Chronic LPS exposure produces changes in intrinsic membrane properties and a sustained IL-β-dependent increase in GABAergic inhibition in hippocampal CA1 pyramidal neurons

Abstract

Chronic inflammation has been reported to be a significant factor in the induction and progression of a number of chronic neurological disorders including Alzheimer's disease and Down syndrome. It is believed that inflammation may promote synaptic dysfunction, an effect that is mediated in part by pro-inflammatory cytokines such as interleukin-1beta (IL-1beta). However, the role of IL-1beta and other cytokines in synaptic transmission is still poorly understood. In this study, we have investigated how synaptic transmission and neuronal excitability in hippocampal pyramidal neurons are affected by chronic inflammation induced by exposing organotypic slices to the bacterial cell-wall product lipopolysaccharide (LPS). We report that CA1 pyramidal neurons recorded in whole cell from slices previously exposed to LPS for 7 days had resting membrane potential and action potential properties similar to those of the controls. However, they had significantly lower membrane resistance and a more elevated action potential threshold, and displayed a slower frequency of action potential discharge. Moreover, the amplitude of pharmacologically isolated postsynaptic gamma-aminobutyric acid (GABA)ergic potentials, but not excitatory glutamatergic postsynaptic potentials, was significantly larger following chronic LPS exposure. Interestingly, co-incubation of the IL-1 receptor antagonist (IL-1Ra) concurrently with LPS prevented the increase in GABAergic transmission, but not the reduction in intrinsic neuronal excitability. Finally, we confirmed that LPS dramatically increased IL-1beta, and IL-1beta-dependent IL-6 levels in the culture medium for 2 days before returning to baseline. We conclude that CA1 pyramidal neurons in slices chronically exposed to LPS show a persistent decrease in excitability due to a combined decrease in intrinsic membrane excitability and an enhancement in synaptic GABAergic input, the latter being dependent on IL-1beta. Therefore, chronic inflammation in hippocampus produces IL-1beta-dependent and -independent effects in neuronal and synaptic function that could contribute significantly to cognitive disturbances.

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

“…Strikingly, we did not observe neurotoxic effects at either structural or functional levels. This expands previous data from slice cultures (5,25,34), but contrasts with studies of neuron-glia cultures and in vivo, in which LPS exposure alone was neurotoxic (8,12,13,17,18,20,21). Several factors might account for these differences, including (i) insufficient NO levels to amplify inflammatory responses of glial cells and/or inhibit mitochondrial respiration in neurons (14,32); (ii) the neural subtype investigated (42); (iii) suppressive effects on microglia ("off" signals) from active neurons and astrocytes through cell membrane contacts, neurotransmitters, and cytokines (1, 4, 7); and (iv) the presence of antioxidative extracellular matrix components that protect neurons (43).…”

“…Similarly, no or only moderate changes in intrinsic membrane properties and postsynaptic potentials were described for CA1 pyramidal cells, both during acute LPS application in hippocampal slices (26,44) and after LPS exposure for days in slice cultures (25). We also found a regular K + homeostasis after LPS exposure.…”

“…This aspect is highly relevant for several neurologic and psychiatric disorders. Moreover, concomitant alterations in neuronal information processing (i.e., dysfunction in excitatory pyramidal cells and inhibitory GABAergic interneurons, including astrocytes) have been little explored (25)(26)(27).…”

Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior

“…LPS triggers an increase of IL-1 β within the hippocampus (Laye et al, 1994;Hansen et al, 2000b) which is independent of the vagal pathway (Hansen et al, 2000b). This LPS-induced IL1-β expression is responsible for a sustained increase in GABAergic inhibition in hippocampal CA1 pyramidal neurons (Hellstrom et al, 2005). Cytokines also decrease the number of functional NMDA receptors in the hippocampus (Rosi et al, 2004) and the expression of Arc, an IEG involved in synaptic plasticity (Rosi et al, 2005).…”

Pathophysiology of Delirium in the Intensive Care Unit

“…They recently reported that individuals who sustained septic shock exhibited abnormal MRIs with varying degrees of encephalopathy and damage to white matter tracts [76]. Moreover, in sepsis, the prolonged exposure to lipopolysaccharide may impair the synaptic transmission and neuronal excitability of pyramidal neurons of the hippocampus [85]. These indications suggest that the relationship between sepsis and delirium will continue to be a productive area of research.…”