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- Title
12-Lipoxygenase Metabolites of Arachidonic Acid Mediate Metabotropic Glutamate Receptor-Dependent Long-Term Depression at Hippocampal CA3-CA1 Synapses.
- Authors
Feinmark, Steven J.; Begum, Roxana; Tsvetkov, Evgeny; Goussakov, Ivan; Funk, Colin D.; Siegelbaum, Steven A.; Bolshakov, Vadim Y.
- 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.
- Subjects
ARACHIDONIC acid; NERVE endings; NEURAL transmission; LIPOXYGENASES; SYNAPSES
- Publication
Journal of Neuroscience, 2003, Vol 23, Issue 36, p11427
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.23-36-11427.2003