MEMANTINE PROTECTS AGAINST LPS-INDUCED NEUROINFLAMMATION, RESTORES BEHAVIORALLY-INDUCED GENE EXPRESSION AND SPATIAL LEARNING IN THE RAT S. ROSI, a * A. VAZDARJANOVA, a,b V. RAMIREZ-AMAYA, a,c P. F. WORLEY, d C. A. BARNES a,e AND G. L. WENK f a Arizona Research Laboratories, Division of Neural Systems, Memory, and Aging, University of Arizona, Tucson, AZ 85724, USA b Cognitive Neuroscience Center and Department of Neurology, School of Medicine, Medical College of Georgia, Augusta, GA 30912, USA c Departamento de Neurobiologia Conductual y Cognitiva, Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico, Querétaro 76230, Mexico d Departments of Neuroscience and Neurology, John Hopkins Univer- sity, Baltimore, MD 21205, USA e Departments of Psychology and Neurology, University of Arizona, Tucson, AZ 85724, USA f Department of Psychology, Ohio State University, Columbus, OH 43210, USA Abstract—Neuroinflammation is reliably associated with the pathogenesis of a number of neurodegenerative diseases, and can be detected by the presence of activated microglia. Neuroinflammation can be induced by chronic lipopolysac- charide (LPS) infusion into the 4th ventricle of the rat result- ing in region-selective microglia activation and impaired hip- pocampal-dependent memory. Furthermore, this treatment results in altered behaviorally-induced expression of the im- mediate early gene Arc, indicating altered network activity. LPS is known to activate microglia directly, leading to in- creased glutamate release, and in enhanced N-methyl-D-as- partate (NMDA) -dependent signaling. Taken together, the foregoing suggests that decreasing NMDA receptor activa- tion during early stages of chronic neuroinflammation should reduce a) microglia activation, b) overexpression of Arc, and c) spatial memory deficits. Memantine, a low to moderate affinity open channel uncompetitive NMDA receptor antago- nist, at low doses was used here to test these hypotheses. Rats were chronically infused into the 4th ventricle for 28 days with LPS alone, vehicle alone (via osmotic minipump) or LPS and memantine (10 mg/kg/day memantine s.c.). The re- sults reported here demonstrate that memantine reduces OX6-immunolabeling for activated microglia, spares resident microglia, returns Arc (activity-regulated cytoskeletal associ- ated protein, protein) -expressing neuronal populations to control levels (as revealed by Arc immunolabeling and fluo- rescence in situ hybridization), and ameliorates the spatial memory impairments produced by LPS alone. These data indicate that memantine therapy at low doses, recreating plasma levels similar to those of therapeutic doses in human, acts in part through its ability to reduce the effects of neu- roinflammation, resulting in normal gene expression patterns and spatial learning. Combined, these findings suggest that low, therapeuti- cally relevant doses of memantine delivered early in the de- velopment of neuroinflammation-influenced diseases may confer neural and cognitive protection. © 2006 IBRO. Pub- lished by Elsevier Ltd. All rights reserved. Key words: activated microglia, immediate early gene, hip- pocampal function, cognitive impairment, spatial memory consolidation, NMDA receptor. Chronic neuroinflammation is implicated in several neuro- degenerative diseases, such as Alzheimer’s disease (AD), traumatic brain injury, autism, Down syndrome, HIV de- mentia, and demyelinating diseases, such as multiple scle- rosis and amyotrophic later sclerosis and may contribute to learning and memory deficits associated with these disor- ders (McGeer and McGeer, 1998; Akiyama et al., 2000; Morganti-Kossmann et al., 2001; Vargas et al., 2005; Fis- cher-Smith et al., 2004; Banati et al., 2000; Mhatre et al., 2004). During the early stages of AD, the greatest degree of neuroinflammation is found within temporal lobe regions involved in learning and memory (Cagnin et al., 2001). Activated microglia cells and their products are the key mediators of the neuroinflammatory process and contrib- ute to neuronal damage (Barger and Harmon, 1997; Barger and Basile, 2001). Chronic neuroinflammation can be produced by infus- ing lipopolysaccharide (LPS) into the fourth ventricle of young rats resulting in activation of microglia within the hippocampus, piriform and entorhinal cortices (Hauss- Wegrzyniak et al., 1998b). LPS selectively binds to a sig- nal-transduction receptor complex (CD14/toll-like receptor 4) that is expressed only by microglia (Lehnardt et al., 2003). By activating microglia through LPS infusion, young rats can show pathological, biochemical and behavioral changes that are similar to those observed in several neurodegenerative diseases associated with neuroinflam- mation. These include impaired spatial memory, reduction of N-methyl-D-aspartate receptor type 1 (NMDAR1), astro- cytosis, elevated cytokines and proinflammatory transcrip- *Correspondence to: S. Rosi, Departments of Physical Therapy and Rehab Science, and Neurological Surgery, University of California San Francisco, Brain and Spinal Cord Injury Center, San Francisco General Hospital, Building #1, Room 101, Potrero Avenue 1001, San Francisco, CA 94110, USA. Tel: +1-415-206-3708; fax: +1-415-206-3948. E-mail address: rosis@ptrehab.ucsf.edu (S. Rosi). Abbreviations: AA, arachidonic acid; aCSF, artificial cerebrospinal fluid; AD, Alzheimer’s disease; Arc, activity-regulated cytoskeletal associ- ated protein, gene; Arc, activity-regulated cytoskeletal associated pro- tein, protein; CY3, cyanine 3; GC, gas chromatography; IEG, immedi- ately early gene; LPS, lipopolysaccharide; NMDA, N-methyl-D-aspar- tate; NMDAR1, N-methyl-D-aspartate receptor type 1. Neuroscience 142 (2006) 1303–1315 0306-4522/06$30.00+0.00 © 2006 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2006.08.017 1303