The necessity for phospholipase C (PLC), the enzyme which produces the second messenger molecules inositol trisphosphate (IP3) and diacylglycerol, for the induction of long-term depression (LTD) was tested at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. We report here that bath application of a selective cell-permeant PLC inhibitor, U-73122 (10 microM), does block the induction of LTD. In contrast, neither the inactive analog U-73343 (10 microM), nor application of U-73122 during the maintenance phase of LTD, impaired expression of LTD. Furthermore, postsynaptic infusion of U-73122 (100 microM) into single CA1 pyramidal neurons also prevented the induction of LTD. Since mGluR5 is the only metabotropic glutamate receptor subtype coupled to inositide turnover in field CA1, we conclude that the postsynaptic calcium store necessary for the induction of homosynaptic LTD is gated by IP3, through activation of mGluR5 coupled to phospholipase C.