Volume
- 54
- Issue
- 10
- Pages
- 1834-1844
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- OpenAlex
- W2097503778
- Cited by
- 92
- References
- 61
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 10 · 2020: 7 · 2019: 9 · 2018: 12 · 2017: 5 · 2016: 11 · 2015: 4 · 2014: 5 · 2013: 1
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi di Cassino (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion)
- IrInSubria (University of Insubria) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- Vanderbilt University Medical Center
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- fractalkine, CX3CR1, GABAA receptor, GABAergic inhibition, mesial temporal lobe epilepsy, hippocampal sclerosis, rundown, pyramidal neurons, microglial activation, neuroinflammation, epileptogenesis, GABAergic dysfunction, chemokines, human brain tissue, Xenopus oocyte expression, immunohistochemistry
- MeSH terms
- Action Potentials, Adult, Animals, Brain, Cell Membrane, Epilepsy, Temporal Lobe, Female, Humans, Male, Middle Aged, Oocytes, Receptors, GABA-A, Xenopus laevis, Blotting, Western, Pyramidal Cells, Chemokine CX3CL1, Young Adult
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