Interleukin-6 Facilitates Lipopolysaccharide-Induced Disruption in Working Memory and Expression of Other Proinflammatory Cytokines in Hippocampal Neuronal Cell Layers

Abstract

Proinflammatory cytokines inhibit learning and memory but the significance of interleukin-6 (IL-6) in acute cognitive deficits induced by the peripheral innate immune system is not known. To examine the functional role of IL-6 in hippocampus-mediated cognitive impairments associated with peripheral infections, C57BL6/J (IL-6 +/+ ) and IL-6 knock-out (IL-6 −/− ) mice were trained in a matching-to-place version of the water maze. After an acquisition phase, IL-6 +/+ mice injected intraperitoneally with lipopolysaccharide (LPS) exhibited deficits in working memory. However, IL-6 −/− mice were refractory to the LPS-induced impairment in working memory. To determine the mechanism by which IL-6 deficiency conferred protection from disruption in working memory, plasma IL-1β and tumor necrosis factor α (TNFα), c-Fos immunoreactivity in the nucleus of the solitary tract (NTS), and steady-state levels of IL-1β and TNFα mRNA in neuronal layers of the hippocampus were determined in IL-6 +/+ and IL-6 −/− mice after injection of LPS. Plasma IL-1β and TNFα and c-Fos immunoreactivity in the NTS were increased similarly in IL-6 +/+ and IL-6 −/− mice after LPS, indicating high circulating levels of IL-1β and TNFα and activation of vagal afferent pathways were not sufficient to disrupt working memory in the absence of IL-6. However, the LPS-induced upregulation of IL-1β and TNFα mRNA that was evident in hippocampal tissue of IL-6 +/+ mice was greatly attenuated or entirely absent in IL-6 −/− mice. Collectively, these data suggest that humoral and neural immune-to-brain communication pathways are intact in IL-6-deficient mice but that, in the absence of IL-6, the central cytokine compartment is hyporesponsive.