On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus (vol 5, pg 467, 1998)

Perfusion of hippocampal slices with an inhibitor nitric oxide (NO) synthas e blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only sli ghtly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, th e synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by e ither a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One poss ibility is that NO serves a phasic, signaling role, whereas CO provides ton ic, background stimulation. Another possibility is that NO and CO are phasi cally activated under somewhat different circumstances, perhaps involving d ifferent receptors and second messengers. Because NO is known to be activat ed by stimulation of NMDA receptors during tetanus, we investigated the pos sibility that CO might be activated by stimulation of metabotropic glutamat e receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of so luble guanylyl cyclase Ca target of both NO and CO) or cGMP-dependent prote in kinase, and guanylyl cyclase was activated by tACPD in hippocampal slice s. However, biochemical assays indicate that whereas heme oxygenase is cons titutively active in hippocampus, it does not appear to be stimulated by ei ther tetanus or tACPD. These results are most consistent with the possibili ty that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest th at mGluR activation stimulates guanylyl cyclase phasically through some oth er pathway.