title: N-methyl-D-aspartate-stimulated ERK1/2 signaling and the transcriptional up-regulation of plasticity-related genes are developmentally regulated following in vitro neuronal maturation.
abstract: The general features of neuroplasticity are developmentally regulated. Although it has been hypothesized that the loss of plasticity in mature neurons may be due to synaptic saturation and functional reduction of N-methyl-D-aspartate receptors (NMDAR), the molecular mechanisms remain largely unknown. We examined the effects of NMDAR activation and KCl-mediated membrane depolarization on ERK1/2 signaling following in vitro maturation of cultured cortical neurons. Although NMDA stimulated a robust increase in intracellular calcium at both DIV (day in vitro) 3 and 14, the activation of ERK1/2 and cAMP responsive element-binding protein (CREB) was impaired at DIV 14. Specifically, the phosphorylation of ERK1/2 was stimulated by both NMDA and KCl at DIV 3. However, at DIV 14, NMDA- but not KCl-stimulated ERK1/2 and CREB phosphorylation was significantly diminished. Consistently, the NMDA-induced transcription of ERK/CREB-regulated genes Bdnf exon 4, Arc, and zif268 was significantly attenuated at DIV 14. Moreover, in comparison with 3 DIV neurons, the phosphorylated-ERK1/2 in 14 DIV neurons displayed a tremendous increase following maturation and was more susceptible to dephosphorylation. Blocking calcium channels by nifedipine or NMDAR by APV caused a more dramatic ERK dephosphorylation in 14 DIV neurons. We further demonstrate that the loss of plasticity-related signaling is unrelated to NMDA-induced cell death of the 14 DIV neurons. Taken together, these results suggest that the attenuation of certain aspects of neuroplasticity following maturation may be due to the reduction of NMDAR-mediated gene transcription and a saturation of ERK1/2 activity.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Xianju
authors.initials: X
authors.lastname: Zhou
authors.forename: Changjong
authors.initials: C
authors.lastname: Moon
authors.forename: Fei
authors.initials: F
authors.lastname: Zheng
authors.forename: Yongneng
authors.initials: Y
authors.lastname: Luo
authors.forename: Deborah
authors.initials: D
authors.lastname: Soellner
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Nuñez
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000254:growth & development; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D017362:Cyclic AMP Response Element-Binding Protein; D016194:Receptors, N-Methyl-D-Aspartate; D048052:Mitogen-Activated Protein Kinase 3