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Inhibitors of either NO synthase or heme oxygenase, the enzyme that produces CO, blocked induction of LTP in the CA1 region of hippocampal slices. Brief application of either NO or CO to slices produced a rapid and long\u2010lasting increase in the size of synaptic potentials if, and only if, the application occurred at the same time as weak tetanic stimulation of the presynaptic fibers. The long\u2010term enhancement by NO or CO was spatially restricted to synapses from active presynaptic fibers and appeared to involve mechanisms utilized by LTP, occluding the subsequent induction of LTP by strong tetanic stimulation. The enhancement by No or CO was not blocked by the NMDA receptor blocker APV, suggesting that NO and CO act downstream for the NMDA receptor. In other systems, both NO and CO produce many of their effects by activation of soluble guanylyl cyclase nd cGMP\u2010dependent protein kinase. An inhibitor of soluble guabylyl cyclase blocked the induction of normal LTP. Conversely, membrane\u2010permeabel analog 8\u2010Br\u2010cGMP produced a rapid onset and long\u2010lasting synaptic enhancement if, and only if, it was applied at the same time as weak presynaptic stimulation. Similarly, two inhibitors of cGMP\u2010dependent protein kinase blocked the induction of normal LTP, and a selective activator of cGMP\u2010dependent protein kinase produced activity\u2010dependent long\u2010lasting synaptic enhancement. 8\u2010Br\u2010cGMP also produced and activity\u2010dependent, long\u2010lasting increase in the amplitude of evoked synaptic current between pairs of hippocampal neurons in dissociated cell culture. In addition, 8\u2010Br\u2010cGMP, like NO, produced a long\u2010lasting increase in the frequency of spontaneous miniature synaptic currents. These results are consistent with the hypothesis that NO and CO, either alone or in combination, serve as retrograde messengers that produce activity\u2010dependent presynaptic enhancement, perhaps by stimulating soluble guanbylyl cyclase and cGMP\u2010dependent protein kinase, during LTP in hippocampus. 1994 John Wiley &amp; Sons, Inc.<\/jats:p>","DOI":"10.1002\/neu.480250607","type":"journal-article","created":{"date-parts":[[2005,5,27]],"date-time":"2005-05-27T22:13:20Z","timestamp":1117232000000},"page":"652-665","source":"Crossref","is-referenced-by-count":107,"title":["Nitric oxide and carbon monoxide as possible retrograde messengers in hgippocampal long\u2010term potentiation"],"prefix":"10.1002","volume":"25","author":[{"given":"R. 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