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Inflammation, Glutamate, and Glia in Depression: A Literature Review

Published online by Cambridge University Press:  07 November 2014

Leah McNally ,
Zubin Bhagwagar  and
Jonas Hannestad
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Abstract

Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. In this review we provide an overview of how these two systems may interact. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Studies of acute experimental activation of the immune system with endotoxin and of chronic activation during interferon-α treatment show that inflammation can cause depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation. Loss of astroglia, a feature of depression, upsets the balance of anti- and pro-inflammatory mediators and further impairs the removal of excitatory amino acids. Microglia activated by excess inflammation, astroglial loss, and inappropriate glutamate receptor activation ultimately disrupt the delicate balance of neuroprotective versus neurotoxic effects in the brain, potentially leading to depression.

Type
Review Articles
Information
CNS Spectrums , Volume 13 , Issue 6 , June 2008 , pp. 501 - 510
Copyright
Copyright © Cambridge University Press 2008

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References

REFERENCES

1.Kessler, RC, Chiu, WT, Demler, O, Merikangas, KR, Walters, EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617–627.Google Scholar
2.Kessler, RC, Berglund, P, Delmer, O, Jin, R, Merikangas, KR, Walters, EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:590–592.Google Scholar
3.Murray, CJ, Lopez, AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997;349:1436–1442.CrossRefGoogle ScholarPubMed
4.Zheng, D, Macera, CA, Croft, JB, Giles, WH, Davis, D, Scott, WK. Major depression and allcause mortality among white adults in the United States. Ann Epidemiol. 1997;7:213–218.CrossRefGoogle ScholarPubMed
5.Cuijpers, P, Smit, F. Excess mortality in depression: a meta-analysis of community studies. J Affect Disord. 2002;72:227–236.Google Scholar
6.Rivelli, S, Jiang, W. Depression and ischemic heart disease: what have we learned from clinical trials? Curr Opin Cardiol. 2007;22:286–291.CrossRefGoogle ScholarPubMed
7.Taylor, MJ, Freemantle, N, Geddess, JR, Bhagwagar, Z. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry. 2006;63:1217–1223.CrossRefGoogle ScholarPubMed
8.Irwin, MR, Miller, AH. Depressive disorders and immunity: 20 years of progress and discovery. Brain Behav Immun. 2007;21:374–383.CrossRefGoogle ScholarPubMed
9.Dantzer, R, O'Connor, JC, Freund, GG, Johnson, RW, Kelley, KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:45–46.Google Scholar
10.Raison, CL, Capuron, L, Miller, AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.CrossRefGoogle ScholarPubMed
11.Penninx, BW, Kritchevsky, SB, Yaffe, K, et, al. Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composition Study. Biol Psychiatry. 2003;54:566–572.Google Scholar
12.Bremmer, MA, Beekman, AT, Deeg, DJ, et, al. Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord. 2008;106:249–255.CrossRefGoogle ScholarPubMed
13.Zorrilla, EP, Luborsky, L, McKay, JR, et al.The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun. 2001;15:199–226.Google Scholar
14.Tuglu, C, Kara, SH, Caliyurt, O, Vardar, E, Abay, E. Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder. Psychopharmacology (Berl). 2003;170:429–433.Google Scholar
15.Myint, AM, Leonard, BE, Steinbusch, HW, Kim, YK. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord. 2005;88:167–173.CrossRefGoogle ScholarPubMed
16.Leonard, BE. The immune system, depression and the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25:767–780.CrossRefGoogle ScholarPubMed
17.Kenis, G, Maes, M. Effects of antidepressants on the production of cytokines. Int J Neuropsychopharmacol. 2002;5:401–412.CrossRefGoogle ScholarPubMed
18.Hestad, KA, Tønseth, S, Støen, CD, Ueland, T, Aukrust, P. Raised plasma levels of tumor necrosis factor alpha in patients with depression: normalization during electroconvulsive therapy. J Ect. 2003;19:183–188.Google Scholar
