Several neurological disorders have been linked to inflammatory insults suffered during development. We investigated the effects of neonatal systemic inflammation, induced by LPS injections, on blood-brain barrier permeability, endothelial tight junctions and behaviour of juvenile (P20) and adult rats. LPS-treatment resulted in altered cellular localisation of claudin-5 and changes in ultrastructural morphology of a few cerebral blood vessels. Barrier permeability to sucrose was significantly increased in LPS treated animals when adult but not at P20 or earlier. Behavioural tests showed that LPS treated animals at P20 exhibited altered behaviour using prepulse inhibition (PPI) analysis, whereas adults demonstrated altered behaviour in the dark/light test. These data indicate that an inflammatory insult during brain development can change blood-brain barrier permeability and behaviour in later life. It also suggests that the impact of inflammation can occur in several phases (short- and long-term) and that each phase might lead to different behavioural modifications. 1. Introduction Human data related to disorders such as autism, schizophrenia, and cerebral palsy indicate that a period of infection/inflammation during specific stages of brain development may act as a triggering insult [1–4]. In animal experimental studies, inflammation induced during the early postnatal period in rodents has been associated with increased blood-brain barrier permeability [5], white matter damage [6–13], ventricular enlargement [9, 14], and reduced neuron numbers in regions of the hippocampus and cerebellum [15, 16]. In addition, in animals exposed to inflammation in utero or during early postnatal life, long-term behavioural alterations such as deficits in prepulse inhibition test [17, 18], motor behaviour [19], and learning and memory [19, 20] have also been reported. However, the biological mechanisms involved in these pathologies are still not understood. To date there are no studies that directly investigated possible links between changes in blood-brain barrier permeability and behavioural alterations in animals exposed to an inflammatory mediator during early stages of brain development. In this study, we have investigated possible correlations between some behavioural tests and blood-brain barrier morphology and permeability in adolescent and adult rats that were exposed to a prolonged inflammatory stimulus (LPS-injections) as neonates. To examine possible cellular mechanisms behind the alteration in blood-brain barrier permeability, the distribution of claudin-5,
References
[1]
A. S. Brown, “Prenatal infection as a risk factor for schizophrenia,” Schizophrenia Bulletin, vol. 32, no. 2, pp. 200–202, 2006.
[2]
K. B. Nelson and R. E. Willoughby, “Infection, inflammation and the risk of cerebral palsy,” Current Opinion in Neurology, vol. 13, no. 2, pp. 133–139, 2000.
[3]
C. A. Pardo and C. G. Eberhart, “The neurobiology of autism,” Brain Pathology, vol. 17, no. 4, pp. 434–447, 2007.
[4]
H. B. Stolp and K. M. Dziegielewska, “Review: role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases,” Neuropathology and Applied Neurobiology, vol. 35, no. 2, pp. 132–146, 2009.
[5]
H. B. Stolp, K. M. Dziegielewska, C. J. Ek et al., “Breakdown of the blood-brain barrier to proteins in white matter of the developing brain following systemic inflammation,” Cell and Tissue Research, vol. 320, no. 3, pp. 369–378, 2005.
[6]
T. Debillon, C. Gras-Leguen, S. Leroy, J. Caillon, J. C. Rozé, and P. Gressens, “Patterns of cerebral inflammatory response in a rabbit model of intrauterine infection-mediated brain lesion,” Developmental Brain Research, vol. 145, no. 1, pp. 39–48, 2003.
[7]
F. H. Gilles, D. R. Averill, and C. S. Kerr, “Neonatal endotoxin encephalopathy,” Annals of Neurology, vol. 2, no. 1, pp. 49–56, 1977.
[8]
C. Mallard, A. K. Welin, D. Peebles, H. Hagberg, and I. Kjellmer, “White matter injury following systemic endotoxemia or asphyxia in the fetal sheep,” Neurochemical Research, vol. 28, no. 2, pp. 215–223, 2003.
[9]
Y. Pang, Z. Cai, and P. G. Rhodes, “Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide,” Developmental Brain Research, vol. 140, no. 2, pp. 205–214, 2003.
[10]
C. I. Rousset, S. Chalon, S. Cantagrel et al., “Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats,” Pediatric Research, vol. 59, no. 3, pp. 428–433, 2006.
[11]
H. B. Stolp, K. M. Dziegielewska, C. J. Ek, A. M. Potter, and N. R. Saunders, “Long-term changes in blood-brain barrier permeability and white matter following prolonged systemic inflammation in early development in the rat,” European Journal of Neuroscience, vol. 22, no. 11, pp. 2805–2816, 2005.
[12]
X. Wang, G. Hellgren, C. L？fqvist et al., “White matter damage after chronic subclinical inflammation in newborn mice,” Journal of Child Neurology, vol. 24, no. 9, pp. 1171–1178, 2009.
[13]
G. Loron, P. Olivier, H. See, et al., “Ciprofloxacin prevents myelination delay in neonatal rats subjected to E. coli sepsis,” Annals of Neurology. In press.
[14]
L. W. Fan, Y. Pang, S. Lin, P. G. Rhodes, and Z. Cai, “Minocycline attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain,” Neuroscience, vol. 133, no. 1, pp. 159–168, 2005.
[15]
U. Meyer, M. Nyffeler, A. Engler et al., “The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology,” Journal of Neuroscience, vol. 26, no. 18, pp. 4752–4762, 2006.
[16]
L. Shi, S. E. P. Smith, N. Malkova, D. Tse, Y. Su, and P. H. Patterson, “Activation of the maternal immune system alters cerebellar development in the offspring,” Brain, Behavior, and Immunity, vol. 23, no. 1, pp. 116–123, 2009.
