Abstract
After accumulation of data showing that resident brain cells (neurons, astrocytes, and microglia) produce mediators of the immune system, such as cytokines and their receptors under normal physiological conditions, a critical need emerged for investigating the role of these mediators in cognitive processes. The major problem for understanding the functional role of cytokines in the mechanisms of synaptic plasticity, de novo neurogenesis, and learning and memory is the small number of investigated cytokines. Existing concepts are based on data from just three proinflammatory cytokines: interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. The amount of information in the literature on the functional role of antiinflammatory cytokines in the mechanisms of synaptic plasticity and cognitive functions of mature mammalian brain is dismally low. However, they are of principle importance for understanding the mechanisms of local information processing in the brain, since they modulate the activity of individual cells and local neural networks, being able to reconstruct the processes of synaptic plasticity and intercellular communication, in general, depending on the local ratio of the levels of different cytokines in certain areas of the brain. Understanding the functional role of cytokines in cellular mechanisms of information processing and storage in the brain would allow developing preventive and therapeutic means for the treatment of neuropathologies related to impairment of these mechanisms.
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Abbreviations
- AMPA:
-
α-amino-3-hydroxy-5-methyl-4-isoxazole
- BDNF:
-
brain-derived neurotrophic factor
- CaMKII:
-
Ca2+/calmodulin-dependent protein kinase II
- CNS:
-
central nervous system
- CREB:
-
cAMP response element-binding protein
- Erk/MAPK:
-
signaling pathway
- GABA:
-
γ-aminobutyric acid
- GluA1 and GluA2:
-
subunits of AMPA receptors
- IKK:
-
IκΒ kinase complex
- IL-1:
-
interleukin-1
- IL-1ra:
-
interleukin-1 receptor antagonist
- IL-1RI and IL-1RII:
-
interleukin-1 receptors
- IL6:
-
interleukin-6
- JAK/STAT:
-
JAK kinase and signal transducers and activators of transcription
- LSD:
-
long-term synaptic depression
- LSP:
-
long-term synaptic potentiation
- MHC-1:
-
major histocompatibility complex I
- NF-κB:
-
nuclear factor kappa B
- NMDA receptors:
-
N-methyl-D-aspartate receptors
- Rab3:
-
small GTP-binding protein
- RhoA:
-
small G-proteins
- RIM proteins:
-
Rab3-interacting molecules
- SB431542 :
-
inhibitor of TGFβ
- TGFβ:
-
transforming growth factor beta
- TNF:
-
tumor necrosis factor
- TNFR1 and TNFR2:
-
TNF receptors
- TTX:
-
tetrodotoxin
References
Breder, C., Dinarello, C., and Saper, C. (1998) Interleukin-1 immunoreactive innervation of the human hypothalamus, Science, 240, 321–324.
Plata-Salaman, C. R., Oomura, Y., and Kai, Y. (1988) Tumor necrosis factor and interleukin-1 beta: suppression of food intake by direct action in the central nervous system, Brain Res., 448, 106–114.
Stepanichev, M. Yu. (2005) Cytokines as neuromodulators in the central nervous system, Neurochemistry, 22, 5–11.
Vitkovic, L., Bockaert, J., and Jacque, C. (2000) “Inflammatory” cytokines: neuromodulators in normal brain? J. Neurochem., 74, 457–471.
Allan, S. M., and Rothwell, N. J. (2001) Cytokines and acute neurodegeneration, Nature Neurosci., 2, 734–744.
Konsman, J. P., Parnet, P., and Dantzer, R. (2002) Cytokine-induced sickness behavior: mechanisms and implications, Trends Neurosci., 25, 154–159.
Wrona, D. (2006) Neural–immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems, J. Neuroimmunol., 172, 38–58.
Turrigiano, G. G. (1999) Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same, Trends Neurosci., 22, 221–227.
Malenka, R. C., and Nicoll, R. A. (1999) Long-term potentiation–a decade of progress? Science, 285, 1870–1874.
Vitureira, N., and Goda, Y. (2013) The interplay between Hebbian and homeostatic synaptic plasticity, J. Cell Biol., 203, 175–186.
McAfoose, J., and Baune, B. T. (2009) Evidence for a cytokine model of cognitive function, Neurosci. Biobehav. Rev., 33, 355–366.
