Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator

Nature. 1995 Sep 28;377(6547):340-4. doi: 10.1038/377340a0.


Neuronal degeneration in the hippocampus, a region of the brain important for acquisition of memory in humans, occurs in various pathological conditions, including Alzheimer's disease, brain ischaemia and epilepsy. When neuronal activity is stimulated in the adult rat and mouse hippocampus, tissue plasminogen activator (tPA), a serine protease that converts inactive plasminogen to the active protease plasmin, is transcriptionally induced. The activity of tPA in neural tissue is correlated with neurite outgrowth, regeneration and migration, suggesting that it might be involved in neuronal plasticity. Here we show that tPA is produced primarily by microglia in the hippocampus. Using excitotoxins to induce neuronal cell loss, we demonstrate that tPA-deficient mice are resistant to neuronal degeneration. These mice are also less susceptible to pharmacologically induced seizures than wild-type mice. These findings identify a role for tPA in neuronal degeneration and seizure.

Publication types

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

MeSH terms

  • Animals
  • Drug Resistance
  • Excitatory Amino Acid Agonists / pharmacology*
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Kainic Acid / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism
  • Nerve Degeneration / drug effects*
  • Seizures / chemically induced
  • Seizures / metabolism
  • Tissue Plasminogen Activator / deficiency
  • Tissue Plasminogen Activator / genetics
  • Tissue Plasminogen Activator / metabolism*


  • Excitatory Amino Acid Agonists
  • Tissue Plasminogen Activator
  • Kainic Acid