Perinatal immune challenge leads to neurodevelopmental dysfunction, permanent immune dysregulation and abnormal behaviour, which have been shown to have translational validity to findings in human neuropsychiatric disorders (e.g. schizophrenia, mood and anxiety disorders, autism, Parkinson's disease and Alzheimer's disease). The aim of this animal study was to elucidate the influence of early immune stimulation triggered by systemic postnatal lipopolysaccharide administration on biochemical, histopathological and morphological measures, which may be relevant to the neurobiology of human psychopathology. In the present study of adult male Wistar rats we examined the brain and plasma levels of monoamines (dopamine, serotonin), their metabolites, the levels of the main excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid and the levels of tryptophan and its metabolites from the kynurenine catabolic pathway. Further, we focused on histopathological and morphological markers related to pathogenesis of brain diseases--glial cell activation, neurodegeneration, hippocampal volume reduction and dopaminergic synthesis in the substantia nigra. Our results show that early immune stimulation in adult animals alters the levels of neurotransmitters and their metabolites, activates the kynurenine pathway of tryptophan metabolism and leads to astrogliosis, hippocampal volume reduction and a decrease of tyrosine hydroxylase immunoreactivity in the substantia nigra. These findings support the crucial pathophysiological role of early immune stimulation in the above mentioned neuropsychiatric disorders.

Institute of Chemical Technology Prague Czech Republic

Prague Psychiatric Center Prague Czech Republic; National Institute of Mental Health Klecany Czech Republic

Prague Psychiatric Center Prague Czech Republic; National Institute of Mental Health Klecany Czech Republic; 3rd Faculty of Medicine Charles University Prague Czech Republic

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Schmitt A, Malchow B, Hasan A, Falkai P (2014) The impact of environmental factors in severe psychiatric disorders. Front Neurosci 8: 19 10.3389/fnins.2014.00019 PubMed DOI PMC

Wang X, Rousset CI, Hagberg H, Mallard C (2006) Lipopolysaccharide-induced inflammation and perinatal brain injury. Semin Fetal Neonatal Med 11: 343–353. 10.1016/j.siny.2006.04.002 PubMed DOI

Spencer SJ, Galic MA, Pittman QJ (2011) Neonatal programming of innate immune function. Am J Physiol Endocrinol Metab 300: E11–E18. 10.1152/ajpendo.00516.2010 PubMed DOI PMC

Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, et al. (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175: 4320–4330. 10.4049/jimmunol.175.7.4320 PubMed DOI

Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, et al. (2002) The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 22: 2478–2486. PubMed PMC

Rolls A, Shechter R, London A, Ziv Y, Ronen A, et al. (2007) Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 9: 1081–1088. 10.1038/ncb1629 PubMed DOI

Shanks N, Larocque S, Meaney MJ (1995) Neonatal endotoxin exposure alters the development of the hypothalamic-pituitary-adrenal axis: early illness and later responsivity to stress. J Neurosci 15: 376–384. PubMed PMC

Shanks N, Windle RJ, Perks PA, Harbuz MS, Jessop DS, et al. (2000) Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation. Proc Natl Acad Sci U S A 97: 5645–5650. 10.1073/pnas.090571897 PubMed DOI PMC

Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, et al. (2008) Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 63: 801–808. 10.1016/j.biopsych.2007.09.024 PubMed DOI

Tejkalová H, Jelínek F, Klaschka J, Šťastný F (2007) Vliv perinatální zánětlivé reakce na rozvoj psychóze podobného chování: experimentální studie (Effect of perinatal inflammatory reaction on the induction of psychotic-like behaviour: experimental study). Psychiatrie 11: 12–15.

Tejkalová H, Jelínek F, Klaschka J, Šťastný F (2008) Vliv chronického podávání klozapinu na chování potkanů v neuroinfekčním modelu schizofrenie (Effect of chronic clozapine administration on the behavioural pattern of rats in the neuroinfectional model of schizophrenia). Psychiatrie 12: 68–72.

Tejkalová H, Růžičková Š, Klaschka J (2010) Vliv chronického podávání antipsychotik na expresi cytokinů v neuroinfekčním modelu schizofrenie (Effect of antipsychotic chronic administration on cytokine expression in neuroinfectious model of schizophrenia). Psychiatrie 14: 19–21.

