Tumor necrosis factor-α impairs the recovery of synaptic transmission from hypoxia in rat hippocampal slices

Abstract 

Cerebral ischaemia is a common occurrence in a range of pathological conditions, including stroke and traumatic brain injury. Two of the components in ischaemia are tissue hypoxia and the release of pro-inflammatory agents such as TNF-α. The role of TNF-α in an ischaemic/hypoxic episode is still controversial, although deleterious effects of pro-inflammatory cytokines in the area of injury are well documented. One of the prime adaptive mechanisms in response to hypoxia is the cellular activation of adenosine 1 receptors (A1Rs), which inhibits excitatory synaptic transmission. In the present study we have examined the effect of TNF-α application on synaptic transmission during hypoxic exposure and re-oxygenation using extracellular recordings in the CA1 region of the rat hippocampal slice. Hypoxia caused a reversible depression of the field EPSP (29.6±9.7% of control, n=5), which was adenosine A₁ receptor-dependent (85.7±4.3%, in the presence of DPCPX (200nM), the adenosine A₁ receptor antagonist). DPCPX inhibited the maintenance of long-term potentiation obtained 30min post hypoxia (143.8±8.2% versus 96.4±10.6% respectively, 1h post tetanus; n=5; p<0.005). In TNF-α (150pM) treated slices hypoxic depression was similar to controls but a reduction in fEPSP slope was observed during re-oxygenation (66.8±1.4%, n=5). This effect was reversed by pre-treatment with SB 203580 (1µM), a p38 MAP kinase inhibitor (91.8±6.9%, n=5). These results demonstrate a novel p38 MAPK dependent role for TNF-α in attenuating synaptic transmission after a hypoxic episode.

Keywords: Hypoxia, Adenosine A₁ receptor, TNF-α, LTP, Hippocampus, p38 MAP kinase