Long-term potentiation inhibition by low-level N-methyl-D-aspartate receptor activation involves calcineurin, nitric oxide, and p38 mitogen-activated protein kinase

Hippocampus. 2008;18(3):258-65. doi: 10.1002/hipo.20383.


Low-level activation of N-methyl-d-aspartate receptors (NMDARs) results in a decrease in the ability of tetanic stimulation to induce long-term potentiation (LTP). This NMDAR-mediated LTP inhibition is observed with low micromolar concentrations of NMDA or chelation of ambient extracellular zinc. In rat hippocampal slices, we examined whether LTP inhibition by 1 muM NMDA and zinc chelation share common mechanisms. We found that both forms of LTP inhibition involve nitric oxide (NO) synthase (NOS) and calcineurin. Furthermore, both forms of LTP inhibition are overcome by block of p38 mitogen-activated protein kinase (MAPK), but not by inhibition of extracellular signal-regulated kinase 1/2 or c-Jun-N-terminal kinase. A p38 antagonist also overcame the block of LTP by sodium nitroprusside, an agent that releases NO, suggesting that NO release occurs upstream of MAPK activation. Despite the involvement of p38 MAPK in NMDAR-mediated LTP inhibition, p38 antagonism did not enhance LTP induction in response to weak tetanic stimulation under baseline conditions. These results indicate that p38 MAPK is part of a complex NMDAR-driven signaling pathway involving calcineurin and NO that helps to regulate synaptic plasticity in the CA1 region.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Chelating Agents / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • N-Methylaspartate / pharmacology
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Nitric Oxide / metabolism
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase / metabolism
  • Organ Culture Techniques
  • Rats
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Zinc / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Chelating Agents
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Nitric Oxide Donors
  • Receptors, N-Methyl-D-Aspartate
  • Nitric Oxide
  • N-Methylaspartate
  • Nitric Oxide Synthase
  • p38 Mitogen-Activated Protein Kinases
  • Calcineurin
  • Zinc