Sustained hippocampal IL-1β overexpression impairs contextual and spatial memory in transgenic mice

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Abstract

Neuroinflammatory conditions such as traumatic brain injury, aging, Alzheimer’s disease, and Down syndrome are often associated with cognitive dysfunction. Much research has targeted inflammation as a causative mediator of these deficits, although the diverse cellular and molecular changes that accompany these disorders obscure the link between inflammation and impaired memory. Therefore, we used a transgenic mouse model with a dormant human IL-1β excisional activation transgene to direct overexpression of IL-1β with temporal and regional control. Two weeks of hippocampal IL-1β overexpression impaired long-term contextual and spatial memory in both male and female mice, while hippocampal-independent and short-term memory remained intact. Human IL-1β overexpression activated glia, elevated murine IL-1β protein and PGE2 levels, and increased pro-inflammatory cytokine and chemokine mRNAs specifically within the hippocampus, while having no detectable effect on inflammatory mRNAs in the liver. Sustained neuroinflammation also reduced basal and conditioning-induced levels of the plasticity-related gene Arc.

Introduction

Neuroinflammatory conditions such as traumatic brain injury, aging, Alzheimer’s disease, and Down syndrome are often associated with cognitive dysfunction, including memory deficits (Casadesus et al., 2007, Griffin et al., 1989, Montine et al., 1999). Much research has focused on anti-inflammatory treatments to try and prevent these memory deficits with mixed results (ADAPT Research Group et al., 2007, Hurley et al., 2002, Rogers et al., 1993). It is clear that acute inflammation, caused by injection of lipopolysaccharide or interleukin-1β (IL-1β) itself, impairs memory (Gibertini et al., 1995, Hein et al., 2007, Oitzl et al., 1993, Pugh et al., 1998, Pugh et al., 2001, Thomson and Sutherland, 2005). However, a lack of experimental models has made the study of the effects of chronic neuroinflammation on memory difficult, especially when trying to parse the potential influences of resulting sickness or neurodegeneration on memory. Therefore, we utilized a recently developed mouse model, which can maintain sustained IL-1β overexpression with temporal and regional control, to study the effects of prolonged IL-1β overexpression and ensuing neuroinflammation on learning and memory processes.

This mouse model retains a dormant human IL-1β excisional activation transgene (IL-1βXAT). When activated by microinjection of a virus expressing Cre, astrocytes local to the injection site express human IL-1β (Shaftel et al., 2007b). Human IL-1β binds to the murine IL-1 receptor and signals downstream pathways to induce inflammation. Research in this model has shown that a single microinjection of virus expressing Cre into the hippocampus causes sustained IL-1β overexpression for up to nearly a year after injection (Shaftel et al., 2007b). Within 2 weeks of transgene activation, IL-1β overexpression within the hippocampus leads to glial activation, elevated cytokines, elevated chemokines, leukocyte infiltration, and increased vascular permeability (Moore et al., 2009, Shaftel et al., 2007a, Shaftel et al., 2007b). However, after 2 weeks or 2 months of IL-1β overexpression, no overt loss of neurons or neuronal integrity is apparent within the hippocampus as measured by apoptotic stains and neuronal, synaptophysin, and acetylcholinesterase labeling (Moore et al., 2009, Shaftel et al., 2007a). Therefore, this model allows us to study the role of chronic IL-1β driven neuroinflammation on learning and memory processes.

Initial behavioral studies in this mouse model revealed spatial learning deficits in the Morris water maze 2 weeks following transgene activation (Moore et al., 2009). Here we further characterize these deficits by testing hippocampal-dependent and -independent, as well as short- and long-term, fear memory and potential gender differences in fear conditioning and the Morris water maze. We also further characterize the central and peripheral inflammatory responses to sustained hippocampal IL-1β overexpression and find changes in one plasticity-related gene, activity-regulated cytoskeleton-associated protein (Arc; also Arg 3.1).

Section snippets

hIL-1βXAT construct

Creation and genotyping of IL-1βXAT mice on a C57BL/6 background has been described previously (Shaftel et al., 2007b). Briefly, a construct with a murine GFAP promoter, loxP flanked transcriptional stop, and downstream signal sequence for the human IL-1RA was fused to the cDNA of human mature IL-1β to allow extracellular release of IL-1β.

Feline immunodeficiency virus (FIV)

The construction and packaging of FIV-Cre has been described previously (Lai et al., 2006). Briefly, the FIV-Cre virus encodes a modified Cre recombinase

Experiment 1: Sustained and localized hippocampal IL-1β expression leads to neuroinflammation and memory impairments

In the first experiment, WT-Cre (n = 10) and IL-1βXAT-GFP injected mice (n = 9) served as controls for the IL-1βXAT-Cre injected experimental mice (n = 13). These three groups of mice underwent contextual and auditory fear conditioning 2 weeks after viral microinjection (Fig. 1A). No significant differences in freezing behavior between groups were found during the 3 min acclimation period prior to shock presentation (Fig. 1B). Freezing during the intervals following shock presentation increased across

Discussion

The present experiments extend and confirm previous work in our lab by showing that sustained hippocampal IL-1β overexpression in a transgenic mouse model impairs contextual and spatial long-term memory, but not hippocampal-independent and short-term memory (Moore et al., 2009). We also found increases in inflammation specifically within the hippocampus, but no measurable changes in inflammatory mRNAs in the liver. Interestingly, the observed behavioral and molecular effects of sustained

Acknowledgments

We thank S. Kyrkanides and J. Miller for FIV packaging, M. Olschowka and J. Walter for animal colony management, L. Trojancyzk for help with tissue processing, and R. Johnson for assistance with ELISA. The present work was supported by NIH RO1AG030149, HD056235, and AG028271, the Coleman Institute, and the Anna & John J. Sie Foundation. The present work was supported by NIH RO1 AG030149, HD056235, AG028271, and T32 NS051152, the Coleman Institute, and the Anna & John J. Sie Foundation.

References (37)

  • N. Plath et al.

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

    Neuron

    (2006)
  • C.R. Pugh et al.

    Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning

    Brain Behav. Immun.

    (1998)
  • M. Stasko et al.

    Experimental parameters affecting the Morris water maze performance of a mouse model of Down syndrome

    Behav. Brain Res.

    (2004)
  • L.M. Thomson et al.

    Systemic administration of lipopolysaccharide and interleukin-1beta have different effects on memory consolidation

    Brain Res. Bull.

    (2005)
  • C. Lyketsos et al.

    Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial

    Neurology

    (2007)
  • A. Bouman et al.

    Sex hormones and the immune response in humans

    Hum. Reprod. Update

    (2005)
  • A.J. Bruce-Keller et al.

    Gender and estrogen manipulation do not affect traumatic brain injury in mice

    J. Neurotrauma

    (2007)
  • G. Casadesus et al.

    Increased isoprostane and prostaglandin are prominent in neurons in Alzheimer disease

    Mol. Neurodegener.

    (2007)
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