Hebb, D. O. (1949) Organization of Behavior: A Neuropsychological Theory (Weig, J., ed.) N. Y.
Bliss, T. V. P., and Lynch, M. A. (1988) Long-Term Potentiation of Synaptic Transmission in the Hippocampus: Properties and Mechanisms in Long-Term Potentiation: from Biophysics to Behavior (Landfield, P. W., and Deadwyler, S. A., eds.) Liss, N. Y., pp. 3–72.
Godukhin A. V., and Shchipakina, T. G. (1995) Mechanisms of synaptic plasticity: the role of phosphorylation of synaptic proteins and gene expression, Adv. Physiol. Sci., 26, 41–56.
Citri, A., and Malenka, R. C. (2008) Synaptic plasticity: multiple forms, functions, and mechanisms, Neuropsychopharmacol. Rev., 33, 18–41.
Collingridge, G. L., Isaac, J. T., and Wang, Y. T. (2004) Receptor trafficking and synaptic plasticity, Nat. Rev. Neurosci., 5, 952–962.
Malenka, R. C., and Bear, M. F. (2004) LTP and LTD: an embarrassment of riches, Neuron, 44, 5–21.
Cingolani, L. A., and Goda, Y. (2008) Differential involvement of β3 integrin in pre- and postsynaptic forms of adaptation to chronic activity deprivation, Neuron Glia Biol., 4, 179–187.
Murphy, T. H., and Corbett, D. (2009) Plasticity during stroke recovery: from synapse to behavior, Nat. Rev. Neurosci., 10, 861–872.
Greer, P. L., and Greenberg, M. E. (2008) From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function, Neuron, 59, 846–860.
West, A. E., and Greenberg, M. E. (2011) Neuronal activity-regulated gene transcription in synapse development and cognitive function, Cold Spring Harbor Perspect. Biol., 3.
Wood, M. A., Attner, M., Oliveira, A. M., Brindle, P. K., and Abel, T. (2006) A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of specific target genes, Learn. Memory, 13, 609–617.
Miller, P., Zhabotinsky, A. M., Lisman, J. E., and Wang, X. J. (2005) The stability of a stochastic CaMKII switch: dependence on the number of enzyme molecules and protein turnover, PLoS Biol., 3, 107.
Casar, B., Pinto, A., and Crespo, P. (2008). Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes, Mol. Cell, 31, 708–721.
Sajikumar, S., Navakkode, S., and Frey, J. U. (2005) Protein synthesis-dependent long-term functional plasticity: methods and techniques, Curr. Opin. Neurobiol., 15, 607–613.
Lscher, C., and Malenka, R. C. (2012) NMDA ReceptorDependent Long-Term Potentiation and Long-Term Depression (LTP/LTD), Cold Spring Harbor Laboratory Press, N. Y., pp. 1–10.
Raymond, C. R. (2007) LTP forms 1, 2 and 3: different mechanisms for the “long” in long-term potentiation, Trends Neurosci., 30, 168–175.
Spedding, M., and Gressens, P. (2008) Neurotrophins and cytokines in neuronal plasticity, Novartis Found Symp., 28, 222–233.
McClung, C. A., and Nestler, E. J. (2008) Neuroplasticity mediated by altered gene expression, Neuropsychopharmacology, 33, 3–17.
Pozo, K., and Goda, Y. (2010) Unraveling mechanisms of homeostatic synaptic plasticity, Neuron, 66, 337–351.
Turrigiano, G. (2008) Homeostatic synaptic plasticity, in Structural and Functional Organization of the Synapse (Hell, J. W., and Ehlers, M. D., eds.) Springer Science, N. Y., pp. 535–548.
Echegoyen, J., Neu, A., Graber, K. D., and Soltesz, I. (2007) Homeostatic plasticity studied using in vivo hippocampal activity-blockade: synaptic scaling, intrinsic plasticity and age-dependence, PLoS One, 2, e700.
Bartley, A. F., Huang, Z. J., Huber, K. M., and Gibson, J. R. (2008) Differential activity-dependent, homeostatic plasticity of two neocortical inhibitory circuits, J. Neurophysiol., 100, 1983–1994.
