Activation of p38 Plays a Pivotal Role in the Inhibitory Effect of Lipopolysaccharide and Interleukin-1β on Long Term Potentiation in Rat Dentate Gyrus

Abstract

Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, has been shown to induce profound changes both peripherally and centrally. It has recently been reported that intraperitoneal injection of LPS inhibited long term potentiation (LTP) in perforant path-granule cell synapses and that this effect was coupled with an increase in the concentration of the proinflammatory cytokine, interleukin-1␤ (IL-1␤). The LPS-induced effects were abrogated by inhibition of caspase-1, suggesting that IL-1␤ may mediate the effects of LPS. Here we report that the inhibition of LTP induced by LPS and IL-1␤ was coupled with stimulation of the stress-activated protein kinase p38 in hippocampus and entorhinal cortex and that this effect was abrogated by the p38 inhibitor SB203580, while the effect of LPS was markedly attenuated in C57BL/6 IL-1RI ؊/؊ mice. The data also indicate that activation of the transcription factor, nuclear factor B (NFB), may play a role, since the inhibitory effect of LPS and IL-1␤ on LTP was attenuated by the NFB inhibitor, SN50; consistently, LPS and IL-1␤ led to activation of NFB in entorhinal cortex. We suggest that one consequence of these LPSand IL-1␤-induced changes is a compromise in glutamate release in dentate gyrus, which was coupled with the inhibition of LTP. The evidence is consistent with the idea that the LPS-induced impairment in LTP is mediated by IL-1␤ and is a consequence of activation of p38.The proinflammatory cytokine, interleukin-1␤ (IL-1␤), 1 exerts numerous effects in the central nervous system; among these effects is inhibition of long term potentiation (LTP) in the hippocampus (1-6). LTP in perforant path-granule cell synapses has been shown to be attenuated in aged and stressed rats (4, 5) and in rats that were treated intraperitoneally with lipopolysaccharide (LPS; Ref. 7) or intracerebroventricularly with IL-1␤ (4, 5); IL-1␤ concentration in hippocampus was increased in each of these experimental conditions, and a negative correlation between the ability of rats to sustain LTP and IL-1␤ concentration in hippocampus has been described previously (8, 9). The finding that the effect of LPS on LTP is mimicked by IL-1␤, together with the finding that the effect of LPS on LTP was abrogated by inhibiting IL-1␤ converting enzyme (caspase-1; Ref. 7), suggested that IL-1␤ may mediate this effect of LPS.Among the downstream effects of IL-1␤ is activation of the mitogen-activated protein kinases, c-Jun NH 2 -terminal kinase (JNK), or stress-activated protein kinase (SAPK) and p38; this effect has been reported in several tissues, for example, IL-1␤ increases activity of p38 in Chinese hamster CCl39 (10) and HeLa (11) cells, while IL-1␤-induced activation of JNK has been reported in human glomerular mesangial (12) and HeLa (11) cells. In the hippocampus, activation of JNK and p38 is coupled with elevated IL-1␤ concentrations in aged rats (13) and in rats treated intracerebroventricularly with IL-1␤ (6), and the LTP-associated increase in KCl-stimulated glutamate rele...

Interleukin-1α and HMGB1 Mediate Hippocampal Dysfunction in SIGIRR-Deficient Mice

“…Enhanced activation of both have been reported in aged animals, and following LPS or A␤ administration, and is associated with impaired LTP Kelly et al, 2003;Minogue et al, 2003;Costello and Herron, 2004;Barry et al, 2005). Similarly, inhibition of JNK or NF-B alleviates the depression of LTP observed in response to LPS and/or A␤ (Kelly et al, 2003;Minogue et al, 2003;Costello and Herron, 2004;Barry et al, 2005). Interestingly, the evidence indicates that wedelolactone, which inhibits NF-B activation (Kobori et al, 2004), increases LTP above control levels.…”

“…Investigations into the mechanisms underlying these inflammatory processes have illustrated that proinflammatory cytokines induce an impairment in hippocampal-dependent memory (Barrientos et al, 2002;Hein et al, 2010) and LTP Curran and O'Connor, 2001). Additionally, inflammatory challenges associated with age, ␤-amyloid, or lipopolysaccharide (LPS) elicit similar deficits in LTP through activation of stress-activated protein kinases Kelly et al, 2003;Minogue et al, 2003;Costello and Herron, 2004;Barry et al, 2005).…”

Receptor for Advanced Glycation End Product-Dependent Activation of p38 Mitogen-Activated Protein Kinase Contributes to Amyloid-β-Mediated Cortical Synaptic Dysfunction

“…In particular, we considered two different kinases, namely JNK and p38 MAPK as potentially involved in inhibition of LTP. Recent results showed that p38 MAPK and JNK activation are required for LTP inhibition induced by proinflammatory agents such as interleukin-1␤ and lipopolysaccharide (Curran et al, 2003;Kelly et al, 2003). These results prompted us to test whether p38 MAPK and JNK were involved in LTP inhibition by A␤.…”

Microglial Receptor for Advanced Glycation End Product-Dependent Signal Pathway Drives β-Amyloid-Induced Synaptic Depression and Long-Term Depression Impairment in Entorhinal Cortex

“…Activated microglial cells produce a wide spectrum of proinflammatory and cytotoxic factors, including TNF-␣ and IL-1␤ (for review, see Simm et al, 2004), two cytokines implicated in AD pathogenetic mechanisms (Akiyama et al, 2000). Importantly, IL-1␤ is implicated in disruption of synaptic efficacy induced by proinflammatory agents (Curran et al, 2003;Kelly et al, 2003). Moreover, in the hippocampus, IL-1␤ induced synaptic depression, inhibiting the subsequent induction of LTD in response to a 1 Hz electrical stimulation (Ikegaya et al, 2003).…”

“…Microglial RAGE has been implicated in the development of inflammatory response and cellular dysfunction (Lue et al, 2001;Bianchi et al, 2010). Cytokines, in particular IL-1␤ and TNF-␣, released by microglial cells, are key molecules that are capable of modulating synaptic function and plasticity (Coogan et al, 1999;Ikegaya et al, 2003;Kelly et al, 2003;Pickering et al, 2005). To test the possible involvement of cytokines, we first tried to mimic A␤-dependent synaptic depression by exogenously applying IL-1␤ (1 ng/ml) and TNF-␣ (5 ng/ml) on slices for 10 min.…”