Nitric oxide acts directly in the presynaptic neuron to produce long-term potentiation in cultured hippocampal neurons

Cell. 1996 Dec 13;87(6):1025-35. doi: 10.1016/s0092-8674(00)81797-3.


Nitric oxide (NO) has been proposed to act as a retrograde messenger during long-term potentiation (LTP) in the CA1 region of hippocampus, but the inaccessibility of the presynaptic terminal has prevented a definitive test of this hypothesis. Because both sides of the synapse are accessible in cultured hippocampal neurons, we have used this preparation to investigate the role of NO. We examined LTP following intra- or extracellular application of an NO scavenger, an inhibitor of NO synthase, and a membrane-impermeant NO donor that releases NO only upon photolysis with UV light. Our results indicate that NO is produced in the postsynaptic neuron, travels through the extracellular space, and acts directly in the presynaptic neuron to produce long-term potentiation, supporting the hypothesis that NO acts as a retrograde messenger during LTP.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured / enzymology
  • Extracellular Space / metabolism
  • Fluorescent Antibody Technique
  • Hippocampus / cytology*
  • Hippocampus / physiology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Methemoglobin / pharmacology
  • Microinjections
  • Myoglobin / pharmacology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / enzymology*
  • Neurotransmitter Agents / metabolism
  • Nitric Oxide / biosynthesis
  • Nitric Oxide / metabolism
  • Nitric Oxide / pharmacology*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Photolysis
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / enzymology*
  • Rats
  • Rats, Sprague-Dawley
  • Tetanus Toxin / pharmacology
  • Ultraviolet Rays


  • Myoglobin
  • Neurotransmitter Agents
  • Tetanus Toxin
  • oxymyoglobin
  • Nitric Oxide
  • Methemoglobin
  • Nitric Oxide Synthase