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. 2010 Feb;24(2):254-62.
doi: 10.1016/j.bbi.2009.10.005. Epub 2009 Oct 12.

IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats

Matthew G Frank  1 , Ruth M Barrientos, Amy M Hein, Joseph C Biedenkapp, Linda R Watkins, Steven F Maier
Affiliations

IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats

Matthew G Frank et al. Brain Behav Immun. 2010 Feb.

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-1beta and IL-6) mediate the effects of peripheral E. coli infection on Arc and LTM. In 24 months F344xBN 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 24h 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.

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Figures

Fig. 1
Fig. 1
Peripheral E. Coli reduced basal hippocampal Arc gene expression in 24 mo animals. 3 mo and 24 mo animals were administered E. coli or vehicle i.p. At 2 h, 4 h, 24 h and 96 h post-treatment, hippocampal Arc expression was measured. E. Coli treatment reduced basal Arc expression 2 h, 4 h, and 24 h post-E. coli in 24 mo animals compared to all other experimental groups (**p < .01, *** p < .001). E. coli treatment did not significantly alter Arc expression in 3 mo animals nor did Arc expression differ between vehicle treated 3 and 24 mo animals. At 96 h post-infection, Arc expression was not altered by E. coli treatment in either 3 or 24 mo animals. N = 5-9 animals/group.
Fig. 2A
Fig. 2A
Peripheral E. coli treatment induced a protracted IL-1β protein response in the hippocampus of 24 mo animals. 3 mo and 24 mo animals were administered E. coli or vehicle i.p. 4 d post-treatment, animals underwent contextual fear conditioning or served as HCC. 30 min post-conditioning, hippocampal IL-1β was measured. Peripheral E. coli treatment increased IL-1β protein in 24 mo animals compared to all other experimental groups (*** p < .001). E. coli treatment had no effect on IL-1β in 3 mo animals. N = 4 animals/group.
Fig. 2B
Fig. 2B
E. coli treatment suppressed conditioning-induced Arc gene expression in 24 mo animals. 3 mo and 24 mo animals were administered E. coli or vehicle i.p. 4 d post-treatment, animals underwent contextual fear conditioning or served as HCC. 30 min post-conditioning, hippocampal Arc was measured. E. coli- treatment suppressed conditioning-induced Arc (174% of control) in 24 mo animals compared to 3 mo and 24 mo vehicle conditioned animals as well as 3 mo E. coli-conditioned animals (* p < .05). In the vehicle treated animals, conditioning increased Arc gene expression to similar levels in 3 mo (244% of control) and 24 mo (237% of control) animals and significantly above 3 mo and 24 mo vehicle and E. coli HCC animals (*** p < .001). In E. coli treated 3 mo animals, conditioning-induced Arc was not altered (238% of control) compared to 3 mo and 24 mo vehicle conditioned animals. E. coli treatment in HCC animals did not significantly increase Arc expression compared to vehicle treated HCC in both 3 mo and 24 mo animals. N = 6 - 8 animals/group.
Fig. 2C
Fig. 2C
E. coli treatment did not suppress conditioning-induced c-Fos gene expression in 24 mo animals. 3 mo and 24 mo animals were administered E. coli or vehicle i.p. 4 d post-treatment, animals underwent contextual fear conditioning or served as HCC. 30 min post-conditioning, hippocampal c-Fos was measured. Conditioning induced a robust increase in c-Fos expression compared to HCC (*** p < .001). E. Coli treatment had no effect on c-Fos expression. N = 6 - 8 animals/group.
Fig. 3A
Fig. 3A
Exogenous IL-1RA blocked the E. coli-induced increase in hippocampal IL-6 protein. 24 mo animals were injected ICM with either vehicle or IL-1RA. Immediately following ICM injection, animals were administered vehicle or E. coli i.p. 24 h post-treatments, hippocampal IL-6 protein levels were measured. In ICM vehicle treated animals, E. coli i.p. treatment significantly increased IL-6 levels compared to all other experimental groups (** p < .01). IL-1RA treatment completely blocked the E. coli-induced increase in IL-6 protein resulting in IL-6 protein levels similar to the vehicle ICM/vehicle i.p. and IL-1RA ICM/vehicle i.p. groups. N = 4 animals/group.
Fig. 3B
Fig. 3B
Exogenous IL-1RA blocked the E. coli-induced decrease in hippocampal Arc expression. 24 mo animals were injected ICM with either vehicle or IL-1RA. Immediately following ICM injection, animals were administered vehicle or E. coli i.p. 24 post-treatments, hippocampal Arc gene expression levels were measured. In vehicle ICM treated animals, E. coli treatment significantly decreased Arc levels compared to the vehicle ICM/vehicle i.p. (** p < .01), IL-1RA ICM/vehicle i.p. (** p < .01), and IL-1RA ICM/E. coli i.p. (** p < .01) groups. IL-1RA treatment completely blocked the E. coli-induced decrease in Arc gene expression resulting in Arc levels similar to the vehicle ICM/vehicle i.p. and IL-1RA ICM/vehicle i.p. groups. N = 5-7 animals/group.
Fig. 4A
Fig. 4A
Exogenous IL-1RA blocked the E. coli-induced LTM impairments in 24 mo animals. 24 mo animals were injected ICM with either vehicle or IL-1RA. Immediately following ICM injection, animals were injected i.p. with either vehicle or E. coli. 4 d post-injections, all animals underwent contextual fear conditioning. 3 d post-conditioning, all animals were given a LTM test for the context. In vehicle ICM treated animals, E. coli treatment resulted in a significant impairment of LTM (% freezing to the context) compared to vehicle ICM/vehicle i.p. (*** p < .001), IL-1RA ICM/vehicle i.p. (* p < .05), and IL-1RA ICM/E. coli i.p. (** p < .01) groups. IL-1RA treatment completely blocked the E. coli-induced impairment in LTM resulting in LTM similar to the vehicle ICM/vehicle i.p. and IL-1RA ICM/vehicle i.p. groups. N = 4 animals/group.
Fig. 4B
Fig. 4B
Exogenous IL-1RA blocked the E. coli-induced increase in hippocampal IL-6 protein 8 d post-infection. 24 mo animals were injected ICM with either vehicle or IL-1RA. Immediately following ICM injection, animals were injected i.p. with either vehicle or E. coli. 1 d post-test for fear of the context, hippocampal IL-6 protein was measured. In vehicle ICM treated animals, E. coli induced a significant increase in IL-6 protein compared to vehicle ICM/vehicle i.p. (** p < .01), IL-1RA ICM/vehicle i.p. (* p < .05), and IL-1RA ICM/E. coli i.p. (* p < .05) groups. IL-1RA blocked the E. coli-induced increase in hippocampal IL-6 resulting in IL-6 levels that did not significantly differ from the vehicle ICM/vehicle i.p. and IL-1RA ICM/vehicle i.p. groups. N = 4 animals/group.
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