ABSTRACT
In the current study, the partial NMDA receptor agonist D-cycloserine (DCS) rescued memory consolidation following systemic bacterial endotoxin exposure. DCS failed, however, to restore hippocampal BDNF mRNA levels that were diminished following a systemic administration of LPS, and did not alter NR1 or NR2C NMDA receptor subunit expression. These results extend prior research into the role of DCS in neural-immune interactions, and indicate that the detrimental effects of peripheral LPS administration on consolidation of contextual fear memory may be ameliorated with DCS treatment, though the mechanisms underlying these effects are currently unclear.
Subject(s)
Cycloserine/therapeutic use , Escherichia coli , Hippocampus/drug effects , Lipopolysaccharides/pharmacology , Memory/drug effects , Animals , Antimetabolites/pharmacology , Antimetabolites/therapeutic use , Behavior, Animal/drug effects , Cycloserine/pharmacology , Escherichia coli/drug effects , Fear/drug effects , Hippocampus/metabolism , Hippocampus/microbiology , Lipopolysaccharides/administration & dosage , Male , Mice , Mice, Inbred C57BL , Neuropsychological Tests , RNA, Messenger/drug effects , Receptors, N-Methyl-D-Aspartate/biosynthesisABSTRACT
Alzheimer's disease (AD) is characterized by neuronal cell death and atrophy in regions of the adult brain, including the hippocampus and cortex, due to formation of amyloid beta (Aß) plaques and neurofibrillary tangles. The presence of these pathologies can limit normal signaling properties and ultimately lead to learning and memory deficits. Chronic inflammation has been implicated in the onset and progression of these AD-related pathologies. Our study was designed to assess the effects of peripheral inflammation on pathologies associated with AD by using the bacterial endotoxin lipopolysaccharide (LPS). C57BL/6J mice were given intraperitoneal injections of LPS or saline for 1, 3, or 7 consecutive days. Hippocampal tissue from animals receiving LPS contained significantly higher levels of Aß1-42, a peptide component of AD plaques, than did those from saline control animals. Central and peripheral pro-inflammatory cytokine levels were increased following a single injection of LPS, but retuned to baseline levels before cognitive testing began. We show that one injection of LPS leads to sickness behavior, but 7 consecutive days does not, indicating tolerance to the endotoxin. Cognitive testing was then conducted to determine if whether deficits from increased Aß1-42 was evident. Results from both Morris water maze and contextual fear conditioning revealed cognitive deficits in LPS-treated mice. In summary, multiple injections of LPS resulted in increased Aß1-42 in the hippocampus and cognitive deficits in mice.