Abstract
Cognitive decline is a common problem of aging. Whereas multiple neural and glial mechanisms may account for these declines, microglial sensitization and/or dystrophy has emerged as a leading culprit in brain aging and dysfunction. However, glial activation is consistently observed in normal brain aging as well, independent of frank neuroinflammation or functional impairment. Such variability suggests the existence of additional vulnerability factors that can impact neuronal-glial interactions and thus overall brain and cognitive health. The goal of this review is to elucidate our working hypothesis that an individual’s risk or resilience to neuroinflammatory disorders and poor cognitive aging may critically depend on their early life experience, which can change immune reactivity within the brain for the remainder of the lifespan. For instance, early-life infection in rats can profoundly disrupt memory function in young adulthood, as well as accelerate age-related cognitive decline, both of which are linked to enduring changes in glial function that occur in response to the initial infection. We discuss these findings within the context of the growing literature on the role of immune molecules and neuroimmune crosstalk in normal brain development. We highlight the intrinsic factors (e.g., chemokines, hormones) that regulate microglial development and their colonization of the embryonic and postnatal brain, and the capacity for disruption or “re-programming” of this crucial process by external events (e.g., stress, infection). An impact on glia, which in turn alters neural development, has the capacity to profoundly impact cognitive and mental health function at all stages of life.
Similar content being viewed by others
References
Abraham WC, Williams JM (2003) Properties and mechanisms of LTP maintenance. Neuroscientist 9:463–474
Adler MW, Geller EB, Chen X, Rogers TJ (2005) Viewing chemokines as a third major system of communication in the brain. AAPS J 7:E865–E870
Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511
Anderson KV, Jurgens G, Nusslein-Volhard C (1985) Establishment of dorsal-ventral polarity in the drosophila embryo: genetic studies on the role of the toll gene product. Cell 42:779–789
Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208–215
Aylward GP (2005) Neurodevelopmental outcomes of infants born prematurely. J Dev Behav Pediatr 26:427–440
Banerjee R, Mosley RL, Reynolds AD, Dhar A, Jackson-Lewis V, Gordon PH, Przedborski S, Gendelman HE (2008) Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS One 3:e2740
Barclay AN, Wright GJ, Brooke G, Brown MH (2002) CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol 23:285–290
Barrientos RM, Higgins EA, Sprunger DB, Watkins LR, Rudy JW, Maier SF (2002) Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus. Behav Brain Res 134:291–298
Barrientos RM, Sprunger DB, Campeau S, Watkins LR, Rudy JW, Maier SF (2004) BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration. J Neuroimmunol 155:119–126
Barrientos RM, Higgins EA, Biedenkapp JC, Sprunger DB, Wright-Hardesty KJ, Watkins LR, Rudy JW, Maier SF (2006) Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol Aging 27:723–732
Barrientos RM, Frank MG, Watkins LR, Maier SF (2011) Memory impairments in healthy aging: role of aging-induced microglial sensitization. Aging Dis 1:212–231
Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC (2002) Control of synaptic strength by glial TNFalpha. Science 295:2282–2285
Becher B, Bechmann I, Greter M (2006) Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain. J Mol Med 84:532–543