Yu, W., Morishita, W., Tsui, J., Gaietta, G., Deerinck, T. J., Adams, S. R., Garner, C. C., Tsien, R. Y., Ellisman, M. H., and Malenka, R. C. (2004) Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors, Nat. Neurosci., 7, 244–253.
Sutton, M. A., Ito, H. T., Cressy, P., Kempf, C., Woo, J. C., and Schuman, E. M. (2006) Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis, Cell, 125, 785–799.
Rabinowitch, I., and Segev, I. (2008) Two opposing plasticity mechanisms pulling a single synapse, Trends Neurosci., 31, 377–383.
Lee, K. J., Park, T. S., Kim, H., Greenough, W. T., Pak, D. T., and Rhyn, I. J. (2013) Motor skill training induces coordinated strengthening and weakening between neighboring synapses, J. Neurosci., 33, 9794–9799.
Arendt, K. L., Sarti, F., and Chen, L. (2013) Chronic inactivation of a neural circuit enhances LTP by inducing silent synapse formation, J. Neurosci., 33, 2087–2096.
Goshen, I., and Yirmia, R. (2007) The role of pro-inflammatory cytokines in memory processes and neural plasticity, Psychoneuroimmunology, 1, 337–367.
Pribiag, H., and Stellwagen, D. (2014) Neuroimmune regulation of homeostatic synaptic plasticity, Neuropharmacology, 78, 13–22.
Yirmiya, R., and Goshen, I. (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis, Brain Behav. Immun., 25, 181–213.
Donna, L., and Gruol, C. (2015) IL-6 regulation of synaptic function in the CNS, Neuropharmacology, 96, 42–54.
Tancredi, V., D’Antuono, M., Cafe, C., Giovedi, S., Bue, M. C., D’Arcangelo, G., Onofri, F., and Benfenati, F. (2000) The inhibitory effects of interleukin-6 on synaptic plasticity in the rat hippocampus are associated with an inhibition of mitogen-activated protein kinase ERK, J. Neurochem., 75, 634–643.
Beattle, T. C., Stellwagen, D., Morishita, W., Bresnahan, J. C., Ha, B. K., Von Zastrow, M., Beattle, M. S., and Malenka, R. C. (2002) Control of synaptic strength by glial TNF alpha, Science, 295, 2282–2285.
Stellwagen, D., Beattie, E. C., Seo, J. Y., and Malenka, R. C. (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha, J. Neurosci., 25, 3219–3228.
Grilli, M., Barbieri, I., Basudev, H., Brusa, R., Casati, C., Lozza, G., and Ongini, E. (2000) Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage, Eur. J. Neurosci., 12, 2265–2272.
Molina-Holgado, E., Vela, J. M., Arevalo-Martin, A., and Guaza, C. (2001) LPS/IFN-gamma cytotoxicity in oligodendroglial cells: role of nitric oxide and protection by the antiinflammatory cytokine IL-10, Eur. J. Neurosci., 13, 493–502.
Krieglstein, K., Zheng, F., Unsicker, K., and Alzheimer, C. (2011) More than being protective: functional roles for TGF/activin signaling pathways at central synapses, Trends Neurosci., 34, 421–429.
Yu, C. Y., Gui, W., He, H. Y., Wang, X. S., Zuo, J., Huang, L., Zhou, N., Wang, K., and Wang, Y. (2014) Neuronal and astroglial TGFβ-Smad3 signaling pathways differentially regulate dendrite growth and synaptogenesis, Neuronal Med., 16, 457–472.
Caraci, F., Gulisano, W., Guida, C. A., Impellizzeri, A. A., Drago, F., Puzzo, D., and Palmeri, A. (2015) A key role for TGF-β1 in hippocampal synaptic plasticity and memory, Sci. Rep., 5, 1–10.
Nicolas, C. S., Peineau, S., Amici, M., Csaba, Z., Fatouri, A., Javalet, C., Colett, V. J., Hilderbrandt, L., Seaton, G., Choi, S. L., Sim, S. E., Bradley, C., Lee, K., Zhuo, M., Kaang, B. K., Gressens, P., Dournaud, P., Fitzjohn, S. M., Bortolotto, Z. A., Cho, K., and Collingridge, G. L. (2012) The JAK/STAT pathway is involved in synaptic plasticity, Neuron, 73, 374–390.