19.Eller, T, Vasar, V, Shlik, J, Maron, E. Pro-inflammatory cytokines and treatment response to escitaloprsam in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008,15;32:445–450.CrossRefGoogle Scholar
20.van den Biggelaar, AH, Gussekloo, J, de Craen, AJ. Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age. Exp Gerontol. 2007;42:693–701.Google Scholar
21.Campbell, SJ, Deacon, RM, Jiang, Y, Ferrari, C, Pitossi, FJ, Anthony, DC. Overexpression of IL-1 beta by adenoviral-mediated gene transfer in the rat brain causes a pro-longed hepatic chemokine response, axonal injury and the suppression of spontaneous behaviour. Neurobiol Dis. 2007;27:151–63.Google Scholar
22.Reyes, TM, Coe, CL. Interleukin-1 beta differentially affects interleukin-6 and soluble interleukin-6 receptor in the blood and central nervous system of the monkey. J Neuroimmunol. 1996;66:135–141.CrossRefGoogle ScholarPubMed
23.Levine, J, Barak, Y, Chengappa, KN, Rapoport, A, Rebey, M, Barak, V. Cerebrospinal cytokine levels in patients with acute depression. Neuropsychobiology. 1999;40:71–76.Google Scholar
24.Foster, SL, Hargreaves, DC, Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature. 2007;447:972–978.CrossRefGoogle Scholar
25.Asnis, GM, De La Garza, R 2nd. Interferon-induced depression in chronic hepatitis C: a review of its prevalence, risk factors, biology, and treatment approaches. J Clin Gastroenterol. 2006;40:322–335.Google Scholar
26.Taylor, JL, Grossberg, SE. The effects of interferon-alpha on the production and action of other cytokines. Semin Oncol. 1998;25:23–29.Google ScholarPubMed
27.Juengling, FD, Ebert, D, Gut, O. Prefrontal cortical hypometabolism during low-dose interferon alpha treatment. Psychopharmacology (Berl). 2000;152:383–389.Google Scholar
28.Tanaka, H, Maeshima, S, Shigekawa, Y, et, al. Neuropsychological impairment and decreased regional cerebral blood flow by interferon treatment in patients with chronic hepatitis: a preliminary study. Clin Exp Med. 2006;6:124–128.CrossRefGoogle ScholarPubMed
29.Michie, HR, Manogue, KR, Spriggs, DR, et, al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl Med. 1988;318:1481–1486.CrossRefGoogle ScholarPubMed
30.Suffredini, AF, Hochstein, HD, McMahon, FG. Dose-related inflammatory effects of intravenous endotoxin in humans: evaluation of a new clinical lot of Escherichia coli 0:113 endotoxin. J Infect Dis. 1999;179:1278–1282.CrossRefGoogle Scholar
31.Reichenberg, A, Yirmiya, R, Schuld, A, et, al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445–452.CrossRefGoogle ScholarPubMed
32.Wright, CE, Strike, PC, Brydon, L, Steptoe, A. Acute inflammation and negative mood: mediation by cytokine activation. Brain Behav Immun. 2005;19:345–350.CrossRefGoogle ScholarPubMed
33.Müller, N, Schwarz, MJ, Dehning, S, et, al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11:680–684.Google Scholar
34.Tyring, S, Gottlieb, A, Papp, K, et, al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367:29–35.Google Scholar
35.Simen, BB, Duman, CH, Simen, AA, Duman, RS. TNF alpha signaling in depression and anxiety: behavioral consequences of individual receptor targeting. Biol Psychiatry. 2006;59:775–785.CrossRefGoogle ScholarPubMed
36.Benton, T, Staab, J, Evans, DL. Medical co-morbidity in depressive disorders. Ann Clin Psychiatry. 2007;19:289–303.CrossRefGoogle ScholarPubMed
37.Elenkov, IJ. Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. Neurochem Int. 2008;52:40–51.CrossRefGoogle ScholarPubMed
38.Huffman, JC, Smith, FA, Quinn, DK, Fricchione, GL. Post-Ml psychiatric syndromes: six unanswered questions. Harv Rev Psychiatry. 2006;14:305–318.CrossRefGoogle Scholar
39.Constant, A, Castera, L, Dantzer, R, et al.Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry. 2005;66:1050–1057.Google Scholar
40.Bower, JE. Cancer-related fatigue: links with inflammation in cancer patients and survivors. Brain Behav Immun. 2007;21:863–871.CrossRefGoogle ScholarPubMed
41.Stewart, JC, Janicki, DL, Muldoon, MF, Sutton-Tyrrell, K, Kamarck, TW. Negative emotions and 3-year progression of subclinical atherosclerosis. Arch Gen Psychiatry. 2007;64:225–233.Google Scholar