Bell MJ, Hallenbeck JM (2002) Effects of intrauterine inflammation on developing rat brain. J Neurosci Res 70:570–579
Ben Menachem-Zidon O, Avital A, Ben-Menahem Y, Goshen I, Kreisel T, Shmueli EM, Segal M, Ben Hur T, Yirmiya R (2011) Astrocytes support hippocampal-dependent memory and long-term potentiation via interleukin-1 signaling. Brain Behav Immun 25:1008–1016
Bennet L, Gunn A (2006) The fetal origins of adult mental illness. In: Wintour-Coghlan M, Owens J (eds) Early life origins of health and disease (advances in experimental medicine and biology). Springer, New York, pp 204–211
Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5
Bilbo SD (2010) Early-life infection is a vulnerability factor for aging-related glial alterations and cognitive decline. Neurobiol Learn Mem 94:57–64
Bilbo SD, Schwarz JM (2009) Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci 3:14
Bilbo SD, Tsang V (2010) Enduring consequences of maternal obesity for brain inflammation and behavior of offspring. FASEB J 24:2104–2115
Bilbo SD, Biedenkapp JC, Der-Avakian A, Watkins LR, Rudy JW, Maier SF (2005a) Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition. J Neurosci 25:8000–8009
Bilbo SD, Levkoff LH, Mahoney JH, Watkins LR, Rudy JW, Maier SF (2005b) Neonatal infection induces memory impairments following an immune challenge in adulthood. Behav Neurosci 119:293–301
Bilbo SD, Rudy JW, Watkins LR, Maier SF (2006) A behavioural characterization of neonatal infection-facilitated memory impairment in adult rats. Behav Brain Res 169:39–47
Bilbo SD, Newsum NJ, Sprunger DB, Watkins LR, Rudy JW, Maier SF (2007) Differential effects of neonatal handling on early life infection-induced alterations in cognition in adulthood. Brain Behav Immun 21:332–342
Bilbo SD, Barrientos RM, Eads AS, Northcutt A, Watkins LR, Rudy JW, Maier SF (2008) Early-life infection leads to altered BDNF and IL-1beta mRNA expression in rat hippocampus following learning in adulthood. Brain Behav Immun 22:451–455
Bland ST, Beckley JT, Young S, Tsang V, Watkins LR, Maier SF, Bilbo SD (2010) Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain. Brain Behav Immun 24:329–338
Buchanan JB, Sparkman NL, Chen J, Johnson RW (2008) Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology 33:755–765
Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M (2005) Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Neurosci 29:381–393
Cai Z, Pan ZL, Pang Y, Evans OB, Rhodes PG (2000) Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatr Res 47:64–72
Carpentier PA, Palmer TD (2009) Immune influence on adult neural stem cell regulation and function. Neuron 64:79–92
Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW (2008) Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 22:301–311
Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TK, Brown RH Jr, Carroll MC (2008) T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci U S A 105:17913–17918
Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–433
Colton CA, Wilcock DM (2009) assessing activation states in microglia. CNS Neurol Disord Drug Targets
Colton CA, Wilcock DM (2010) Assessing activation states in microglia. CNS Neurol Disord Drug Targets 9:174–191
Corriveau RA, Huh GS, Shatz CJ (1998) Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21:505–520
Costello DA, Watson MB, Cowley TR, Murphy N, Murphy Royal C, Garlanda C, Lynch MA (2011) Interleukin-1alpha and HMGB1 mediate hippocampal dysfunction in SIGIRR-deficient mice. J Neurosci 31:3871–3879
Cui K, Ashdown H, Luheshi GN, Boksa P (2009) Effects of prenatal immune activation on hippocampal neurogenesis in the rat. Schizophr Res 113:288–297
Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25:9275–9284.
Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21:153–160
Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207:1067–1080
Deverman BE, Patterson PH (2009) Cytokines and CNS development. Neuron 64:61–78
Dziegielewska KM, Moller JE, Potter AM, Ek J, Lane MA, Saunders NR (2000) Acute-phase cytokines IL-1beta and TNF-alpha in brain development. Cell Tissue Res 299:335–345
Eriksen W, Sundet JM, Tambs K (2009) Register data suggest lower intelligence in men born the year after flu pandemic. Ann Neurol 66:284–289
Eroglu C, Barres BA (2010) Regulation of synaptic connectivity by glia. Nature 468:223–231
Eroglu C, Allen NJ, Susman MW, O'Rourke NA, Park CY, Ozkan E, Chakraborty C, Mulinyawe SB, Annis DS, Huberman AD, Green EM, Lawler J, Dolmetsch R, Garcia KC, Smith SJ, Luo ZD, Rosenthal A, Mosher DF, Barres BA (2009) Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139:380–392
Fan LW, Tien LT, Mitchell HJ, Rhodes PG, Cai Z (2008) Alpha-phenyl-n-tert-butyl-nitrone ameliorates hippocampal injury and improves learning and memory in juvenile rats following neonatal exposure to lipopolysaccharide. Eur J Neurosci 27:1475–1484
Fan LW, Tien LT, Zheng B, Pang Y, Rhodes PG, Cai Z (2010) Interleukin-1beta-induced brain injury and neurobehavioral dysfunctions in juvenile rats can be attenuated by alpha-phenyl-n-tert-butyl-nitrone. Neuroscience 168:240–252
Fee D, Grzybicki D, Dobbs M, Ihyer S, Clotfelter J, Macvilay S, Hart MN, Sandor M, Fabry Z (2000) Interleukin 6 promotes vasculogenesis of murine brain microvessel endothelial cells. Cytokine 12:655–665
Fortier ME, Luheshi GN, Boksa P (2007) Effects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy. Behav Brain Res 181:270–277
Frank MG, Barrientos RM, Biedenkapp JC, Rudy JW, Watkins LR, Maier SF (2006) mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol Aging 27:717–722
Frank MG, Barrientos RM, Watkins LR, Maier SF (2011) Aging sensitizes rapidly isolated hippocampal microglia to LPS ex vivo. J Neuroimmunol 226:181–184
Gadient RA, Otten U (1994) Expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat brain during postnatal development. Brain Res 637:10–14
Gallo P, Frei K, Rordorf C, Lazdins J, Tavolato B, Fontana A (1989) Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system: an evaluation of cytokines in cerebrospinal fluid. J Neuroimmunol 23:109–116
Garay PA, McAllister AK (2010) Novel roles for immune molecules in neural development: implications for neurodevelopmental disorders. Front Synaptic Neurosci 2:136
Garcia O, Torres M, Helguera P, Coskun P, Busciglio J (2010) A role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in Down’s syndrome. PLoS One 5:e14200
Garden GA, Moller T (2006) Microglia biology in health and disease. J Neuroimmune Pharm 1:127–137
Gensel JC, Nakamura S, Guan Z, van Rooijen N, Ankeny DP, Popovich PG (2009) Macrophages promote axon regeneration with concurrent neurotoxicity. J Neurosci 29:3956–3968
Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845
Giulian D, Young DG, Woodward J, Brown DC, Lachman LB (1988) Interleukin-1 is an astroglial growth factor in the developing brain. J Neurosci 8:709–714
Godbout JP, Johnson RW (2009) Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Immunol Allergy Clin North Am 29:321–337
Godbout JP, Moreau M, Lestage J, Chen J, Sparkman NL, O' Connor J, Castanon N, Kelley KW, Dantzer R, Johnson RW (2008) Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology 33:2341–2351
Golan HM, Lev V, Hallak M, Sorokin Y, Huleihel M (2005) Specific neurodevelopmental damage in mice offspring following maternal inflammation during pregnancy. Neuropharmacology 48:903–917
Gomez-Gonzalez B, Escobar A (2010) Prenatal stress alters microglial development and distribution in postnatal rat brain. Acta Neuropathol 119:303–315
Goshen I, Kreisel T, Ounallah-Saad H, Renbaum P, Zalzstein Y, Ben-Hur T, Levy-Lahad E, Yirmiya R (2007) A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 32:1106–1115
