IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344 × BN F1 rats

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Abstract

In normal aging, a peripheral immune challenge induces a sensitized and protracted neuroinflammatory response in parallel with long-term memory (LTM) impairments. Pro-inflammatory mediators of neuroinflammation impair LTM, synaptic plasticity and LTP. The immediate early gene Arc is considered a critical protein regulating LTM and synaptic plasticity. The present investigation examined whether (1) a peripheral Escherichia coli infection suppresses hippocampal Arc expression, and (2) central pro-inflammatory cytokines (IL-1β and IL-6) mediate the effects of peripheral E. coli infection on Arc and LTM. In 24 months F344 × BN F1 rats, E. coli infection suppressed basal Arc gene expression as well as contextual fear conditioning-induced Arc expression. E. coli treatment failed to alter either basal or conditioning-induced c-Fos expression. At 24 h post-infection, intra-cisterna magna (ICM) treatment with the anti-inflammatory cytokine IL-1RA blocked the E. coli-induced suppression of hippocampal Arc and increases in IL-6 protein. At 4-day post-infection, IL-1RA blocked the E. coli-induced LTM impairments and increases in IL-6 protein. The present results suggest that central pro-inflammatory cytokines play a salient role in the suppression of Arc and impairments of LTM by a peripheral immune challenge in older animals.

Introduction

In older animals, the CNS exhibits a sensitized neuroinflammatory response to peripheral as well as central administration of pro-inflammatory agents (Abraham et al., 2008, Barrientos et al., 2009, Barrientos et al., 2006, Chen et al., 2008, Godbout et al., 2005). Induction of neuroinflammatory processes or treatment with neuroinflammatory mediators/products has profound effects on learning and memory, in particular hippocampus-dependent memory processes (Barrientos et al., 2009, Barrientos et al., 2006, Barrientos et al., 2002, Barrientos et al., 2003, Barrientos et al., 2004, Gibertini et al., 1995, Hauss-Wegrzyniak et al., 1998, Hein et al., 2007, Oitzl et al., 1993, Pugh et al., 2000, Pugh et al., 1998, Shaw et al., 2001, Tanaka et al., 2006, Thomson and Sutherland, 2005). The time course of hippocampal-dependent memory deficits occurs in parallel with a protracted neuroinflammatory response to peripheral infection in aged animals (Barrientos et al., 2009, Barrientos et al., 2006). It is important to note that peripheral infection in young animals (3 months) does not induce a protracted neuroinflammatory response as well as a deficit in hippocampal-dependent memory (Barrientos et al., 2009). However, how the neuroinflammatory response to peripheral infection may compromise memory processes in older animals is unknown and is the focus of the present investigation.

Mediators of neuroinflammation, including pro-inflammatory cytokines (IL-1β, IL-6, TNFα, and IL-18), are known to modulate the putative neurobiological substrates (LTP) of memory formation (Cumiskey et al., 2007, Curran and O’Connor, 2003, Tancredi et al., 2000, Vereker et al., 2000). Aged animals show deficits in LTP, which are accompanied by increases in pro-inflammatory cytokines (Lynch, 1998). However, the molecular mechanism(s) mediating pro-inflammatory cytokine suppression of LTP has yet to be fully characterized.

Investigations into the molecular basis of LTP have yielded several genetic targets (Tzingounis and Nicoll, 2006). Of these targets, the effector immediate early gene (IEG) Arc (activity-dependent cytoskeletal-associated protein) exhibits several unique features, which underscore its importance in memory consolidation (Bramham et al., 2008). Arc mRNA is rapidly and specifically distributed throughout the dendritic arbor post-induction (Link et al., 1995, Lyford et al., 1995) and localized to regions receiving direct synaptic activation (Steward et al., 1998). Suppression of Arc impairs long-term memory (LTM) consolidation, whereas acquisition and short-term memory (STM) are unaffected (Guzowski et al., 2000). This is noted because we have previously found that a peripheral immune challenge in older animals impairs LTM, but not STM (Barrientos et al., 2006).