42.Papakostas, GI, Nutt, DJ, Hallett, LA, Tucker, VL, Krishen, A, Fava, M. Resolution of sleepiness and fatigue in major depressive disorder: a comparison of bupropion and the selective serotonin reuptake inhibitors. Biol Psychiatry. 2006;60:1350–1355.Google ScholarPubMed
43.Capuron, L, Pagnoni, G, Demetrashvili, MF, et al.Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacology. 2007;32:2384–2392.Google Scholar
44.Neumeister, A. Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacol Bull. 2003;37:99–115.Google ScholarPubMed
45.Müller, N, Schwarz, MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007;12:988–1000.Google Scholar
46.Capuron, L, Neurauter, G, Musselman, DL, et al.Interferon-alpha-induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment. Biol Psychiatry. 2003;54:906–914.CrossRefGoogle ScholarPubMed
47.Pittenger, C, Sanacora, G, Krystal, JH. The NMDA receptor as a therapeutic target in major depressive disorder. CNS Neurol Disord Drug Targets. 2007;6:101–115.Google Scholar
48.Palucha, A, Pilc, A. Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol Ther. 2007;115:116–147.CrossRefGoogle ScholarPubMed
49.Sanacora, G, Gueorguieva, R, Epperson, CN, et al.Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry. 2004;61:705–713.Google Scholar
50.Bhagwagar, Z, Wylezinska, M, Jezzard, P, et al.Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry. 2007;61:806–812.CrossRefGoogle ScholarPubMed
51.Berman, RM, Cappiello, A, Anand, A, et al.Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–354.Google Scholar
52.Zarate, CA Jr, Singh, JB, Carlson, PJ, et al.A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–864.Google Scholar
53.Zarate, CA Jr, Payne, JL, Quiroz, J, et al.An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161:171–174.Google Scholar
54.Sanacora, G, Kendell, SF, Levin, Y, et al.Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61:822–825.Google Scholar
55.Saito, K, Crowley, JS, Markey, SP, Heyes, MP. A mechanism for increased quinolinic acid formation following acute systemic immune stimulation. J Biol Chem. 1993;268:15496–15503.Google Scholar
56.Myint, AM, Kim, YK, Verkerk, R, Scharpé, S, Steinbusch, H, Leonard, B. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord. 2007;98:143–151.Google Scholar
57.Fedele, E, Foster, AC. An evaluation of the role of extracellular amino acids in the delayed neurodegeneration induced by quinolinic acid in the rat striatum. Neuroscience. 1993;52:911–917.CrossRefGoogle ScholarPubMed
58.Pocock, JM, Kettenmann, H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007;30:527–535.Google Scholar
59.Shibakawa, YS, Sasaki, Y, Goshima, Y, et al.Effects of ketamine and propofol on inflammatory responses of primary glial cell cultures stimulated with lipopolysaccharide. Br J Anaesth. 2005;95:803–810.Google Scholar
60.Rosi, S, Vazdarjanova, A, Ramirez-Amaya, V, Worley, PF, Barnes, CA, Wenk, GL. Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience. 2006;142:1303–1315.CrossRefGoogle ScholarPubMed
61.Danbolt, NC. Glutamate uptake. Prog Neurobiol. 2001;65:1–105.Google Scholar
62.Bergles, DE, Jahr, CE. Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus. J Neurosci. 1998;18:7709–7716.CrossRefGoogle ScholarPubMed
63.Rothstein, JD, Dykes-Hoberg, M, Pardo, CA, et al.Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16:675–686.CrossRefGoogle Scholar
64.Tanaka, K, Watase, K, Manabe, T, et al.Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science. 1997;276:1699–1702.Google Scholar
65.Vercellino, M, Merola, A, Piacentino, C, et al.Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. J Neuropathol Exp Neurol. 2007;66:732–739.Google Scholar
66.McEwen, BS. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism. 2005;54(5 suppl 1):20–23.Google Scholar
67.Duman, RS, Monteggia, LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–1127.CrossRefGoogle ScholarPubMed
68.Fuchs, E, Czéh, B, Kole, MH, Michaelis, T, Lucassen, PJ. Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur Neuropsychopharmacol. 2004;14(suppl 5):S481–S490.Google Scholar
69.Block, ML, Zecca, L, Hong, JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8:57–69.CrossRefGoogle ScholarPubMed