Greene MF, Creasy RK, Resnik R, Iams JD, Lockwood CJ, Moore T (2008) Creasy and Resnik’s maternal-fetal medicine: principles and practice, 6th edn. Saunders, Philadelphia
Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL 3rd, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in down syndrome and alzheimer disease. Proc Natl Acad Sci U S A 86:7611–7615
Hao LY, Hao XQ, Li SH, Li XH (2010) Prenatal exposure to lipopolysaccharide results in cognitive deficits in age-increasing offspring rats. Neuroscience 166:763–770
Harre EM, Galic MA, Mouihate A, Noorbakhsh F, Pittman QJ (2008) Neonatal inflammation produces selective behavioural deficits and alters N-methyl-D-aspartate receptor subunit mRNA in the adult rat brain. Eur J Neurosci 27:644–653
Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P, Bacon KB, Feng L (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A 95:10896–10901
Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86:1009–1031
Henneberger C, Papouin T, Oliet SH, Rusakov DA (2010) Long-term potentiation depends on release of D-serine from astrocytes. Nature 463:232–236
Henry CJ, Huang Y, Wynne AM, Godbout JP (2009) Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav Immun 23:309–317
Hornig M, Lipkin WI (2001) Infectious and immune factors in the pathogenesis of neurodevelopmental disorders: epidemiology, hypotheses, and animal models. Ment Retard Dev Disabil Res Rev 7:200–210
Hornig M, Weissenbock H, Horscroft N, Lipkin WI (1999) An infection-based model of neurodevelopmental damage. Proc Natl Acad Sci U S A 96:12102–12107
Hornig M, Solbrig M, Horscroft N, Weissenbock H, Lipkin WI (2001) Borna disease virus infection of adult and neonatal rats: models for neuropsychiatric disease. Curr Top Microbiol Immunol 253:157–177
Hsiao EY, Patterson PH (2011) Activation of the maternal immune system induces endocrine changes in the placenta via IL-6. Brain Behav Immun 25:604–615
Husband AJ (1995) The immune system and integrated homeostasis. Immunol Cell Biol 73:377–382
Hutchinson MR et al (2010) Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun 24:83–95
Inoue K, Takano H, Yanagisawa R, Hirano S, Kobayashi T, Ichinose T, Yoshikawa T (2006a) Effects of organic chemicals derived from ambient particulate matter on lung inflammation related to lipopolysaccharide. Arch Toxicol 80:833–838
Inoue K, Takano H, Yanagisawa R, Hirano S, Ichinose T, Shimada A, Yoshikawa T (2006b) The role of toll-like receptor 4 in airway inflammation induced by diesel exhaust particles. Arch Toxicol 80:275–279
Isaacs EB, Lucas A, Chong WK, Wood SJ, Johnson CL, Marshall C, Vargha-Khadem F, Gadian DG (2000) Hippocampal volume and everyday memory in children of very low birth weight. Pediatr Res 47:713–720
Ito HT, Smith SE, Hsiao E, Patterson PH (2010) Maternal immune activation alters nonspatial information processing in the hippocampus of the adult offspring. Brain Behav Immun 24:930–941
Jakubs K, Bonde S, Iosif RE, Ekdahl CT, Kokaia Z, Kokaia M, Lindvall O (2008) Inflammation regulates functional integration of neurons born in adult brain. J Neurosci 28:12477–12488
Johnson WJ, Marino PA, Schreiber RD, Adams DO (1983) Sequential activation of murine mononuclear phagocytes for tumor cytolysis: differential expression of markers by macrophages in the several stages of development. J Immunol 131:1038–1043
Jurgens HA, Johnson RW (2010) Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation. Exp Neurol
Kohman RA, Tarr AJ, Sparkman NL, Bogale TM, Boehm GW (2008) Neonatal endotoxin exposure impairs avoidance learning and attenuates endotoxin-induced sickness behavior and central IL-1beta gene transcription in adulthood. Behav Brain Res 194:25–31
Lieberam I, Agalliu D, Nagasawa T, Ericson J, Jessell TM (2005) A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Neuron 47:667–679
Lowe GC, Luheshi GN, Williams S (2008) Maternal infection and fever during late gestation are associated with altered synaptic transmission in the hippocampus of juvenile offspring rats. Am J Physiol Regul Integr Comp Physiol 295:R1563–R1571
