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Changes in Behavior and the Expression of Ionotropic Glutamate Receptor Genes in the Brains of Adult Rats after Neonatal Administration of Bacterial Lipopolysaccharide

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Many studies have shown that early experience, particularly of neonatal infections, has a role in forming high anxiety levels in later life. One of the mechanisms of these changes may consist of impairments to the functional activity of ionotropic glutamate receptors associated with rearrangements in their subunit composition. The aim of the present work was to study measures of anxiety and levels of expression of genes for NMDA receptor (Grin1, Grin2a, Grin2b) and AMPA receptor (Gria1, Gria2) subunits in the medial prefrontal cortex, ventral and dorsal parts of the hippocampus in adult rats which at an early age had received bacterial lipopolysaccharide (LPS) at doses inducing the development of neuroinflammatory processes. Gene expression was studied by real-time reverse transcription PCR (qRT-PCR). Administration of LPS at doses of 25 and 50 μg/kg to male Wistar rats on days 15, 18, and 21 of life induced increases in the expression of genes for proinflammatory cytokines IL-1β and tumor necrosis factor in parts of the hippocampus. Increases in the expression of the Grin2b, Gria1, and Gria2 genes in the ventral parts of the hippocampus were seen three months after LPS administration (after injection of 50 μg/kg LPS), as were increases in expression of the Gria2 gene in the dorsal part of the hippocampus (after injection of 25 μg/kg LPS). These changes were accompanied by impairment to exploratory behavior in the open field test and decreased anxiety levels in the elevated plus maze. These studies showed that administration of bacterial LPS in early postnatal ontogeny leads to time-delayed changes in the expression of genes for NMDA and AMPA receptor subunits in the hippocampus and the associated forms of behavior.

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References

  1. B. Bandelow and S. Michaelis, “Epidemiology of anxiety disorders in the 21st century,” Dialog. Clin. Neurosci., 17, No. 3, 327–335 (2015).

    Google Scholar 

  2. O. Remes, C. Brayne, R. van der Linde, and L. Lafortune, “A systematic review of reviews on the prevalence of anxiety disorders in adult populations,” Brain Behav., 6, No. 7, e00497 (2016).

    PubMed  PubMed Central  Google Scholar 

  3. S. Maccari, H. J. Krugers, S. Morley-Fletcher, et al., “The consequences of early-life adversity: neurobiological, behavioural and epigenetic adaptations,” J. Neuroendocrinol., 26, No. 10, 707–723 (2014).

    CAS  PubMed  Google Scholar 

  4. R. D. Goodwin, “Association between infection early in life and mental disorders among youth in the community: a cross-sectional study,” BMC Public Health, 11, 878 (2011).

    PubMed  PubMed Central  Google Scholar 

  5. M. M. Buchanan, M. Hutchinson, L. R. Watkins, and H. Yin, “Toll-like receptor 4 in CNS pathologies,” J. Neurochem., 114, No. 1, 13–27 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. R. Dantzer, “Cytokine, sickness behavior, and depression,” Immunol. Allergy Clin. North Am., 29, No. 2, 247–264 (2009).

    PubMed  PubMed Central  Google Scholar 

  7. Z. Ling, Y. Zhu, C. W. Tong, et al., “Prenatal lipopolysaccharide does not accelerate progressive dopamine neuron loss in the rat as a result of normal aging,” Exp. Neurol., 216, No. 2, 312–320 (2009).

    CAS  PubMed  Google Scholar 

  8. J. Majidi, M. Kosari-Nasab, and A.-A. Salari, “Developmental minocycline treatment reverses the effects of neonatal immune activation on anxiety- and depression-like behaviors, hippocampal inflammation, and HPA axis activity in adult mice,” Brain Res. Bull., 120, 1–13 (2016).

    CAS  PubMed  Google Scholar 

  9. J. Majidi-Zolbanin, M. Azarfarin, H. Samadi, et al., “Adolescent fluoxetine treatment decreases the effects of neonatal immune activation on anxiety-like behavior in mice,” Behav. Brain Res., 250, 123–132 (2013).

    CAS  PubMed  Google Scholar 

  10. A.-L. Dinel, C. Joffre, P. Trifi lieff, et al., “Inflammation early in life is a vulnerability factor for emotional behavior at adolescence and for lipopolysaccharide-induced spatial memory and neurogenesis alteration at adulthood,” J. Neuroinflammation, 11, 155 (2014).

    PubMed  PubMed Central  Google Scholar 

  11. M.-H. Doosti, A. Bakhtiari, P. Zare, et al., “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 (2013).

    CAS  PubMed  Google Scholar 

  12. A. Tishkina, M. Stepanichev, I. Kudryashova, et al., “Neonatal proinflammatory challenge in male Wistar rats: Effects on behavior, synaptic plasticity, and adrenocortical stress response,” Behav. Brain Res., 304, 1–10 (2016).