Copf, T., Goguel, V., Lampin- Saint-Amaux, A., Scaplehorn, N., and Preat, T. (2011) Cytokine signaling through the JAK/STAT pathway is required for long-term memory in Drosophila, PNAS, 108, 8059–8064.
Rothwell, N. J., and Luheshi, G. N. (2000) Interleukin I in the brain: biology, pathology and therapeutic target, Trends Neurosci., 23, 618–625.
Thornberry, N. A., Bull, H. G., Calaycay, J. R., Chapman, K. T., Howard, A. D., Kosture, M. J., Miller, D. K., Molineaux, S. M., Weidner, J. R., Aunins, J., Elliston, K. O., Avala, J. M., Casano, F. J., Chin, J., Ding, G. J. F., Egger, L. A., Gaffney, E. P., Limjnco, G., Palyha, O. C., Rajn, S. M., Rolando, A. M., Salley, J. P., Yamin, T. T., Lee, T. D., Shivelly, J. E., Maccross, M., Mumford, R. A., Schmidt, J. A., and Tocci, M. J. (1992) A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes, Nature, 356, 768–774.
Rothwell, N. J. (1991) Functions and mechanisms of interleukin-1 in the brain, Trends Pharm. Sci., 12, 430–436.
Di Donato, J. A., Nayakawa, M., Rothware, D. M., Zandi, E., and Karin, M. (1997) A cytokine-responsive IkB kinase that activates the transcription factor NF-κB, Nature, 388, 548–554.
O’Neill, L. A., and Greene, C. (1998) Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants, J. Leukocyte Biol., 63, 650–657.
Turnbull, A. V., and Rivier, C. L. (1999) Regulation of the hypothalamic–pituitary–adrenal axis by cytokines: actions and mechanisms of action, Physiol. Rev., 79, 1–71.
Kluger, M. J., Kozak, W., Leon, L. R., Soszynski, D., and Conn, C. A. (1998) Fever and antipyresis, Prog. Brain Res., 115, 465–475.
Krueger, J. M., Fang, J., Taishi, P., Chen, Z., Kushikata, T., and Gardi, J. (1998) Sleep: a physiologic role for IL-1 beta and TNF-alpha, Ann. N. Y. Acad. Sci., 856, 148–159.
Diana, A., Van Dam, A. M., Winblad, B., and Schultzberg, M. (1999) Co-localization of interleukin-1 receptor type I and interleukin-1 receptor antagonist with vasopressin in magnocellular neurons of the paraventricular and supraoptic nuclei of the rat hypothalamus, Neuroscience, 89, 137–147.
Pringle, A. K., Gardner, C. R., and Walker, R. J. (1996) Reduction of cerebellar GABAA responses by interleukin-1 (IL-1) through an indometacin insensitive mechanism, Neuropharmacology, 35, 147–152.
Cunningham, A. J., Murray, C. A., O’Neill, L. A. J., Lynch, M. A., and O’Connor, J. J. (1996) Interleukin-1β (IL-1β) and tumor necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro, Neurosci. Lett., 203, 17–20.
Zhou, C., Ye, H. H., Wang, S. Q., and Chai, Z. (2006) Interleukin-1β regulation of N-type Ca2+ channels in cortical neurons, Neurosci. Lett., 403, 181–185.
Wang, C. X., and Shuaib, A. (2002) Involvement of inflammatory cytokines in central nervous system injury, Prog. Neurobiol., 67, 161–172.
Miller, L. G., Galpern, W. R., Dunlap, K., Dinarello, C. A., and Turner, T. J. (1991) Interleukin-1 augments gamma-aminobutyric acid A receptor function in brain, Mol. Pharmacol., 39, 105–108.
Plata-Salaman, C. R., and Ffrench-Mullen, J. M. (1992) Interleukin-1 beta depresses calcium currents in CA1 hippocampal neurons at pathophysiological concentrations, Brain Res., 29, 221–223.
Viviani, B., Gardoni, F., and Marinovich, M. (2007) Cytokines and neuronal ion channels in health and disease, Inter. Rev. Neurobiol., 82, 247–263.