Lu M, Grove EA, Miller RJ (2002) Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc Natl Acad Sci U S A 99:7090–7095
Lue LF, Kuo YM, Beach T, Walker DG (2010) Microglia activation and anti-inflammatory regulation in Alzheimer’s disease. Mol Neurobiol 41:115–128
Lynch MA (2010) Age-related neuroinflammatory changes negatively impact on neuronal function. Front Aging Neurosci in press
Maier SF, Watkins LR (1998) Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 105:83–107
Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461
Matzinger P (2002) The danger model: a renewed sense of self. Science 296:301–305
McAfoose J, Baune BT (2009) Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev 33:355–366
Merrill JE (1992) Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathological. Dev Neurosci 14:1–10
Meyer U, Feldon J, Schedlowski M, Yee BK (2006) Immunological stress at the maternal-foetal interface: a link between neurodevelopment and adult psychopathology. Brain Behav Immun 20:378–388
Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J (2008) Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun 22:469–486
Meyers CA (2000) Neurocognitive dysfunction in cancer patients. Oncology (Huntingt) 14:75–79, discussion 79, 81–72, 85
Mignini F, Streccioni V, Amenta F (2003) Autonomic innervation of immune organs and neuroimmune modulation. Auton Autacoid Pharmacol 23:1–25
Miller LC, Isa S, LoPreste G, Schaller JG, Dinarello CA (1990) Neonatal interleukin-1 beta, interleukin-6, and tumor necrosis factor: cord blood levels and cellular production. J Pediatr 117:961–965
Miller RJ, Rostene W, Apartis E, Banisadr G, Biber K, Milligan ED, White FA, Zhang J (2008) Chemokine action in the nervous system. J Neurosci 28:11792–11795
Msall ME (2004) Developmental vulnerability and resilience in extremely preterm infants. JAMA 292:2399–2401
Muller CM, Best J (1989) Ocular dominance plasticity in adult cat visual cortex after transplantation of cultured astrocytes. Nature 342:427–430
Murphy K, Travers P, Walport M (2008) Janeway’s immunobiology, 7th edn. Garland Science, New York
Murphy AC, Lalor SJ, Lynch MA, Mills KH (2010) Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun 24:641–651
Nelson KB, Willoughby RE (2000) Infection, inflammation and the risk of cerebral palsy. Curr Opin Neurol 13:133–139
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318
Osrin D, Vergnano S, Costello A (2004) Serious bacterial infections in newborn infants in developing countries. Curr Opin Infect Dis 17:217–224
Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M (2006) Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatr 59:546–554
Pace JL, Russell SW, Torres BA, Johnson HM, Gray PW (1983) Recombinant mouse gamma interferon induces the priming step in macrophage activation for tumor cell killing. J Immunol 130:2011–2013
Pang Y, Cai Z, Rhodes PG (2003) Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide. Brain Res Dev Brain Res 140:205–214
Perry VH, Newman TA, Cunningham C (2003) The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci 4:103–112
Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161–167
Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201
Pocock JM, Kettenmann H (2007) Neurotransmitter receptors on microglia. Trends Neurosci 30:527–535
Pugh CR, Nguyen KT, Gonyea JL, Fleshner M, Wakins LR, Maier SF, Rudy JW (1999) Role of interleukin-1 beta in impairment of contextual fear conditioning caused by social isolation. Behav Brain Res 106:109–118
Pugh P, Adlaf E, Zhao CS, Markwardt S, Gavin C, Wadiche J, Overstreet-Wadiche L (2011) Enhanced integration of newborn neurons after neonatal insults. Front Neurosci 5:45
Rakic S, Zecevic N (2000) Programmed cell death in the developing human telencephalon. Eur J Neurosci 12:2721–2734