To understand how the neuroinflammatory sequelae of peripheral infection may impair LTM in older animals, we examined whether (1) a peripheral Escherichia coli infection suppresses hippocampal Arc expression, and (2) central pro-inflammatory cytokines (IL-1β and IL-6) mediate the effects of peripheral E. coli infection on Arc as well as LTM.

Section snippets

Subjects

As in our prior investigations (Barrientos et al., 2009, Barrientos et al., 2006, Frank et al., 2006), the present set of experiments compared 3 and 24 months old male F344 × BN F1 rats. Twenty-four months was selected as the older age because at this age animals do not show major age-related pathologies and in the absence of a peripheral immune challenge, STM and LTM processes do not differ between 24 and 3 months old animals in this hybrid strain. Therefore, differences in basal and contextual

Experiment 1: Peripheral E. coli reduced basal hippocampal Arc gene expression in 24 months animals (Fig. 1)

As an initial experiment to assess whether a peripheral immune challenge differentially alters Arc expression in 3 and 24 months animals, E. coli was administered to animals at a dose that induces increased hippocampal IL-1β along with memory impairments in older animals 4-day post-infection (Barrientos et al., 2006). Here, the effects of E. coli on Arc expression were measured 2, 4, 24, and 96 h post-infection. In the absence of E. coli, basal Arc expression was similar in 3 and 24 months animals

Discussion

Prior work has shown that aging renders hippocampal-based LTM formation vulnerable to disruption by peripheral immune challenge (Barrientos et al., 2009, Barrientos et al., 2006). At 24 months of age, male F344 × BN F1 rats show normal memory formation in both contextual fear conditioning and spatial water maze tasks. However, for a number of days after infection with E. coli these subjects are impaired in forming LTM for both contextual fear and spatial water maze escape (hippocampal). However,

Acknowledgments

The present work was supported by an NIH Grant (AG028271) to M.G.F., R.M.B, and S.F.M.

References (54)

  • P. Chomczynski et al.

    Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction

    Anal. Biochem.

    (1987)
  • D. Cumiskey et al.

    A role for inflammatory mediators in the IL-18 mediated attenuation of LTP in the rat dentate gyrus

    Neuropharmacology

    (2007)
  • B.P. Curran et al.

    The inhibition of long-term potentiation in the rat dentate gyrus by pro-inflammatory cytokines is attenuated in the presence of nicotine

    Neurosci. Lett.

    (2003)
  • S. Davis et al.

    How necessary is the activation of the immediate early gene zif268 in synaptic plasticity and learning?

    Behav. Brain Res.

    (2003)
  • C.A. Dinarello

    Interleukin-1

    Cytokine Growth Factor Rev.

    (1997)
  • M.G. Frank et al.

    MRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging

    Neurobiol. Aging

    (2006)
  • M. Gibertini et al.

    Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-beta

    Brain Behav. Immun.

    (1995)
  • E.V. Granowitz et al.

    Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans

    Blood

    (1993)
  • B. Hauss-Wegrzyniak et al.

    Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease

    Brain Res.

    (1998)
  • A.M. Hein et al.

    Prostaglandins are necessary and sufficient to induce contextual fear learning impairments after interleukin-1 beta injections into the dorsal hippocampus

    Neuroscience

    (2007)
  • Y. Huang et al.

    Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide

    Neurobiol. Aging

    (2008)
  • J.D. Johnson et al.

    The role of IL-1beta in stress-induced sensitization of proinflammatory cytokine and corticosterone responses

    Neuroscience

    (2004)
  • K.J. Livak et al.

    Analysis of relative gene expression data using real-time quantitative PCR and the 2(ΔΔCT) method

    Methods

    (2001)
  • G.L. Lyford et al.

    Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites

    Neuron

    (1995)
  • M.A. Lynch

    Age-related impairment in long-term potentiation in hippocampus: a role for the cytokine, interleukin-1 beta?

    Prog. Neurobiol.

    (1998)
  • M.S. Oitzl et al.

    Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning

    Brain Res.

    (1993)
  • N. Plath et al.

    Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories

    Neuron

    (2006)
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