    PubMed  Google Scholar 

  13. H. Sun, N. Jia, L. Guan, et al., “Involvement of NR1, NR2A different expression in brain regions in anxiety-like behavior of prenatally stressed offspring,” Behav. Brain Res., 257, 1–7 (2013).

    CAS  PubMed  Google Scholar 

  14. J. D. Sweatt, “Neural plasticity and behavior – sixty years of conceptual advances,” J. Neurochem., 139, Supplement, 179–199 (2016).

  15. G. H. Diering and R. L. Huganir, “The AMPA Receptor code of synaptic plasticity,” Neuron, 100, No. 2, 314–329 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. J. Lisman, “Glutamatergic synapses are structurally and biochemically complex because of multiple plasticity processes: long-term potentiation, long-term depression, short-term potentiation and scaling,” Philos. Trans. R. Soc. Lond. B Biol. Sci., 372, No. 1715) (2017).

  17. K. Sarantis, K. Antoniou, N. Matsokis, and F. Angelatou, “Exposure to novel environment is characterized by an interaction of D1/NMDA receptors underlined by phosphorylation of the NMDA and AMPA receptor subunits and activation of ERK1/2 signaling, leading to epigenetic changes and gene expression in rat hippocampus,” Neurochem. Int., 60, No. 1, 55–67 (2012).

    CAS  PubMed  Google Scholar 

  18. J. Du, J. Quiroz, P. Yuan, C. Zarate, and H. K. Manji, “Bipolar disorder: involvement of signaling cascades and AMPA receptor trafficking at synapses,” Neuron Glia Biol., 1, No. 3, 231–243 (2004).

    PubMed  PubMed Central  Google Scholar 

  19. J. Du, T. K. Creson, L.-J. Wu, et al., “The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior,” J. Neurosci., 28, No. 1, 68–79 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. R. Machado-Vieira, I. D. Henter, and C. A. Zarate, “New targets for rapid antidepressant action,” Prog. Neurobiol., 152, 21–37 (2017).

    CAS  PubMed  Google Scholar 

  21. C. Barkus, S. B. McHugh, R. Sprengel, et al., “Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion,” Eur. J. Pharmacol., 626, No. 1, 49–56 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. J. Solati, “Dorsal hippocampal N-methyl-D-aspartate glutamatergic and δ-opioidergic systems modulate anxiety behaviors in rats in a noninteractive manner,” Kaohsiung J. Med. Sci., 27, No. 11, 485–493 (2011).

    CAS  PubMed  Google Scholar 

  23. M. Gielen, B. Siegler Retchless, L. Mony, et al., “Mechanism of differential control of NMDA receptor activity by NR2 subunits,” Nature, 459, No. 7247, 703–707 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. K. B. Hansen, F. Yi, R. E. Perszyk, H. Furukawa, et al., “Structure, function, and allosteric modulation of NMDA receptors,” J. Gen. Physiol., 150, No. 8, 1081–1105 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. J. M. Henley and K. A. Wilkinson, “Synaptic AMPA receptor composition in development, plasticity and disease,” Nat. Rev. Neurosci., 17, No. 6, 337–350 (2016).

    CAS  PubMed  Google Scholar 

  26. I. H. Greger and J. A. Esteban, “AMPA receptor biogenesis and trafficking,” Curr. Opin. Neurobiol., 17, No. 3, 289–297 (2007).

    CAS  PubMed  Google Scholar 

  27. S. Liu, L. Lau, J. Wei, et al., “Expression of Ca(2+)-permeable AMPA receptor channels primes cell death in transient forebrain ischemia,” Neuron, 43, No. 1, 43–55 (2004).

    PubMed  Google Scholar 

  28. A. Wenzel, J. M. Fritschy, H. Mohler, and D. Benke, “NMDA receptor heterogeneity during postnatal development of the rat brain: differential expression of the NR2A, NR2B, and NR2C subunit proteins,” J. Neurochem., 68, No. 2, 469–478 (1997).

    CAS  PubMed  Google Scholar 

  29. T. L. Babb, N. Mikuni, I. Najm, et al., “Pre- and postnatal expressions of NMDA receptors 1 and 2B subunit proteins in the normal rat cortex,” Epilepsy Res., 64, No. 1–2, 23–30 (2005).

    CAS  PubMed  Google Scholar 

  30. T. M. du Bois and X.-F. Huang, “Early brain development disruption from NMDA receptor hypofunction: relevance to schizophrenia,” Brain Res. Rev., 53, No. 2, 260–270 (2007).