Rantakallio P, Jones P, Moring J, Von Wendt L (1997) Association between central nervous system infections during childhood and adult onset schizophrenia and other psychoses: a 28-year follow-up. Int J Epidemiol 26:837–843
Rezaie P, Male D (1999) Colonisation of the developing human brain and spinal cord by microglia: a review. Microsc Res Tech 45:359–382
Rezaie P, Male D (2002) Mesoglia & microglia—a historical review of the concept of mononuclear phagocytes within the central nervous system. J Hist Neurosci 11:325–374
Rice D, Barone S Jr (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108(Suppl 3):511–533
Richardson-Burns SM, Tyler KL (2004) Regional differences in viral growth and central nervous system injury correlate with apoptosis. J Virol 78:5466–5475
Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, Schwartz M (2007) Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 9:1081–1088
Rosczyk HA, Sparkman NL, Johnson RW (2008) Neuroinflammation and cognitive function in aged mice following minor surgery. Exp Gerontol 43:840–846
Rose SA, Feldman JF, Jankowski JJ (2005a) Recall memory in the first 3 years of life: a longitudinal study of preterm and term children. Dev Med Child Neurol 47:653–659
Rose SA, Feldman JF, Jankowski JJ, Van Rossem R (2005b) Pathways from prematurity and infant abilities to later cognition. Child Dev 76:1172–1184
Ross FM, Allan SM, Rothwell NJ, Verkhratsky A (2003) A dual role for interleukin-1 in LTP in mouse hippocampal slices. J Neuroimmunol 144:61–67
Santello M, Bezzi P, Volterra A (2011) TNFalpha controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69:988–1001
Sauce D, Larsen M, Fastenackels S, Duperrier A, Keller M, Grubeck-Loebenstein B, Ferrand C, Debre P, Sidi D, Appay V (2009) Evidence of premature immune aging in patients thymectomized during early childhood. J Clin Invest 119:3070–3078
Schaeffler A, Gross P, Buettner R, Bollheimer C, Buechler C, Neumeier M, Kopp A, Schoelmerich J, Falk W (2009) Fatty acid-induced induction of toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology 126:233–245
Schmitz T, Chew LJ (2008) Cytokines and myelination in the central nervous system. Sci World J 8:1119–1147
Schwartz M, Kipnis J (2010) A conceptual revolution in the relationships between the brain and immunity. Brain Behav Immun
Schwartz M, Butovsky O, Bruck W, Hanisch UK (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29:68–74
Schwarz JM, Bilbo SD (2011) LPS elicits a much larger and broader inflammatory response than Escherichia coli infection within the hippocampus of neonatal rats. Neurosci Lett
Shi L, Fatemi SH, Sidwell RW, Patterson PH (2003) Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci 23:297–302
Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:483–495
Skogstrand K, Hougaard DM, Schendel DE, Bent NP, Svaerke C, Thorsen P (2008) Association of preterm birth with sustained postnatal inflammatory response. Obstet Gynecol 111:1118–1128
Smith SE, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27:10695–10702
Soumiya H, Fukumitsu H, Furukawa S (2011) Prenatal immune challenge compromises development of upper-layer but not deeper-layer neurons of the mouse cerebral cortex. J Neurosci Res
Spencer SJ, Heida JG, Pittman QJ (2005) Early life immune challenge—effects on behavioural indices of adult rat fear and anxiety. Behav Brain Res 164:231–238
Spulber S, Mateos L, Oprica M, Cedazo-Minguez A, Bartfai T, Winblad B, Schultzberg M (2009) Impaired long term memory consolidation in transgenic mice overexpressing the human soluble form of IL-1ra in the brain. J Neuroimmunol
Stanley LC, Mrak RE, Woody RC, Perrot LJ, Zhang S, Marshak DR, Nelson SJ, Griffin WS (1994) Glial cytokines as neuropathogenic factors in HIV infection: pathogenic similarities to Alzheimer’s disease. J Neuropathol Exp Neurol 53:231–238
Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440:1054–1059
Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178
Streit WJ (2001) Microglia and macrophages in the developing CNS. Neurotoxicology 22:619–624
