Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus.
Long-term potentiation (LTP) in the hippocampus has an early phase (E-LTP) that can be induced by one- or two-train tetanization, lasts approximately 1 hr, and is cAMP-dependent protein kinase (PKA) and protein synthesis independent and a late phase (L-LTP) that can be induced by three- or four-train tetanization, lasts >3 hr, and is reduced by inhibitors of PKA and of protein or RNA synthesis. Nitric oxide (NO) is thought to be involved in E-LTP, but until now there has been no information about the role of the NO-signaling pathway in L-LTP. We examined this question at the Schaffer collateral-CA1 synapses in slices of mouse hippocampus. An inhibitor of NO synthase blocked L-LTP induced by three-train tetanization and reduced L-LTP induced by four-train tetanization, whereas an inhibitor of PKA was more effective in blocking four-train L-LTP than three-train L-LTP. Three-train L-LTP was also blocked by inhibitors of guanylyl cyclase or cGMP-dependent protein kinase (PKG). Conversely, either NO or cGMP analogs paired with one-train tetanization produced late-phase potentiation, and the cGMP-induced potentiation was blocked by inhibitors of protein or RNA synthesis and an inhibitor of PKG, but not by an inhibitor of PKA. To test a possible downstream target of PKG, we examined changes in phospho-CRE-binding protein (phospho-CREB) immunofluorescence in the CA1 cell body area and obtained results similar to those of the electrophysiology experiments. These results suggest that NO contributes to L-LTP by stimulating guanylyl cyclase and cGMP-dependent protein kinase, which acts in parallel with PKA to increase phosphorylation of the transcription factor CREB.
Lu
Y F
YF
Center for Neurobiology, College of Physicians and Surgeons, Columbia University, New York, USA.
Kandel
E R
ER
Hawkins
R D
RD
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases; D006624:Hippocampus / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009569:Nitric Oxide / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology; D012313:RNA / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D012313:RNA; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP