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Cyclin D1 induction preceding neuronal death via the excitotoxic NMDA pathway involves selective stimulation of

L Efthimiadi1, M Farso, R Quirion

  • 1Institut de Neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale U901, Marseille, France.

Neuro-Degenerative Diseases
|February 23, 2012
PubMed

Insights

Extrasynaptic N-methyl-D-aspartate receptors (NMDARs) trigger neuronal death by inducing cell cycle re-entry via cyclin D1. Blocking this pathway offers neuroprotection while preserving essential synaptic NMDAR functions.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • N-methyl-D-aspartate receptors (NMDARs) mediate both neuronal survival and excitotoxicity.
  • Synaptic and extrasynaptic NMDAR pools differentially regulate these responses.
  • Extrasynaptic NMDAR activation is predominant and linked to excitotoxic neuronal death.

Purpose of the Study:

  • Identify selective postreceptor effectors of extrasynaptic NMDARs.
  • Investigate the role of cyclin D1 in extrasynaptic NMDAR-mediated excitotoxicity.
  • Determine if targeting cyclin D1 can offer neuroprotection.

Main Methods:

  • Primary cultures of rat hippocampal neurons.
  • Selective NMDAR stimulation.
  • Western blot and immunocytochemistry analyses.
  • Pharmacological blockade and RNA silencing of cyclin D1 and JNK.

Main Results:

  • Extrasynaptic NMDAR activation induces cell cycle re-entry (not beyond S-phase) associated with neuronal death.
  • This process is mediated by c-Jun N-terminal protein kinase (JNK)-induced cyclin D1 expression.
  • Inhibition of JNK or cyclin D1 significantly reduced NMDA-elicited neuronal death.

Conclusions:

  • Cyclin D1 induction is causally linked to extrasynaptic NMDAR-triggered neuronal death.
  • Cyclin D1 is a potential therapeutic target for neuroprotection against excitotoxicity.
  • Targeting cyclin D1 may spare beneficial synaptic NMDAR signaling.

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