Lipopolysaccharide Inhibits Long Term Potentiation in the Rat Dentate Gyrus by Activating Caspase-1

Abstract

Lipopolysaccharide, a component of the cell wall of Gram-negative bacteria, may be responsible for at least some of the pathophysiological sequelae of bacterial infections, probably by inducing an increase in interleukin-1␤ (IL-1␤) concentration. We report that intraperitoneal injection of lipopolysaccharide increased hippocampal caspase-1 activity and IL-1␤ concentration; these changes were associated with increased activity of the stress-activated kinase c-Jun NH 2 -terminal kinase, decreased glutamate release, and impaired long term potentiation. The degenerative changes in hippocampus and entorhinal cortical neurones were consistent with apoptosis because translocation of cytochrome c and poly(ADP-ribose) polymerase cleavage were increased. Inhibition of caspase-1 blocked these changes, suggesting that IL-1␤ mediated the lipopolysaccharide-induced changes.There is increasing awareness of the existence of bidirectional communication between the immune and nervous systems. The proinflammatory cytokine, interleukin-1␤ (IL-1␤), 1 is one molecule that may play a pivotal role in integrating neuronal immune responses with those of the endocrine system because it exerts significant effects in all systems, for example in response to stressors such as infection. Gram-negative bacterial infections are associated with multiple pathophysiological changes; it is widely accepted that these changes are stimulated by lipopolysaccharide (LPS), a component of the outer membrane of most Gram-negative bacteria. These changes, which include fever, changes in sleep pattern, and anorexia (1), are mimicked by, and therefore thought to be mediated through production of, IL-1␤. Thus LPS, injected centrally or peripherally, increases IL-1␤ concentrations (2, 3) and IL-1␤ mRNA expression (4) in rat brain.Although it appears that in certain circumstances IL-1␤ may be neuroprotective, the consensus is that prolonged exposure, or exposure of tissue to high concentrations of IL-1␤, results in degenerative changes (5). Therefore it is significant that increased IL-1 concentrations in different brain areas have been correlated with neurodegenerative disorders such as Down syndrome, Alzheimer's disease (6), and Parkinson's disease (7), whereas in experimental models, IL-1␤ is considered to be responsible for the cell damage associated with ischemia (8) and excitotoxicity (9) and is increased after experimental traumatic lesions (10). A striking example of a neuronal deficit induced by IL-1␤ is the impairment in long term potentiation (LTP) in the hippocampus in vitro (11-13) and in vivo (14 -16).IL-1␤ is produced by glia (17, 18) and neurones (19,20) in response to tissue stress. It is cleaved from the inactive percursor, pro-IL-1␤, by the action of caspase-1, a member of a large family of cysteine proteases that have been implicated in apoptotic cell death (21-25). It might be predicted therefore that any trigger such as LPS, which induces an increase in IL-1␤, will do so by increasing activity of caspase-1.Our objective was to investigate th...

Inflammation Regulates Functional Integration of Neurons Born in Adult Brain

“…This treatment caused increased numbers of microglia with phagocytotic activity (Iba1 ϩ /ED1 ϩ ) in the SGZ/ GCL, both at the time when the new cells were born (1 week after LPS injection) and when they had reached the mature state (at the time of recording and morphological analysis, 7 weeks later). Consistent with our findings, Herber et al (2006) potentiation (Vereker et al, 2000;Hennigan et al, 2007). Furthermore, injection of LPS in the hippocampal CA1 area of rats gives rise to learning and memory deficits and decreased glutamatergic neurotransmission but no cell death (Tanaka et al, 2006).…”

Long-Term Potentiation and Memory

“…4), and this finding is supported by data from several experiments that were conducted in vitro and that revealed that application of IL-1␤ to hippocampal slices inhibited LTP in dentate gyrus (118), CA1 (54), and CA3 (279). Consistently, LTP has been shown to be impaired in several circumstances in which IL-1␤ concentration in hippocampus is increased, for example, in aged (380,442,441,627) and stressed (442,629) rats, rats treated with LPS (627), and rats exposed to ␥-irradiation (A. M. Lynch, M. Moore, S. Craig, P. E. Lonergan, and M. A. Lynch, unpublished data; see Fig. 5).…”

“…4) arising from an increase in SOD activity in the absence of concomitant changes in activities of glutathione peroxidase or catalase (87,191,466,467). Increased ROS accumulation is closely coupled with increased concentration of IL-1␤, and these changes have been correlated with deficits in LTP in the aged animal (400,441,442,467,627,628). The consequences of a chronic increase in ROS production are profound and lead to lipid peroxidation, which in turn results in a decrease in the membrane concentration of polyunsaturated fatty acids, altering membrane fluidity (353,355,441,443).…”

COX-2 oxidative metabolism of endocannabinoids augments hippocampal synaptic plasticity

“…This may explain the enhanced LTP and diminished DSI in LPS-treated and COX-2 transgenic mice we observed in the present study. Of note however are studies indicating that LPS inhibits LTP in the rat dentate gyrus (Vereker et al, 2000). The discrepancy between our observations and these is not clear, but may be due to differences in doses used (3 mg/kg versus 0.2 mg/kg) and in the methods used to record (ex-vivo slices versus in vivo).…”