HighlightsRepeated peripheral LPS administration increases expression of central A&bgr;.Administration of MRK‐016 post‐training rescues memory consolidation following LPS administration.MRK‐016‐treated animals showed BDNF mRNA expression comparable to control animals.Repeated injections of LPS… Click to show full abstract
HighlightsRepeated peripheral LPS administration increases expression of central A&bgr;.Administration of MRK‐016 post‐training rescues memory consolidation following LPS administration.MRK‐016‐treated animals showed BDNF mRNA expression comparable to control animals.Repeated injections of LPS and increased A&bgr; expression are congruent with downregulation of TrkB.Nurr1 expression is reduced following repeated LPS treatment, but is increased following behavioral training. Abstract Alzheimer’s disease is marked by the presence of amyloid‐beta (A&bgr;) plaques, elevated central cytokine levels, dysregulation of BDNF‐related gene expression, and cognitive decline. Previously, our laboratory has demonstrated that repeated administration of peripheral LPS is sufficient to significantly increase the presence of central A&bgr; in the hippocampus, and that this upregulation corresponds with deficits in learning and memory. We have also previously demonstrated that the inverse benzodiazepine agonist MRK‐016 (MRK) can protect against memory acquisition and consolidation errors in mice. To extend these findings, the current study explored the protective effects of MRK in the context of LPS‐induced hippocampal A&bgr; accumulation. Hippocampal A&bgr; was significantly elevated, relative to saline‐treated animals, following seven days of peripheral LPS injections. Animals were then trained in a contextual fear conditioning paradigm and were immediately treated with MRK or saline once training was complete. Behavioral testing occurred the day after training. Results from this study demonstrate that repeated injections of LPS significantly elevate hippocampal A&bgr;, and inhibit acquisition of contextual fear. Post‐training treatment with MRK restored behavioral expression of fear in LPS‐treated animals, despite elevated hippocampal A&bgr;, an effect that may be attributed to increased BDNF mRNA expression. Therefore, our data indicate that MRK can prevent LPS‐ induced cognitive deficits associated with elevated A&bgr;, and restore hippocampal BDNF expression.
               
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