Doosti MH, Bakhtiari A, Zare P, Amani M, Majidi-Zolbanin N, et al. (2013) Impacts of early intervention with fluoxetine following early neonatal immune activation on depression-like behaviors and body weight in mice. Prog Neuropsychopharmacol Biol Psychiatry 43: 55–65. 10.1016/j.pnpbp.2012.12.003 PubMed DOI

Kirsten TB, Chaves-Kirsten GP, Chaible LM, Silva AC, Martins DO, et al. (2012) Hypoactivity of the central dopaminergic system and autistic-like behavior induced by a single early prenatal exposure to lipopolysaccharide. J Neurosci Res 90: 1903–1912. 10.1002/jnr.23089 PubMed DOI

Sominsky L, Walker AK, Ong LK, Tynan RJ, Walker FR, et al. (2012) Increased microglial activation in the rat brain following neonatal exposure to a bacterial mimetic. Behav Brain Res 226: 351–356. 10.1016/j.bbr.2011.08.038 PubMed DOI

Sominsky L, Fuller EA, Bondarenko E, Ong LK, Averell L, et al. (2013) Functional programming of the autonomic nervous system by early life immune exposure: implications for anxiety. PLoS One 8: e57700 10.1371/journal.pone.0057700 PubMed DOI PMC

Zhu F, Zhang L, Ding YQ, Zhao J, Zheng Y (2014) Neonatal intrahippocampal injection of lipopolysaccharide induces deficits in social behavior and prepulse inhibition and microglial activation in rats: Implication for a new schizophrenia animal model. Brain Behav Immun 38: 166–174. 10.1016/j.bbi.2014.01.017 PubMed DOI

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 10.3389/neuro.08.014.2009 PubMed DOI PMC

Cai Z, Fan LW, Kaizaki A, Tien LT, Ma T, et al. (2013) Neonatal systemic exposure to lipopolysaccharide enhances susceptibility of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Dev Neurosci 35: 155–171. 10.1159/000346156 PubMed DOI PMC

Fan LW, Tien LT, Zheng B, Pang Y, Lin RC, et al. (2011) Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity. Brain Behav Immun 25: 286–297. 10.1016/j.bbi.2010.09.020 PubMed DOI PMC

Smith PL, Hagberg H, Naylor AS, Mallard C (2014) Neonatal Peripheral Immune Challenge Activates Microglia and Inhibits Neurogenesis in the Developing Murine Hippocampus. Dev Neurosci. 10.1159/000359950 PubMed DOI

Campbell BM, Charych E, Lee AW, Moller T (2014) Kynurenines in CNS disease: regulation by inflammatory cytokines. Front Neurosci 8: 12 10.3389/fnins.2014.00012 PubMed DOI PMC

Brambilla P, Hatch JP, Soares JC (2008) Limbic changes identified by imaging in bipolar patients. Curr Psychiatry Rep 10: 505–509. 10.1007/s11920-008-0080-8 PubMed DOI

Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, et al. (2000) Hippocampal volume reduction in major depression. Am J Psychiatry 157: 115–118. PubMed

Haukvik UK, Hartberg CB, Agartz I (2013) Schizophrenia—what does structural MRI show? Tidsskr Nor Laegeforen 133: 850–853. 10.4045/tidsskr.12.1084 PubMed DOI

Laakso MP, Partanen K, Riekkinen P, Lehtovirta M, Helkala EL, et al. (1996) Hippocampal volumes in Alzheimer’s disease, Parkinson’s disease with and without dementia, and in vascular dementia: An MRI study. Neurology 46: 678–681. 10.1212/WNL.46.3.678 PubMed DOI

Woon FL, Sood S, Hedges DW (2010) Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 34: 1181–1188. 10.1016/j.pnpbp.2010.06.016 PubMed DOI

Najmanova V, Rambousek L, Syslova K, Bubenikova V, Slamberova R, et al. (2011) LC-ESI-MS-MS Method for Monitoring Dopamine, Serotonin and Their Metabolites in Brain Tissue. Chromatographia 73: 143–149. 10.1007/s10337-011-1959-9 DOI

Paxinos G. and Watson C. (1-January-2007) The Rat Brain In Strereotactic Coordinates. Elsevier Inc.

Wang KC, Fan LW, Kaizaki A, Pang Y, Cai Z, et al. (2013) Neonatal lipopolysaccharide exposure induces long-lasting learning impairment, less anxiety-like response and hippocampal injury in adult rats. Neuroscience 234: 146–157. 10.1016/j.neuroscience.2012.12.049 PubMed DOI PMC

Craig A, Ling LN, Beardsley DJ, Wingate-Pearse N, Walker DW, et al. (2003) Quantitative analysis of perinatal rodent oligodendrocyte lineage progression and its correlation with human. Exp Neurol 181: 231–240. 10.1016/S0014-4886(03)00032-3 PubMed DOI

Feleder C, Tseng KY, Calhoon GG, O’Donnell P (2010) Neonatal intrahippocampal immune challenge alters dopamine modulation of prefrontal cortical interneurons in adult rats. Biol Psychiatry 67: 386–392. 10.1016/j.biopsych.2009.09.028 PubMed DOI PMC

Ratnayake U, Quinn T, Walker DW, Dickinson H (2013) Cytokines and the neurodevelopmental basis of mental illness. Front Neurosci 7: 180 10.3389/fnins.2013.00180 PubMed DOI PMC

