NEUROINFLAMMATION DISRUPTS ARC IMMEDIATE EARLY GENE EXPRESSION IN THE DG

S. Rosi¹*; A. Vazdarjanova¹; V. Ramirez-Amaya¹;
P.F. Worley²; C.A. Barnes¹; G.L. Wenk¹

1. NSMA, Univ Arizona, Tucson, AZ, USA
2. Neurosci & Neurol, Johns Hopkins Univ, Baltimore, MD, USA

Neuroinflammation is associated with some neurodegenerative diseases. In early Alzheimer's Disease, brain regions involved in learning and memory have the greatest degree of activated microglia. We investigated whether experimental neuroinflammation in the hippocampus alters the molecular processes associated with learning. Rats were chronically infused with lipopolysaccharide (LPS) (0.25 g/hr) into the 4th ventricle for 28 days. On day 29, the animals explored twice a novel environment for 5 min with 45 or 90 min between exposures. The brains were processed for Arc and OX-6 immunolabeling, and Arc fluorescence in-situ hybridization. The presence of activated microglia (OX-6 immunoreactivity) in the DG hilar region of LPS-infused animals was positively correlated with exploration-induced Arc mRNA levels in both the upper and lower blade of the DG compared to aCSF-infused controls. In contrast, in CA1, where there was no activated microglia, exploration-induced Arc expression remained similar in both the LPS- and aCSF-treated animals. Arc protein levels in the DG were also selectively elevated in LPS-treated rats at both 45 and 90 min. Because spatial exploration selectively increases Arc expression in the upper blade of the DG of untreated or aCSF-treated rats, the present results of increased Arc expression in both DG upper and lower blade of LPS-treated rats suggest that neuroinflamation non-selectively increases Arc levels in the DG. Indeed the increased Arc expression may result from altered excitatory input to the dentate. Alternatively neuroinflammation could alter the coupling of electrical neural activity with protein synthesis of molecular processes linked to learning and plasticity, which may contribute to the cognitive deficits associated with AD.

Support Contributed By: AG10546, IIRG-01-2654, AG09219, HFSP LT00112-2002-C & MH64357