Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain

Neurobiol Dis. 2004 Jul;16(2):440-53. doi: 10.1016/j.nbd.2004.03.013.


The developing rodent brain is vulnerable to pharmacological blockade of N-methyl-d-aspartate (NMDA) receptors which can lead to severe and disseminated apoptotic neurodegeneration. Here, we show that systemic administration of the NMDA receptor antagonist MK801 to 7-day-old rats leads to impaired activity of extracellular signal-regulated kinase 1/2 (ERK1/2) and reduces levels of phosphorylated cAMP-responsive element binding protein (CREB) in brain regions which display severe apoptotic neurodegeneration. Impaired ERK1/2 and CREB activity were temporally paralleled by sustained depletion of neurotrophin expression, particularly brain-derived neurotrophic factor (BDNF). BDNF supplementation fully prevented MK801-induced neurotoxicity in immature neuronal cultures and transgenic constitutive activation of Ras was associated with marked protection against MK801-induced apoptotic neuronal death. These data indicate that uncoupling of NMDA receptors from the ERK1/2-CREB signaling pathway in vivo results in massive apoptotic deletion of neurons in the developing rodent brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Apoptosis / physiology*
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dizocilpine Maleate / pharmacology
  • Down-Regulation / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gene Expression / drug effects
  • Gyrus Cinguli / drug effects
  • Gyrus Cinguli / growth & development*
  • Gyrus Cinguli / pathology*
  • MAP Kinase Signaling System / drug effects
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / pathology*
  • Nerve Growth Factors / genetics
  • Neurons / cytology
  • Neurons / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Messenger / analysis
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Transcription, Genetic / drug effects
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • Cyclic AMP Response Element-Binding Protein
  • Excitatory Amino Acid Antagonists
  • Nerve Growth Factors
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Receptors, N-Methyl-D-Aspartate
  • Dizocilpine Maleate
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • ras Proteins