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The Journal of Neuroscience, December 10, 2003, 23(36):11427-11435

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Cellular/Molecular
12-Lipoxygenase Metabolites of Arachidonic Acid Mediate Metabotropic Glutamate Receptor-Dependent Long-Term Depression at Hippocampal CA3-CA1 Synapses

Steven J. Feinmark,^1,2 Roxana Begum,¹ Evgeny Tsvetkov,⁵ Ivan Goussakov,⁵ Colin D. Funk,⁴ Steven A. Siegelbaum,^1,3 and Vadim Y. Bolshakov⁵

¹Department of Pharmacology, ²Center for Molecular Therapeutics, and ³Howard Hughes Medical Institute, Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, ⁴Department of Pharmacology, Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ⁵Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478

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.

Key words: hippocampus; synaptic transmission; LTD; 12-lipoxygenase; retrograde messenger; metabotropic glutamate receptors; arachidonic acid

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Received Aug 4, 2003; revised October 21, 2003; accepted October 21, 2003.

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