[17]
M. E. Fortier, G. N. Luheshi, and P. Boksa, “Effects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy,” Behavioural Brain Research, vol. 181, no. 2, pp. 270–277, 2007.
[18]
L. Shi, S. H. Fatemi, R. W. Sidwell, and P. H. Patterson, “Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring,” Journal of Neuroscience, vol. 23, no. 1, pp. 297–302, 2003.
[19]
Y. Pang, L. W. Fan, B. Zheng, Z. Cai, and P. G. Rhodes, “Role of interleukin-6 in lipopolysaccharide-induced brain injury and behavioral dysfunction in neonatal rats,” Neuroscience, vol. 141, no. 2, pp. 745–755, 2006.
[20]
S. D. Bilbo, J. C. Biedenkapp, A. Der-Avakian, L. R. Watkins, J. W. Rudy, and S. F. Maier, “Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition,” Journal of Neuroscience, vol. 25, no. 35, pp. 8000–8009, 2005.
[21]
K. Morita, H. Sasaki, M. Furuse, and S. Tsukita, “Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells,” Journal of Cell Biology, vol. 147, no. 1, pp. 185–194, 1999.
[22]
T. Nitta, M. Hata, S. Gotoh et al., “Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice,” Journal of Cell Biology, vol. 161, no. 3, pp. 653–660, 2003.
[23]
C. J. Ek, M. D. Habgood, K. M. Dziegielewska, A. Potter, and N. R. Saunders, “Permeability and route of entry for lipid-insoluble molecules across brain barriers in developing Monodelphis domestica,” Journal of Physiology, vol. 536, no. 3, pp. 841–853, 2001.
[24]
A. R. Wolff and D. K. Bilkey, “Immune activation during mid-gestation disrupts sensorimotor gating in rat offspring,” Behavioural Brain Research, vol. 190, no. 1, pp. 156–159, 2008.
[25]
R. E. Fisher, N. A. Karrow, M. Quinton et al., “Endotoxin exposure during late pregnancy alters ovine offspring febrile and hypothalamic-pituitary-adrenal axis responsiveness later in life,” Stress, vol. 13, no. 4, pp. 334–342, 2010.
[26]
S. L. Kj？r, G. Wegener, R. Rosenberg, S. P. Lund, and K. S. Hougaard, “Prenatal and adult stress interplay—behavioral implications,” Brain Research, vol. 1320, pp. 106–113, 2010.
[27]
D. Ibi, T. Nagai, Y. Kitahara et al., “Neonatal polyI:C treatment in mice results in schizophrenia-like behavioral and neurochemical abnormalities in adulthood,” Neuroscience Research, vol. 64, no. 3, pp. 297–305, 2009.
[28]
N. Davies, A. Russell, P. Jones, and R. M. Murray, “Which characteristics of schizophrenia predate psychosis?” Journal of Psychiatric Research, vol. 32, no. 3-4, pp. 121–131, 1998.
[29]
M. Weinstock, “Alterations induced by gestational stress in brain morphology and behaviour of the offspring,” Progress in Neurobiology, vol. 65, no. 5, pp. 427–451, 2001.
[30]
G. Hava, L. Vered, M. Yael, H. Mordechai, and H. Mahoud, “Alterations in behavior in adult offspring mice following maternal inflammation during pregnancy,” Developmental Psychobiology, vol. 48, no. 2, pp. 162–168, 2006.
[31]
S. J. Spencer, J. G. Heida, and Q. J. Pittman, “Early life immune challenge—effects on behavioural indices of adult rat fear and anxiety,” Behavioural Brain Research, vol. 164, no. 2, pp. 231–238, 2005.
[32]
S. J. Spencer, S. Martin, A. Mouihate, and Q. J. Pittman, “Early-life immune challenge: defining a critical window for effects on adult responses to immune challenge,” Neuropsychopharmacology, vol. 31, no. 9, pp. 1910–1918, 2006.
[33]
T. S. Reese and M. J. Karnovsky, “Fine structural localization of a blood-brain barrier to exogenous peroxidase,” Journal of Cell Biology, vol. 34, no. 1, pp. 207–217, 1967.
[34]
P. Lindahl, B. R. Johansson, P. Levéen, and C. Betsholtz, “Pericyte loss and microaneurysm formation in PDGF-B-deficient mice,” Science, vol. 277, no. 5323, pp. 242–245, 1997.
[35]
C. J. Ek, K. M. Dziegielewska, H. Stolp, and N. R. Saunders, “Functional effectiveness of the blood-brain barrier to small water-soluble molecules in developing and adult opossum (Monodelphis domestica),” Journal of Comparative Neurology, vol. 496, no. 1, pp. 13–26, 2006.
[36]
N. S. Harhaj and D. A. Antonetti, “Regulation of tight junctions and loss of barrier function in pathophysiology,” International Journal of Biochemistry and Cell Biology, vol. 36, no. 7, pp. 1206–1237, 2004.
[37]
M. A. Petty and E. H. Lo, “Junctional complexes of the blood-brain barrier: permeability changes in neuroinflammation,” Progress in Neurobiology, vol. 68, no. 5, pp. 311–323, 2002.
[38]
B. Engelhardt and L. Sorokin, “The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction,” Seminars in Immunopathology, vol. 31, no. 4, pp. 497–511, 2009.
[39]
Y. Sonobe, H. Takeuchi, K. Kataoka et al., “Interleukin-25 expressed by brain capillary endothelial cells maintains blood-brain barrier function in a protein kinase Cε-dependent manner,” Journal of Biological Chemistry, vol. 284, no. 46, pp. 31834–31842, 2009.
