12-lipoxygenase metabolites of arachidonic acid mediate metabotropic glutamate receptor-dependent long-term depression at hippocampal CA3-CA1 synapses

Arachidonic acid metabolites have been proposed as signaling molecules in hippocampal long-term potentiation (LTP) and long-term depression (LTD) for > 15 years. However, the functional role of these molecules remains controversial. Here we used a multidisciplinary biochemical, electrophysiological, and genetic approach to examine the function of the 12-lipoxygenase metabolites of arachidonic acid in long-term synaptic plasticity at CA3-CA1 synapses. We found that the 12-lipoxygenase pathway is required for the induction of metabotropic glutamate receptor-dependent LTD (mGluR-LTD), but is not required for LTP: ( 1) Hippocampal homogenates were capable of synthesizing the 12-lipoxygenase metabolite of arachidonic acid, 12( S)-hydroxyeicosa-5Z, 8Z, 10E, 14Z-tetraenoic acid ( HETE). ( 2) Stimulation protocols that induce mGluR-LTD lead to a release of 12-(S)-HETE from acute hippocampal slices. ( 3) A mouse in which the leukocyte-type 12- lipoxygenase ( the neuronal isoform) was deleted through homologous recombination was deficient in mGluR-LTD, but showed normal LTP. ( 4) Pharmacological inhibition of 12- lipoxygenase also blocked induction of mGluR-LTD. ( 5) Finally, direct application of 12( S)-HPETE, but not 15(S)-HPETE, to hippocampal slices induced a long-term depression of synaptic transmission that mimicked and occluded mGluR-LTD induced by synaptic stimulation. Thus, 12( S)-hydroperoxyeicosa-5Z, 8Z, 10E, 14Z-tetraenoic acid ( 12( S)-HPETE), a 12- lipoxygenase metabolite of arachidonic acid, satisfies all of the criteria of a messenger molecule that is actively recruited for the induction of mGluR-LTD.