4-Aminopyridine-induced epileptogenesis depends on activation of mitogen-activated protein kinase ERK

J Neurochem. 2004 May;89(3):654-9. doi: 10.1111/j.1471-4159.2004.02382.x.


Extracellular signal-regulated kinases such as ERK1 [p44 mitogen-activated protein kinase (MAPK)] and ERK2 (p42 MAPK) are activated in the CNS under physiological and pathological conditions such as ischemia and epilepsy. Here, we studied the activation state of ERK1/2 in rat hippocampal slices during application of the K(+) channel blocker 4-aminopyridine (4AP, 50 micro m), a procedure that enhances synaptic transmission and leads to the appearance of epileptiform activity. Hippocampal slices superfused with 4AP-containing medium exhibited a marked activation of ERK1/2 phosphorylation that peaked within about 20 min. These effects were not accompanied by changes in the activation state of c-Jun N-terminal kinase (JNK), another member of the MAP kinase superfamily. 4AP-induced ERK1/2 activation was inhibited by the voltage-gated Na(+) channel blocker tetrodotoxin (1 micro m). We also found that application of the ERK pathway inhibitors U0126 (50 micro m) or PD98059 (100 micro m) markedly reduced 4AP-induced epileptiform synchronization, thus abolishing ictal discharges in the CA3 area. The effects induced by U0126 or PD98059 were not associated with changes in the amplitude and latency of the field potentials recorded in the CA3 area following electrical stimuli delivered in the dentate hylus. These data demonstrate that activation of ERK1/2 accompanies the appearance of epileptiform activity induced by 4AP and suggest a cause-effect relationship between the ERK pathway and epileptiform synchronization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / pharmacology*
  • Animals
  • Electric Stimulation
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Epilepsy / chemically induced*
  • Epilepsy / enzymology*
  • Hippocampus / drug effects
  • Hippocampus / physiopathology*
  • In Vitro Techniques
  • Membrane Potentials / drug effects
  • Mitogen-Activated Protein Kinase 1 / drug effects
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Potassium Channel Blockers / pharmacology
  • Rats
  • Rats, Wistar
  • Sodium Channel Blockers / pharmacology


  • Enzyme Inhibitors
  • Potassium Channel Blockers
  • Sodium Channel Blockers
  • 4-Aminopyridine
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases