12-Lipoxygenase Regulates Hippocampal Long-Term Potentiation by Modulating L-Type Ca2+ Channels

Although long-term potentiation (LTP) has been intensively studied, there is disagreement as to which molecules mediate and modulate LTP. This is partly attributable to the presence of mechanistically distinct forms of LTP that are induced by different patterns of stimulation and that depend on distinct Ca2+ sources. Here, we report a novel role for the arachidonic acid-metabolizing enzyme 12-lipoxygenase (12-LO) in LTP at CA3-CA1 hippocampal synapses that is dependent on the pattern of tetanic stimulation. We find that 12-LO activity is required for the induction of LTP in response to a theta burst stimulation protocol that depends on Ca2+ influx through both NMDA receptors and L-type voltage-gated Ca2+ channels. In contrast, LTP induced by 100 Hz tetanic stimulation, which requires Ca2+ influx through NMDA receptors but not L-type channels, does not require 12-LO. We find that 12-LO regulates LTP by enhancing postsynaptic somatodendritic Ca2+ influx through L-type channels during theta burst stimulation, an action exerted via 12(S)-HPETE [12(S)-hydroperoxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid], a downstream metabolite of 12-LO. These results help define the role of a long-disputed signaling enzyme in LTP.