Brain-derived neurotrophic factor uses CREB and Egr3 to regulate NMDA receptor levels in cortical neurons.
Regulation of gene expression via brain-derived neurotrophic factor (BDNF) is critical to the development of the nervous system and may well underlie cognitive performance throughout life. We now describe a mechanism by which BDNF can exert its effects on postsynaptic receptor populations that may have relevance to both the normal and diseased brain where BDNF levels either rise or fall in association with changes in excitatory neurotransmission. Increased levels of NMDA receptors (NMDARs) occur in rat cortical neurons via synthesis of new NMDA receptor 1 (NR1) subunits. The majority of synthesis is controlled by binding of cAMP response element binding protein (CREB) and early growth response factor 3 (Egr3) to the core NR1 promoter (NR1-p) region. BDNF-mediated NR1 transcription depends upon induction of the mitogen-activated protein kinase (MAPK) pathway through activation of the TrK-B receptor. Taken together with the fact that NMDAR activation stimulates BDNF synthesis, our results uncover a feed-forward gene regulatory network that may enhance excitatory neurotransmission to change neuronal behavior over time.
Laboratory of Translational Epilepsy, Boston University School of Medicine, Boston, Massachusetts, USA.
Julia H
JH
Kim
Daniel S
DS
Roberts
Yinghui
Y
Hu
Garrick C
GC
Lau
Amy R
AR
Brooks-Kayal
David H
DH
Farb
Shelley J
SJ
Russek
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D016335:Zinc Fingers / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C486376:KCNH7 protein, human; D008164:Luminescent Proteins; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C413663:fluorescent protein 583; D012694:Serine; D050882:CREB-Binding Protein; D020813:Receptor, trkB; D020930:MAP Kinase Kinase Kinases; D013755:Tetradecanoylphorbol Acetate