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. 10.1016/S0165-3806(02)00606-5 PubMed DOI

Guillemin GJ (2012) Quinolinic acid, the inescapable neurotoxin. FEBS J 279: 1356–1365. 10.1111/j.1742-4658.2012.08493.x PubMed DOI

St’astny F, Skultetyova I, Pliss L, Jezova D (2000) Quinolinic acid enhances permeability of rat brain microvessels to plasma albumin. Brain Res Bull 53: 415–420. 10.1016/S0361-9230(00)00368-3 PubMed DOI

Chung DW, Yoo KY, Hwang IK, Kim DW, Chung JY, et al. (2010) Systemic administration of lipopolysaccharide induces cyclooxygenase-2 immunoreactivity in endothelium and increases microglia in the mouse hippocampus. Cell Mol Neurobiol 30: 531–541. 10.1007/s10571-009-9477-0 PubMed DOI

Terrazzino S, Bauleo A, Baldan A, Leon A (2002) Peripheral LPS administrations up-regulate Fas and FasL on brain microglial cells: a brain protective or pathogenic event? J Neuroimmunol 124: 45–53. 10.1016/S0165-5728(02)00013-9 PubMed DOI

Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, et al. (2001) Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 50: 521–530. 10.1016/S0006-3223(01)01078-2 PubMed DOI

Linderholm KR, Skogh E, Olsson SK, Dahl ML, Holtze M, et al. (2012) Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull 38: 426–432. 10.1093/schbul/sbq086 PubMed DOI PMC

Almeida-Montes LG, Valles-Sanchez V, Moreno-Aguilar J, Chavez-Balderas RA, Garcia-Marin JA, et al. (2000) Relation of serum cholesterol, lipid, serotonin and tryptophan levels to severity of depression and to suicide attempts. J Psychiatry Neurosci 25: 371–377. PubMed PMC

Lee M, Jayathilake K, Dai J, Meltzer HY (2011) Decreased plasma tryptophan and tryptophan/large neutral amino acid ratio in patients with neuroleptic-resistant schizophrenia: relationship to plasma cortisol concentration. Psychiatry Res 185: 328–333. 10.1016/j.psychres.2010.07.013 PubMed DOI

Gauthier C, Hassler C, Mattar L, Launay JM, Callebert J, et al. (2014) Symptoms of depression and anxiety in anorexia nervosa: links with plasma tryptophan and serotonin metabolism. Psychoneuroendocrinology 39: 170–178. 10.1016/j.psyneuen.2013.09.009 PubMed DOI

Bell C, Abrams J, Nutt D (2001) Tryptophan depletion and its implications for psychiatry. Br J Psychiatry 178: 399–405. 10.1192/bjp.178.5.399 PubMed DOI

Miller CL, Llenos IC, Cwik M, Walkup J, Weis S (2008) Alterations in kynurenine precursor and product levels in schizophrenia and bipolar disorder. Neurochem Int 52: 1297–1303. 10.1016/j.neuint.2008.01.013 PubMed DOI

Issa F, Gerhardt GA, Bartko JJ, Suddath RL, Lynch M, et al. (1994) A multidimensional approach to analysis of cerebrospinal fluid biogenic amines in schizophrenia: I. Comparisons with healthy control subjects and neuroleptic-treated/unmedicated pairs analyses. Psychiatry Res 52: 237–249. PubMed

Ravikumar A, Deepadevi KV, Arun P, Manojkumar V, Kurup PA (2000) Tryptophan and tyrosine catabolic pattern in neuropsychiatric disorders. Neurol India 48: 231–238. PubMed

Bohmer C, Broer A, Munzinger M, Kowalczuk S, Rasko JE, et al. (2005) Characterization of mouse amino acid transporter B0AT1 (slc6a19). Biochem J 389: 745–751. 10.1042/BJ20050083 PubMed DOI PMC

Pratt OE (1979) Kinetics of tryptophan transport across the blood-brain barrier. J Neural Transm Suppl 29–42. PubMed

Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R (2011) The new ‘5-HT’ hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry 35: 702–721. PubMed

Stone TW, Darlington LG (2002) Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1: 609–620. 10.1038/nrd870 PubMed DOI

Stone TW, Forrest CM, Darlington LG (2012) Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection. FEBS J 279: 1386–1397. 10.1111/j.1742-4658.2012.08487.x PubMed DOI

Huang F, Li J, Shi HL, Wang TT, Muhtar W, et al. (2014) Simultaneous quantification of seven hippocampal neurotransmitters in depression mice by LC-MS/MS. J Neurosci Methods 229: 8–14. 10.1016/j.jneumeth.2014.04.004 PubMed DOI

Fan LW, Tien LT, Lin RC, Simpson KL, Rhodes PG, et al. (2011) Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Neurobiol Dis 44: 304–316. 10.1016/j.nbd.2011.07.011 PubMed DOI PMC

