title: BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability.
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.
authors.affiliation: Section on Molecular Genetics, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Jiang
authors.forename: Feng
authors.initials: F
authors.lastname: Tian
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Xuan
authors.initials: X
authors.lastname: Wu
authors.forename: Hongna
authors.initials: H
authors.lastname: Pan
authors.forename: Xian-Zhang
authors.initials: XZ
authors.lastname: Hu
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Heather
authors.initials: H
authors.lastname: Kenney
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.forename: Helen
authors.initials: H
authors.lastname: Turley
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Ann M
authors.initials: AM
authors.lastname: Marini
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lipsky
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology*; D051381:Rats
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor; D018398:Homeodomain Proteins; C491539:Bhlhe40 protein, mouse