Long-term depression (LTD) can be induced at hippocampal CA1 synapses, by activation of either N-methyl-D-aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs). Although NMDAR-LTD has been relatively well characterised, the molecular mechanisms underlying mGluR-LTD are still unknown. However, these can be investigated by bath application of the group 1 mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Previous studies have indicated that DHPG-LTD is calcium independent and does not require activation of CaMKII, protein kinases A or C or serine/threonine phosphatases. It does however require protein tyrosine phosphatases (PTPs), Gαq activation and involve internalisation of AMPA receptors (AMPARs) and NMDARs. In this study, 400 μm thick acute hippocampal slices were obtained from female Wistar rats (10-12 weeks of age), and incubated in 100 μM DHPG for 10 minutes, followed by immunoprecipitation of AMPARs and quantitative immunoblot analysis using an anti-phosphotyrosine antibody at different time-points. We have established that DHPG-LTD involves a transient tyrosine dephosphorylation of the GluR2 AMPAR subunit, and that this is blocked by prior application of the PTP inhibitor, orthovanadate. The total AMPAR content in the slices is unaffected in DHPG-LTD. AMPAR phosphotyrosine levels do not change significantly upon activation of NMDARs implying that the mechanism is specific to mGluR-LTD. The combination of cell surface biotin-labelling and immunoprecipitation revealed that tyrosine dephosphorylation is required for the trafficking of AMPARs away from the synapse. This study has therefore established that AMPAR tyrosine dephosphorylation by PTPs is an important postsynaptic component of mGluR-LTD which does not seem to be involved in NMDAR-LTD.