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. N-methyl-D-aspartate (NMDA) receptor activation derepressed 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 to +/+ littermates under basal and activity-dependent conditions. Bhlhb2 knockout 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Intramural Research (Z01)
Project #
1Z01AA000326-05
Application #
7732119
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2008
Total Cost
$229,939
Indirect Cost

  Institution

Name
National Institute on Alcohol Abuse and Alcoholism
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Tian, Feng; Marini, Ann M; Lipsky, Robert H (2010) NMDA receptor activation induces differential epigenetic modification of Bdnf promoters in hippocampal neurons. Amino Acids 38:1067-74
Jiang, Xueying; Tian, Feng; Du, Yang et al. (2008) BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability. J Neurosci 28:1118-30
Lekman, Magnus; Laje, Gonzalo; Charney, Dennis et al. (2008) The FKBP5-gene in depression and treatment response--an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Cohort. Biol Psychiatry 63:1103-10
Xu, K; Anderson, T R; Neyer, K M et al. (2007) Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence. Pharmacogenomics J 7:368-79
Hu, Xian-Zhang; Rush, A John; Charney, Dennis et al. (2007) Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry 64:783-92
Oroszi, G; Lapteva, L; Davis, E et al. (2006) The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus. Ann Rheum Dis 65:1330-5
McMahon, Francis J; Buervenich, Silvia; Charney, Dennis et al. (2006) Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 78:804-14
Hu, Xian-Zhang; Lipsky, Robert H; Zhu, Guanshan et al. (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 78:815-26
Jiang, Xueying; Xu, Ke; Hoberman, Joelle et al. (2005) BDNF variation and mood disorders: a novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects. Neuropsychopharmacology 30:1353-61
Wu, Xuan; Jiang, Xueying; Marini, Ann M et al. (2005) Delineating and understanding cerebellar neuroprotective pathways: potential implication for protecting the cortex. Ann N Y Acad Sci 1053:39-47

Showing the most recent 10 out of 13 publications