A reduction in blood flow in the brain results in a number of disturbances including the development of a hypoxic condition. During hypoxia a number of physiological changes occur within neurons including the stabilisation of hypoxia-inducible factors. The activity of these proteins is regulated by O2, Fe2+, 2-OG & ascorbate-dependant hydroxylases which contain proyl-4-hydroxylase domains (PHDs). PHD inhibitors have been widely used and shown to have a preconditioning and protective effect against a later and more severe hypoxic insult. However very little research has been carried out on their putative actions on synaptic transmission and plasticity (1,2). In this study we have investigated the acute effects of the PHD inhibitor and hypoxia mimetic, protocatechuic acid ethyl ester (EDHB) on baseline transmission and long-term potentiation (LTP) in isolated rat (Wistar) hippocampus. Excitatory post-synaptic potentials were elicited by stimulation of the medial perforant (mDG) or Schaffer collateral pathway. LTP was induced by high frequency stimulation consisting of 3 trains of 1s duration every 20s at 100Hz. Responses were analysed using WCP software (J Dempster, Straythclyde). Baseline recordings were elicited at 40% of the maximal response and normalised to 100%. Values are means±S.E.M., compared by ANOVA. We report for the first time, an acute, concentration-dependent inhibitory effect of EDHB on synaptic transmission which was seen in the mDG (10µM, 98.0±3.9%, N=5; 100µM 70.5±4.5%, N=9, P<0.001) but not in the CA1 region (100µM 98.3±3.2%, N=7). The effect of EDHB in the mDG was significantly reversed by prior application of APV (25µM, 86.3±2.8% N=6, P<0.01) and picrotoxin (100µM, 83.7±2.7% N=8, P<0.01). There were no changes in the ratio of paired responses (50ms interval) after EDBH application suggesting a post-synaptic mechanism of action. EDHB at higher concentrations (100µM), was found to inhibit LTP in both the mDG and CA1 regions (111.7± 5.6%, vs control 152.1±10.4%, N=5, P<0.05, and 110.0±4.4% vs 143.2±8.2% control, N=5, P<0.01, respectively). Application of exogenous iron (100µM) did not reverse EDHBs inhibitory effect on baseline transmission or LTP, suggesting a HIF-independent mechanism of action. The inhibitory effects of EDHB in both reqions were reversible following washout. These results highlight a novel modulatory role for the PHD inhibitor EDHB in hippocampal synaptic transmission and plasticity. The effects are unlikely to be mediated pre-synaptically as is observed in hypoxia, where O2 levels are decreased in brain tissue and adenosine receptors are activated. A novel post-synaptic mechanism of action may be involved possibly involving NMDA and GABA receptor activation.