DHPG-induced LTD (DHPG-LTD) is a chemically-induced, mGluR-dependent, form of synaptic plasticity commonly studied in the hippocampus. Recent data (Hsieh et al. 2006) suggest the mechanisms engaged by this form of synaptic change may parallel those that contribute to β-amyloid-mediated inhibition of synaptic function. On this basis we have started a new investigation of DHPG-LTD aimed at addressing the involvement of some of the signalling pathways engaged by the pathogenic species present in the Alzheimer’s disease brain. Hippocampal slices were prepared from either 2 or 6 week old male Wistar rats. Extracellular recordings of electrically evoked field EPSPs were made from stratum radiatum of area CA1 of submerged slices. The tissue was constantly perfused with aCSF maintained at 33°C, to which all pharmacological agents were added. In addition standard whole cell patch recordings were made at room temperature from visualised CA1 pyramidal neurones using a Kgluconate-based pipette solution. In whole-cell current-clamp recordings from CA1 neurones in slices obtained from 2 week old animals the mean resting potential was -67 ± 3 mV. Application of S-DHPG (50 μM) depolarised the membrane by 13 ± 3 mV (p<0.05). This change in membrane potential was accompanied by a 28% increase in membrane input resistance (control 209 ± 17 MΩ vs. 268 ± 11 MΩ in DHPG p<0.05). Agonist washout resulted in a recovery of the initial membrane potential and resistance. In extracellular recordings from slices obtained from 6 week old animals 4 minute application of either R,S-DHPG (100 μM) or S-DHPG (50 μM) produced a lasting synaptic depression. After 45 minutes of agonist washout this averaged 65 ± 9.5% (n=5, racemate) and 40 ± 11% (n=12, S-isomer). Induction of DHPG-LTD did not require stimulation during agonist application. The DHPG-mediated depression in fEPSP amplitude was accompanied by an increase in paired-pulse facilitation and a change in synaptic latency. The NMDA antagonist D-AP5 (50 μM) had no effect on the magnitude of DHPG-induced LTD. Similarly the TRPV1 antagonist SB-366791 was without effect. MCPG partially reversed established DHPG-LTD. DHPG-LTD was also observed in slices from 2 week old rats. β-amyloid mediated inhibition of LTP is reported to involve microglial activation (Wang et al 2004). Consequently we have examined the effect of minocycline (20 μM), an inhibitor of microglial activation, on DHPG-LTD. This agent produced no consistent effect on baseline transmission. Furthermore, the extent of DHPG-LTD was similar in minocylcine-treated slices and interleaved controls (n=7 slices per group).