BHLHB2 ControlsBdnfPromoter 4 Activity and Neuronal Excitability

Authors:
  • FTFeng Tian
    Feng Tian
  • YDYang Du
    Yang Du
  • NCNeal G. Copeland
    Neal G. Copeland
  • NJNancy A. Jenkins
    Nancy A. Jenkins
  • LTLino Tessarollo
    Lino Tessarollo
  • XWXuan Wu
    Xuan Wu
  • HPHongna Pan
    Hongna Pan
  • XHXian-Zhang Hu
    Xian-Zhang Hu
  • KXKe Xu
    Ke Xu
  • HKHeather Kenney
    Heather Kenney
  • SESean E. Egan
    Sean E. Egan
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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 withinBdnfpromoter 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.Bhlhb2gene −/− mice showed increased hippocampal exon 4-specificBdnfmRNA levels compared with +/+ littermates under basal and activity-dependent conditions.Bhlhb2knock-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 ofBdnftranscription and neuronal excitability.

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