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 A 1 receptor-dependent (85.7 ± 4.3%, in the presence of DPCPX (200 nM), the adenosine A 1 receptor antagonist). DPCPX inhibited the maintenance of long-term potentiation obtained 30 min post hypoxia (143.8 ± 8.2% versus 96.4 ± 10.6% respectively, 1 h post tetanus; n  = 5; p n  = 5). This effect was reversed by pre-treatment with SB 203580 (1 µM), 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.