Long-term depression (LTD) was studied in hippocampal slices from neonatal rats at the synapse between CA3 and CA1 pyramidal neurons. The induction of LTD requires the pairing of Ca2+ influx into the postsynaptic CA1 neuron through voltage-gated calcium channels with activation of metabotropic glutamate receptors. The expression of this LTD is at least partly presynaptic, implying the need for a retrograde messenger. We present evidence that arachidonic acid might serve such a function. Thus, arachidonic acid applications simulate LTD whereas blockade of arachidonic acid release inhibits LTD.