    PubMed  Google Scholar 

  31. J. J. Lippman-Bell, C. Zhou, H. Sun, et al., “Early-life seizures alter synaptic calcium-permeable AMPA receptor function and plasticity,” Mol. Cell. Neurosci., 76, 11–20 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. T. Yuan and C. Bellone, “Glutamatergic receptors at developing synapses: the role of GluN3A-containing NMDA receptors and GluA2-lacking AMPA receptors,” Eur. J. Pharmacol., 719, No. 1–3, 107–111 (2013).

    CAS  PubMed  Google Scholar 

  33. E. Szczurowska and P. Mareš, “NMDA and AMPA receptors: development and status epilepticus,” Physiol. Res., 62, Suppl. 1, S21–S38 (2013).

    CAS  PubMed  Google Scholar 

  34. H. Monyer, N. Burnashev, D. J. Laurie, et al., “Developmental and regional expression in the rat brain and functional properties of four NMDA receptors,” Neuron, 12, No. 3, 529–540 (1994).

    CAS  PubMed  Google Scholar 

  35. T. R. Guilarte and J. L. McGlothan, “Hippocampal NMDA receptor mRNA undergoes subunit specific changes during developmental lead exposure,” Brain Res., 790, No. 1–2, 98–107 (1998).

    CAS  PubMed  Google Scholar 

  36. I. Farhy-Tselnicker and N. J. Allen, “Astrocytes, neurons, synapses: a tripartite view on cortical circuit development,” Neural Dev., 13, No. 1, 7 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. S. S. Kumar, A. Bacci, V. Kharazia, and J. R. Huguenard, “A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons,” J. Neurosci., 22, No. 8, 3005–3015 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. E. Blanco-Suarez, T.-F. Liu, A. Kopelevich, and N. J. Allen, “Astrocyte-secreted chordin-like 1 drives synapse maturation and limits plasticity by increasing synaptic GluA2 AMPA receptors,” Neuron, 100, No. 5, 1116–1132, e13 (2018).

  39. G. Paxinos and C. Watson, The Rat Brain in Stereotaxic Coordinates, Academic Press (2007), 6th ed.

  40. W. Lin, C. A. Burks, D. R. Hansen, et al., “Taste receptor cells express pH-sensitive leak K+ channels,” J. Neurophysiol, 92, No. 5, 2909–2919 (2004).

    CAS  PubMed  Google Scholar 

  41. I. Rioja, K. A. Bush, J. B. Buckton, et al., “Joint cytokine quantification in two rodent arthritis models: kinetics of expression, correlation of mRNA and protein levels and response to prednisolone treatment,” Clin. Exp. Immunol., 137, No. 1, 65–73 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. C. C. Giza, N. S. S. Maria, and D. A. Hovda, “N-methyl-D-aspartate receptor subunit changes after traumatic injury to the developing brain,” J. Neurotrauma, 23, No. 6, 950–961 (2006).

    PubMed  PubMed Central  Google Scholar 

  43. D. W. Floyd, K.-Y. Jung, and B. A. McCool, “Chronic ethanol ingestion facilitates N-methyl-D-aspartate receptor function and expression in rat lateral/basolateral amygdala neurons,” J. Pharmacol. Exp. Ther., 307, No. 3, 1020–1029 (2003).

    CAS  PubMed  Google Scholar 

  44. S. L. Malkin, D. V. Amakhin, E. A. Veniaminova, et al., “Changes of AMPA receptor properties in the neocortex and hippocampus following pilocarpine-induced status epilepticus in rats,” Neuroscience, 327, 146–155 (2016).

    CAS  PubMed  Google Scholar 

  45. K. J. Livak and T. D. Schmittgen, “Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta C(T)) Method,” Methods, 25, No. 4, 402–408 (2001).

    CAS  Google Scholar 

  46. E.-M. Harré, M. A. Galic, A. Mouihate, et al., “Neonatal inflammation produces selective behavioural defi cits and alters N-methyl-Daspartate receptor subunit mRNA in the adult rat brain,” Eur. J. Neurosci., 27, No. 3, 644–653 (2008).

    PubMed  PubMed Central  Google Scholar 

  47. N. V. Gulyaeva, “Functional neurochemistry of the ventral and dorsal hippocampus: stress, depression, dementia and remote hippocampal damage,” Neurochem. Res., 44, No. 6, 1306–1322 (2019).