70.Li, L, Lu, J, Tay, SS, Moochhala, SM, He, BP. The function of microglia, either neuroprotection or neurotoxicity, is determined by the equilibrium among factors released from activated microglia in vitro. Brain Res. 2007;1159:8–17.Google Scholar
71.Hanisch, UK, Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10:1387–1394.Google Scholar
72.Pinteaux, E, Rothwell, NJ, Boutin, H. Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia. Glia. 2006;53:551–556.Google Scholar
73.Hutchinson, PJ, O'Connell, MT, Rothwell, NJ, et al.Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1 beta, and their endogenous inhibitor IL-1 ra. J Neurotrauma. 2007;24:1545–1557.Google Scholar
74.Qin, L, Wu, X, Block, ML, et al.Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55:453–462.CrossRefGoogle ScholarPubMed
75.Maeda, J, Higuchi, M, Inaji, M, et al.Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor. Brain Res. 2007;1157:100–111.Google Scholar
76.Mastronardi, C, Whelan, F, Yildiz, OA, et al, Caspase 1 deficiency reduces inflammation-induced brain transcription. Proc Natl Acad Sci USA. 2007;104:7205–7210.Google Scholar
77.Tikka, TM, Koistinaho, JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001;166:7527–7533.CrossRefGoogle ScholarPubMed
78.Ishikawa, J, Ishikawa, A, Nakamura, S. Interferon-alpha reduces the density of monoaminergic axons in the rat brain. Neuroreport. 2007;18:137–140.CrossRefGoogle ScholarPubMed
79.Hashioka, S, Klegeris, A, Monji, A, et al.Antidepressants inhibit interferon-gamma-induced microglial production of IL-6 and nitric oxide. Exp Neurol. 2007;206:33–42.Google Scholar
80.Hannestad, J, Levanti, MB, Vega, JA. Distribution of neurotrophin receptors in human palatine tonsils: an immunohistochemical study. J Neuroimmunol. 1995;58:131–137.Google Scholar
81.García-Suáez, O, Hannestad, J, Esteban, I, Sainz, R, Naves, FJ, Vega, JA. Expression of the TrkB neurotrophin receptor by thymic macrophages. Immunology. 1998;94:235–241.Google Scholar
82.Asami, T, Ito, T, Fukumitsu, H, Nomoto, H, Furukawa, Y, Furukawa, S. Autocrine activation of cultured macrophages by brain-derived neurotrophic factor. Biochem Biophys Res Commun. 2006;344:941–947.Google Scholar
83.Martinowich, K, Manji, H, Lu, B. New insights into BDNF function in depression and anxiety. Nat Neurosci. 2007;10:1089–1093.Google Scholar
84.Rajkowska, G, Miguel-Hidalgo, JJ. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets. 2007;6:219–233.Google Scholar
85.Nägler, K, Mauch, DH, Pfrieger, FW. Glia-derived signals induce synapse formation in neurones of the rat central nervous system. J Physiol. 2001;533(pt 3):665–679.Google Scholar
86.Ullian, EM, Sapperstein, SK, Christopherson, KS, Barres, BA. Control of synapse number by glia. Science. 2001;291:657–661.CrossRefGoogle ScholarPubMed
87.Kim, JP, Choi, DW. Quinolinate neurotoxicity in cortical cell culture. Neuroscience. 1987;23:423–432.Google Scholar
88.Myint, AM, Kim, YK. Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses. 2003;61:519–525.Google Scholar
89.Tapia, R. Release and uptake of glutamate as related to excitotoxicity. Rev Bras Biol. 1996;56(suppl 1,pt 1):165–174.Google ScholarPubMed
90.Lobsiger, CS, Cleveland, DW. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci. 2007;10:1355–1360.Google Scholar
91.Frizzo, ME, Dall'Onder, LP, Dalcin, KB, Souza, DO. Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol. 2004;24:123–128.Google Scholar
92.Fatemi, SH, Laurence, JA, Araghi-Niknam, M, et al.Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia. Schizophr Res. 2004;69:317–323.Google Scholar
93.Si, X, Miguel-Hidalgo, JJ, O'Dwyer, G, Stockmeier, CA, Rajkowska, G. Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology. 2004;29:2088–2096.Google Scholar
94.Haddy, N, Sass, C, Maumus, S, et al.Biological variations, genetic polymorphisms and familial resemblance of TNF-alpha and IL-6 concentrations: STANISLAS cohort. Eur J Hum Genet. 2005;13:109–117.CrossRefGoogle ScholarPubMed
95.de Kloet, ER, Joëls, M, Holsboer, F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6:463–475.Google Scholar