title: 12-lipoxygenase metabolites of arachidonic acid mediate metabotropic glutamate receptor-dependent long-term depression at hippocampal CA3-CA1 synapses.
abstract: 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.
authors.affiliation: Department of Pharmacology, Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, USA. sjf1@columbia.edu
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Feinmark
authors.forename: Roxana
authors.initials: R
authors.lastname: Begum
authors.forename: Evgeny
authors.initials: E
authors.lastname: Tsvetkov
authors.forename: Ivan
authors.initials: I
authors.lastname: Goussakov
authors.forename: Colin D
authors.initials: CD
authors.lastname: Funk
authors.forename: Steven A
authors.initials: SA
authors.lastname: Siegelbaum
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Bolshakov
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D005071:Evoked Potentials; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D015289:Leukotrienes / Q000378:metabolism* / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000201:enzymology / Q000502:physiology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013569:Synapses / Q000502:physiology
chemical_list: D015289:Leukotrienes; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016718:Arachidonic Acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C021201:12-HPETE; D001092:Arachidonate 12-Lipoxygenase