    CAS  PubMed  Google Scholar 

  48. M. S. Fanselow and H.-W. Dong, “Are the dorsal and ventral hippocampus functionally distinct structures?” Neuron, 65, No. 1, 7–19 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. A. Floriou-Servou, L. von Ziegler, L. Stalder, et al., “Distinct proteomic, transcriptomic, and epigenetic stress responses in dorsal and ventral hippocampus,” Biol. Psychiatry, 84, No. 7, 531–541 (2018).

    CAS  PubMed  Google Scholar 

  50. M. A. Galic, K. Riazi, A. K. Henderson, et al., “Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats,” Neurobiol. Dis., 36, No. 2, 343–351 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. O. Mamad, M. N. Islam, C. Cunningham, and M. Tsanov, “Differential response of hippocampal and prefrontal oscillations to systemic LPS application,” Brain Res., 1681, 64–74 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. W. L. Farrar, P. L. Kilian, M. R. Ruff, et al., “Visualization and characterization of interleukin 1 receptors in brain,” J. Immunol., 139, No. 2, 459–463 (1987).

    CAS  PubMed  Google Scholar 

  53. C. S. Custódio, B. S. F. Mello, A. J. M. C. Filho, et al., “Neonatal immune challenge with lipopolysaccharide triggers long-lasting sex- and age-related behavioral and immune/neurotrophic alterations in mice: Relevance to autism spectrum disorders,” Mol. Neurobiol., 55, No. 5, 3775–3788 (2018).

    PubMed  Google Scholar 

  54. H. Benmhammed, S. El Hayek, A. Nassiri, et al., “Effects of lipopolysaccharide administration and maternal deprivation on anxiety and depressive symptoms in male and female Wistar rats: Neurobehavioral and biochemical assessments,” Behav. Brain Res., 362, 46–55 (2019).

    CAS  PubMed  Google Scholar 

  55. L. Sominsky, E. A. Fuller, E. Bondarenko, et al., “Functional programming of the autonomic nervous system by early life immune exposure: implications for anxiety,” PLoS One, 8, No. 3, e57700 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. J. L. R. Rico, D. B. Ferraz, F. J. Ramalho-Pinto, and S. Morato, “Neonatal exposure to LPS leads to heightened exploratory activity in adolescent rats,” Behav. Brain Res., 215, No. 1, 102–109 (2010).

    PubMed  Google Scholar 

  57. L. D. Claypoole, B. Zimmerberg, and L. L. Williamson, “Neonatal lipopolysaccharide treatment alters hippocampal neuroinflammation, microglia morphology and anxiety-like behavior in rats selectively bred for an infantile trait,” Brain Behav. Immun., 59, 135–146 (2017).

    CAS  PubMed  Google Scholar 

  58. V. M. Doenni, C. M. Song, M. N. Hill, and Q. J. Pittman, “Early-life inflammation with LPS delays fear extinction in adult rodents,” Brain Behav. Immun., 63, 176–185 (2017).

    CAS  PubMed  Google Scholar 

  59. S. J. Spencer, J. G. Heida, and Q. J. Pittman, “Early life immune challenge-effects on behavioural indices of adult rat fear and anxiety,” Behav. Brain Res., 164, No. 2, 231–238 (2005).

    PubMed  Google Scholar 

  60. P. Bina, M. Rezvanfard, S. Ahmadi, and M. R. Zarrindast, “Anxiolytic-Like effects and increase in locomotor activity induced by infusions of NMDA into the ventral hippocampus in rat: Interaction with GABAergic system,” Basic Clin. Neurosci., 5, No. 4, 267–276 (2014).

    PubMed  PubMed Central  Google Scholar 

  61. T. Motevasseli, A. Rezayof, M.-R. Zarrindast, and T. Nayer-Nouri, “Role of ventral hippocampal NMDA receptors in anxiolytic-like effect of morphine,” Physiol. Behav., 101, No. 5, 608–613 (2010).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Experimental Medicine, St. Petersburg, Russia

    A. N. Trofimov, A. Yu. Rotov, E. A. Veniaminova, K. Fomalont, A. P. Schwarz & O. E. Zubareva

  2. Sechenov Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia

    A. Yu. Rotov, A. P. Schwarz & O. E. Zubareva

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  1. A. N. Trofimov
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  2. A. Yu. Rotov
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  3. E. A. Veniaminova
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  4. K. Fomalont
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Correspondence to A. N. Trofimov.

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Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 106, No. 3, pp. 356–372, March, 2020.

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Trofimov, A.N., Rotov, A.Y., Veniaminova, E.A. et al. Changes in Behavior and the Expression of Ionotropic Glutamate Receptor Genes in the Brains of Adult Rats after Neonatal Administration of Bacterial Lipopolysaccharide. Neurosci Behav Physi 50, 1239–1248 (2020). https://doi.org/10.1007/s11055-020-01025-7

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