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The Journal of Neuroscience, January 19, 2005, 25(3):723-731; doi:10.1523/JNEUROSCI.4469-04.2005

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Neurobiology of Disease
Neuroinflammation Alters the Hippocampal Pattern of Behaviorally Induced Arc Expression

Susanna Rosi,² Victor Ramirez-Amaya,² Almira Vazdarjanova,² Paul F. Worley,¹ Carol A. Barnes,^2,3 and Gary L. Wenk²

¹Departments of Neuroscience and Neurology, Johns Hopkins University, Baltimore, Maryland 21218, and ²Arizona Research Laboratories, Division of Neural Systems, Memory, and Aging, and ³Departments of Psychology and Neurology, University of Arizona, Tucson, Arizona 85724-5115

Neuroinflammation is associated with a variety of neurological and pathological diseases, such as Alzheimer's disease (AD), and is reliably detected by the presence of activated microglia. In early AD, the highest degree of activated microglia is observed in brain regions involved in learning and memory. To investigate whether neuroinflammation alters the pattern of rapid de novo gene expression associated with learning and memory, we studied the expression of the activity-induced immediate early gene Arc in the hippocampus of rats with experimental neuroinflammation. Rats were chronically infused with lipopolysaccharide (LPS) (0.25 µg/h) into the fourth ventricle for 28 d. On day 29, the rats explored twice a novel environment for 5 min, separated by 45 or 90 min. In the dentate gyrus and CA3 regions of LPS-infused rats, Arc and OX-6 (specific for major histocompatibility complex class II antigens) immunolabeling and Arc fluorescence in situ hybridization revealed both activated microglia (OX-6 immunoreactivity) and elevated exploration-induced Arc expression compared with control-infused rats. In contrast, in the CA1 of LPS-infused rats, where there was no OX-6 immunostaining, exploration-induced Arc mRNA and protein remained similar in both LPS- and control-infused rats. LPS-induced neuroinflammation did not affect basal levels of Arc expression. Behaviorally induced Arc expression was altered only within the regions showing activated microglia (OX-6 immunoreactivity), suggesting that neuroinflammation may alter the coupling of neural activity with macromolecular synthesis implicated in learning and plasticity. This activity-related alteration in Arc expression induced by neuroinflammation may contribute to the cognitive deficits found in diseases associated with inflammation, such as AD.

Key words: activated microglia; Alzheimer's disease; immediate early gene; hippocampal function; cognitive impairment; spatial memory consolidation

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Received Sep 6, 2004; revised December 2, 2004; accepted December 2, 2004.

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