CREB Family Transcription Factors Are Major Mediators of BDNF Transcriptional Autoregulation in Cortical Neurons

J Neurosci. 2020 Feb 12;40(7):1405-1426. doi: 10.1523/JNEUROSCI.0367-19.2019. Epub 2020 Jan 8.


BDNF signaling via its transmembrane receptor TrkB has an important role in neuronal survival, differentiation, and synaptic plasticity. Remarkably, BDNF is capable of modulating its own expression levels in neurons, forming a transcriptional positive feedback loop. In the current study, we have investigated this phenomenon in primary cultures of rat cortical neurons using overexpression of dominant-negative forms of several transcription factors, including CREB, ATF2, C/EBP, USF, and NFAT. We show that CREB family transcription factors, together with the coactivator CBP/p300, but not the CRTC family, are the main regulators of rat BDNF gene expression after TrkB signaling. CREB family transcription factors are required for the early induction of all the major BDNF transcripts, whereas CREB itself directly binds only to BDNF promoter IV, is phosphorylated in response to BDNF-TrkB signaling, and activates transcription from BDNF promoter IV by recruiting CBP. Our complementary reporter assays with BDNF promoter constructs indicate that the regulation of BDNF by CREB family after BDNF-TrkB signaling is generally conserved between rat and human. However, we demonstrate that a nonconserved functional cAMP-responsive element in BDNF promoter IXa in humans renders the human promoter responsive to BDNF-TrkB-CREB signaling, whereas the rat ortholog is unresponsive. Finally, we show that extensive BDNF transcriptional autoregulation, encompassing all major BDNF transcripts, occurs also in vivo in the adult rat hippocampus during BDNF-induced LTP. Collectively, these results improve the understanding of the intricate mechanism of BDNF transcriptional autoregulation.SIGNIFICANCE STATEMENT Deeper understanding of stimulus-specific regulation of BDNF gene expression is essential to precisely adjust BDNF levels that are dysregulated in various neurological disorders. Here, we have elucidated the molecular mechanisms behind TrkB signaling-dependent BDNF mRNA induction and show that CREB family transcription factors are the main regulators of BDNF gene expression after TrkB signaling. Our results suggest that BDNF-TrkB signaling may induce BDNF gene expression in a distinct manner compared with neuronal activity. Moreover, our data suggest the existence of a stimulus-specific distal enhancer modulating BDNF gene expression.

Keywords: BDNF; CBP; CREB; TrkB; positive feedback loop; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / physiology*
  • Brain-Derived Neurotrophic Factor / biosynthesis
  • Brain-Derived Neurotrophic Factor / genetics*
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Cerebral Cortex / metabolism
  • Cyclic AMP Response Element-Binding Protein / physiology
  • Cytoskeletal Proteins / biosynthesis
  • Cytoskeletal Proteins / genetics
  • Feedback, Physiological
  • Female
  • Gene Expression Regulation / genetics*
  • Genes, Dominant
  • Genes, Reporter
  • Genes, Synthetic
  • Hippocampus / cytology*
  • Hippocampus / metabolism
  • MAP Kinase Signaling System / physiology
  • Male
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Neurons / metabolism*
  • Promoter Regions, Genetic
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, trkB / physiology
  • Recombinant Proteins / pharmacology
  • Response Elements
  • Signal Transduction / physiology*
  • Species Specificity
  • Transcription, Genetic / genetics*
  • Transduction, Genetic


  • Basic-Leucine Zipper Transcription Factors
  • Bdnf protein, rat
  • Brain-Derived Neurotrophic Factor
  • CREB1 protein, rat
  • Cyclic AMP Response Element-Binding Protein
  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • Protein Kinase Inhibitors
  • Recombinant Proteins
  • activity regulated cytoskeletal-associated protein
  • BDNF protein, human
  • Ntrk2 protein, rat
  • Receptor, trkB