BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability

Xueying Jiang, Feng Tian, Yang Du, Neal G. Copeland, Nancy A. Jenkins, Lino Tessarollo, Xuan Wu, Hongna Pan, Xian Zhang Hu, Ke Xu, Heather Kenney, Sean E. Egan, Helen Turley, Adrian L. Harris, Ann M. Marini, Robert H. Lipsky

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Brain-derived neurotrophic factor (BDNF), via activation of TrkB receptors, mediates vital physiological functions in the brain, ranging from neuronal survival to synaptic plasticity, and has been implicated in the pathophysiology of neurodegenerative disorders. Although transcriptional regulation of the BDNF gene (Bdnf) has been extensively studied, much remains to be understood. We discovered a sequence within Bdnf promoter 4 that binds the basic helix-loop-helix protein BHLHB2 and is a target for BHLHB2-mediated transcriptional repression. NMDA receptor activation de-repressed promoter 4-mediated transcription and correlated with reduced occupancy of the promoter by BHLHB2 in cultured hippocampal neurons. Bhlhb2 gene -/- mice showed increased hippocampal exon 4-specific Bdnf mRNA levels compared with +/+ littermates under basal and activity-dependent conditions. Bhlhb2 knock-out mice also showed increased status epilepticus susceptibility, suggesting that BHLHB2 alters neuronal excitability. Together, these results support a role for BHLHB2 as a new modulator of Bdnf transcription and neuronal excitability.

Original languageEnglish (US)
Pages (from-to)1118-1130
Number of pages13
JournalJournal of Neuroscience
Volume28
Issue number5
DOIs
StatePublished - Jan 30 2008

Keywords

  • BDNF
  • BHLHB2
  • Brain-derived neurotrophic factor
  • DEC1/Sharp2/Stra13
  • Neuronal excitability
  • Transcription

ASJC Scopus subject areas

  • Neuroscience(all)

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