Fenster, C. P., Fenster, S. D., Leahy, H. P., Kurschner, C., and Blundon, J. A. (2007) Modulation Kv4.2 K+ currents by neuronal interleukin-16, a PDZ domain-containing protein expressed in the hippocampus and cerebellum, Brain Res., 1162, 19–31.
Liu, Z., Fang, X. X., Chen, Y. P., Qiu, Y. H., and Peng, Y. P. (2013) Interleukin-6 prevents NMDA-induced neuronal Ca2+ overload via suppression of IP3 receptors, Brain Injury, 27, 1047–1055.
Floyd, R., and Krueger, J. (1997) Diurnal variation of TNF alpha in the rat brain, Neuroreport, 8, 915–918.
Szelenyl, J. (2001) Cytokines and the central nervous system, Brain Res. Bull., 54, 329–338.
Kinouchi, K., Brown, G., Pasternak, G., and Donner, D. (1991) Identification and characterization of receptors for tumor necrosis factor alpha in the brain, Biochem. Biophys. Res. Commun., 181, 1532–1538.
MacEwan, D. J. (2002) TNF receptor subtype signaling: differences and cellular consequences, Cell Signal., 14, 477–492.
Furuno, T., and Nakanishi, M. (2006) Neurotrophic factors and tumor necrosis factor-α induced translocation of NF-κB in rat PC12 cells, Neurosci. Lett., 392, 240–244.
Eder, J. (1997) Tumor necrosis factor alpha and interleukin 1 signaling: do MAPKK kinases connect it all? Trends Pharmacol. Sci., 18, 319–322.
Houzen, H., Kikuchi, S., Kanno, M., Shinpo, K., and Tashiro, K. (1997) Tumor necrosis factor enhancement of transient outward potassium currents in cultured rat cortical neurons, J. Neurosci. Res., 50, 990–999.
Furukawa, K., and Mattson, M. P. (1998) The transcription factor NF-κB mediates increases in calcium currents and decreases in NMDAand AMPA/kainite-induced currents induced by tumor necrosis factor-α in hippocampal neurons, J. Neurochem., 70, 1876–1886.
Vezzani, A., and Viviani, B. (2015) Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability, Neuropharmacology, 96, 70–82.
Strle, K., Zhou, J. H., Shen, W. H., Broussard, S. R., Johnson, R. W., Freund, G. G., Dantzer, R., and Kelly, K. W. (2001) Interleukin-10 in the brain, Crit. Rev. Immunol., 21, 427–449.
Beattie, M. S., Harrington, A. W., Lee, R., Kim, J. Y., Boyce, S. L., Longo, F. M., Bresnahan, J. C., Hempstead, B. L., and Yoon, S. O. (2002) ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury, Neuron, 36, 375–386.
Schafers, M., and Sorkin, L. (2008) Effects of cytokines on neuronal excitability, Neurosci. Lett., 437, 188–193.
Levin, S. G., and Godukhin, O. V. (2011) Anti-inflammatory cytokines, TGF-β1 and IL-10, exert anti-hypoxic action and abolish posthypoxic hyperexcitability in hippocampal slice neurons: comparative aspects, Exp. Neurol., 232, 329–332.
Turovskaya, M. V., Turovsky, E. A., Zinchenko, V. P., Levin, S. G., and Godukhin, O. V. (2012) Interleukin-10 modulates [Ca2+]i response induced by repeated NMDA receptor activation with brief hypoxia through inhibition of InsP3-sensitive internal stores in hippocampal neurons, Neurosci. Lett., 516, 151–155.
Savina, T. A., Shchipakina, T. G., Levin, S. G., and Godukhin, O. V. (2013) Interleukin-10 prevents the hypoxia-induced decreases in expressions of AMPA receptor subunit GluA1 and alpha subunit of Ca2+/calmodulindependent protein kinase II in hippocampal neurons, Neurosci. Lett., 534, 279–284.
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Published in Russian in Biokhimiya, 2017, Vol. 82, No. 3, pp. 397-409.
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Levin, S.G., Godukhin, O.V. Modulating effect of cytokines on mechanisms of synaptic plasticity in the brain. Biochemistry Moscow 82, 264–274 (2017). https://doi.org/10.1134/S000629791703004X
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DOI: https://doi.org/10.1134/S000629791703004X