Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders but its role in normal neuronal function is largely unknown. Here we show that GSK3β mediates a novel interaction between the two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD) and long-term potentiation (LTP). First we show that GSK3β is required for LTD; GSK3β inhibitors completely block the induction of LTD and the activity of GSK3β is enhanced during LTD. Next we show that LTP inhibits the activity of GSK3β and completely blocks the ability of synapses to undergo LTD for up to one hour, also via an NMDA receptor dependent mechanism. A key determinant of whether NMDA receptor activation leads to LTD or its inhibition may be the phosphorylation status of ser9 in GSK3β. During LTD, the activation of protein phosphatase 1 (PP1) leads to dephosphorylation of this residue, which equates to an increase in GSK3β activity. In contrast, during LTP, activation of the PI3K/Akt pathway leads to phosphorylation of ser9 and hence inhibition of GSK3β. We conclude that the regulation of GSK3β activity provides a powerful mechanism to preserve NMDA receptor encoded synaptic information from being erased by subsequent LTD, perhaps thereby permitting the consolidation of learnt information.