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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
Author(s) -
Zhou Xianju,
Moon Changjong,
Zheng Fei,
Luo Yongneng,
Soellner Deborah,
Nuñez Joseph L.,
Wang Hongbing
Publication year - 2009
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22103
Subject(s) - creb , nmda receptor , dephosphorylation , microbiology and biotechnology , synaptic plasticity , biology , neuroplasticity , phosphorylation , mapk/erk pathway , calcium signaling , depolarization , signal transduction , neuroscience , chemistry , transcription factor , receptor , endocrinology , biochemistry , phosphatase , gene
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. © 2009 Wiley‐Liss, Inc.