On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus

Perfusion of hippocampal slices with an inhibitor of nitric oxide (NO) synt hase-blocked induction of long-term potentiation (LTP) produced by a one-tr ain tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP b y either a two-train or four-train tetanus. These results suggest that NO a nd CO are both involved in LTP but may play somewhat different roles. One p ossibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are ph asically activated under somewhat different circumstances, perhaps involvin g different receptors and second messengers. Because NO is known to be acti vated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic gluta mate receptors (mGluRs). Consistent with this idea, long-lasting potentiati on by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase b ut not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent pr otein kinase, and guanylyl cyclase was activated, by tACPD in hippocampal s lices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated b y either tetanus or tACPD. These results are most consistent with the possi bility that constitutive (tonic) rather than stimulated (phasic) heme oxyge nase activity is necessary for potentiation by tetanus or tACPD, and sugges t that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.