Streit WJ (2010) Microglial activation and neuroinflammation in Alzheimer’s disease: a critical examination of recent history. Front Aging Neurosci 2:22
Streit WJ, Xue QS (2009) Life and death of microglia. J Neuroimmune Pharm 4:371–379
Streit WJ, Mrak RE, Griffin WS (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 1:14
Streit WJ, Conde JR, Fendrick SE, Flanary BE, Mariani CL (2005) Role of microglia in the central nervous system’s immune response. Neurol Res 27:685–691
Streit WJ, Braak H, Xue QS, Bechmann I (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 118:475–485
Taylor E, Rutter M (1985) Sex differences in neurodevelopmental and psychiatric disorders: One explanation or many? Behav Brain Sci 8:460
Tran PB, Miller RJ (2003) Chemokine receptors: signposts to brain development and disease. Nat Rev Neurosci 4:444–455
Tremblay ME, Majewska AK (2011) A role for microglia in synaptic plasticity? Commun Integr Biol 4:220–222
Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:e1000527
Ullian EM, Sapperstein SK, Christopherson KS, Barres BA (2001) Control of synapse number by glia. Science 291:657–661
Urakubo A, Jarskog LF, Lieberman JA, Gilmore JH (2001) Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain. Schizophr Res 47:27–36
Vereker E, Campbell V, Roche E, McEntee E, Lynch MA (2000) Lipopolysaccharide inhibits long term potentiation in the rat dentate gyrus by activating caspase-1. J Biol Chem 275:26252–26258
Vitkovic L, Bockaert J, Jacque C (2000) “Inflammatory” cytokines: neuromodulators in normal brain? J Neurochem 74:457–471
Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980
Wang H, Li W, Goldstein R, Tracey KJ, Sama AE (2007) HMGB1 as a potential therapeutic target. Novartis Found Symp 280:73–85, discussion 85–91, 160–164
Whitney NP, Eidem TM, Peng H, Huang Y, Zheng JC (2009) Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J Neurochem
Widera D, Holtkamp W, Entschladen F, Niggemann B, Zanker K, Kaltschmidt B, Kaltschmidt C (2004) MCP-1 induces migration of adult neural stem cells. Eur J Cell Biol 83:381–387
Wolff AR, Bilkey DK (2008) Immune activation during mid-gestation disrupts sensorimotor gating in rat offspring. Behav Brain Res 190:156–159
Wrona D (2006) Neural-immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems. J Neuroimmunol 172:38–58
Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, Poo M, Duan S (2003) Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc Natl Acad Sci U S A 100:15194–15199
Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25:181–213
Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi JH, Syn HC (1995) Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 172:960–970
Yu HM, Yuan TM, Gu WZ, Li JP (2004) Expression of glial fibrillary acidic protein in developing rat brain after intrauterine infection. Neuropathology 24:136–143
Zhao C, Teng EM, Summers RG Jr, Ming GL, Gage FH (2006) Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 26:3–11
Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9:268–275
Zuckerman L, Weiner I (2003) Post-pubertal emergence of disrupted latent inhibition following prenatal immune activation. Psychopharmacology (Berl) 169:308–313
Zuckerman L, Weiner I (2005) Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring. J Psychiatr Res 39:311–323
Zuckerman L, Rehavi M, Nachman R, Weiner I (2003) Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology 28:1778–1789
Author information
Authors and Affiliations
Corresponding author
Additional information
Guarantors of the work: Staci D. Bilbo, Susan H. Smith, and Jaclyn M. Schwarz
No disclaimers or disclosures
Supported by NIH R01 MH083698 and R01 DA025978 to S.D.B.
Rights and permissions
About this article
Cite this article
Bilbo, S.D., Smith, S.H. & Schwarz, J.M. A Lifespan Approach to Neuroinflammatory and Cognitive Disorders: A Critical Role for Glia. J Neuroimmune Pharmacol 7, 24–41 (2012). https://doi.org/10.1007/s11481-011-9299-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-011-9299-y