title: Cyclin D1 induction preceding neuronal death via the excitotoxic NMDA pathway involves selective stimulation of extrasynaptic NMDA receptors and JNK pathway.
abstract: The N-methyl-D-aspartate subtype of ionotropic glutamate receptors (NMDARs) signals both prosurvival and death-inducing (excitotoxic) neuronal responses via synaptically (synaptic NMDAR) and extrasynaptically (extrasynaptic NMDAR) located receptor pools, respectively. Both receptor pools share similar, though not identical, postreceptor signaling molecules. The activation of the extrasynaptic NMDAR pathway is predominant. Therefore, in order to inhibit the extrasynaptic death pathway while sparing synaptic responses, it is critical to identify selective postreceptor effectors of extrasynaptic NMDARs. The present study addressed these issues by using primary cultures of rat hippocampal neurons and a pharmacological protocol of selective NMDAR stimulation for Western blot and immunocytochemistry analyses. We found that the activation of extrasynaptic NMDARs, either alone or together with synaptic NMDARs, triggers cyclin-D1-associated re-entry into the cell cycle, which does not proceed beyond the S-phase. This aberrant cell cycle re-entry is particularly associated with neuronal death triggered specifically via extrasynaptic NMDAR-induced c-Jun N-terminal protein kinase (JNK). In addition, NMDA-elicited neuronal death was significantly inhibited by pharmacological blockade of JNK-mediated cyclin D1 expression or by silencing cyclin D1 RNA. Taken together, these data suggest a causal relationship between cyclin D1 induction and extrasynaptic NMDAR-triggered neuronal death along the excitotoxic NMDA pathway. Therefore, cyclin D1 may be a putative target for the development of neuroprotective strategies sparing physiological synaptic NMDAR signaling.
authors.affiliation: Institut de Neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale U901, Marseille, France.
authors.forename: L
authors.initials: L
authors.lastname: Efthimiadi
authors.forename: M
authors.initials: M
authors.lastname: Farso
authors.forename: R
authors.initials: R
authors.lastname: Quirion
authors.forename: S
authors.initials: S
authors.lastname: Krantic
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D002452:Cell Count; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D019394:Ki-67 Antigen / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: D000873:Anthracenes; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D019938:Cyclin D1; C432165:pyrazolanthrone; D016202:N-Methylaspartate