Ong LK, Sominsky L, Dickson PW, Hodgson DM, Dunkley PR (2012) The sustained phase of tyrosine hydroxylase activation in vivo. Neurochem Res 37: 1938–1943. 10.1007/s11064-012-0812-3 PubMed DOI

Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein HG, et al. (2014) The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front Psychiatry 5: 47 10.3389/fpsyt.2014.00047 PubMed DOI PMC

Gulyas B, Pavlova E, Kasa P, Gulya K, Bakota L, et al. (2011) Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-L-deprenyl using whole hemisphere autoradiography. Neurochem Int 58: 60–68. 10.1016/j.neuint.2010.10.013 PubMed DOI

Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91: 461–553. 10.1152/physrev.00011.2010 PubMed DOI

Patro N, Singh K, Patro I (2013) Differential microglial and astrocytic response to bacterial and viral infection in the developing hippocampus of neonatal rats. Indian J Exp Biol 51: 606–614. PubMed

Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36: 180–190. 10.1002/glia.1107 PubMed DOI

Meyer-Franke A, Shen S, Barres BA (1999) Astrocytes induce oligodendrocyte processes to align with and adhere to axons. Mol Cell Neurosci 14: 385–397. 10.1006/mcne.1999.0788 PubMed DOI

Molofsky AV, Krencik R, Ullian EM, Tsai HH, Deneen B, et al. (2012) Astrocytes and disease: a neurodevelopmental perspective. Genes Dev 26: 891–907. 10.1101/gad.188326.112 PubMed DOI PMC

Carson MJ, Thrash JC, Walter B (2006) The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res 6: 237–245. 10.1016/j.cnr.2006.09.004 PubMed DOI PMC

Bsibsi M, Persoon-Deen C, Verwer RW, Meeuwsen S, Ravid R, et al. (2006) Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 53: 688–695. 10.1002/glia.20328 PubMed DOI

Okada K, Yamashita U, Tsuji S (2005) Modulation of Na(+)-dependent glutamate transporter of murine astrocytes by inflammatory mediators. J UOEH 27: 161–170. PubMed

Catts VS, Wong J, Fillman SG, Fung SJ, Weickert CS (2014) Increased expression of astrocyte markers in schizophrenia: Association with neuroinflammation. Aust N Z J Psychiatry. 10.1177/0004867414531078 PubMed DOI

Forno LS, DeLanney LE, Irwin I, Di MD, Langston JW (1992) Astrocytes and Parkinson’s disease. Prog Brain Res 94: 429–436. 10.1016/S0079-6123(08)61770-7 PubMed DOI

Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57: 67–81. 10.1002/ana.20315 PubMed DOI

Wisniewski HM, Wegiel J (1991) Spatial relationships between astrocytes and classical plaque components. Neurobiol Aging 12: 593–600. 10.1016/0197-4580(91)90091-W PubMed DOI

Rajkowska G, Stockmeier CA (2013) Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets 14: 1225–1236. 10.2174/13894501113149990156 PubMed DOI PMC

Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, et al. (2010) Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci 13: 584–591. 10.1038/nn.2535 PubMed DOI PMC

van Bemmelen FJ, Schouten MJ, Fekkes D, Bruinvels J (1985) Succinic semialdehyde as a substrate for the formation of gamma-aminobutyric acid. J Neurochem 45: 1471–1474. 10.1111/j.1471-4159.1985.tb07214.x PubMed DOI

White HL (1981) Glutamate as a precursor of GABA in rat brain and peripheral tissues. Mol Cell Biochem 39: 253–259. 10.1007/BF00232578 PubMed DOI

Krystal JH, Sanacora G, Blumberg H, Anand A, Charney DS, et al. (2002) Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry 7 Suppl 1: S71–S80. 10.1038/sj.mp.4001021 PubMed DOI

Meyerhoff DJ, Mon A, Metzler T, Neylan TC (2014) Cortical gamma-aminobutyric Acid and glutamate in posttraumatic stress disorder and their relationships to self-reported sleep quality. Sleep 37: 893–900. 10.5665/sleep.3654 PubMed DOI PMC

Pollack MH, Jensen JE, Simon NM, Kaufman RE, Renshaw PF (2008) High-field MRS study of GABA, glutamate and glutamine in social anxiety disorder: response to treatment with levetiracetam. Prog Neuropsychopharmacol Biol Psychiatry 32: 739–743. 10.1016/j.pnpbp.2007.11.023 PubMed DOI

Quaak I, Brouns MR, Van de BM (2013) The dynamics of autism spectrum disorders: how neurotoxic compounds and neurotransmitters interact. Int J Environ Res Public Health 10: 3384–3408. 10.3390/ijerph10083384 PubMed DOI PMC

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