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The Journal of Neuroscience, January 30, 2008, 28(5):1118-1130; doi:10.1523/JNEUROSCI.2262-07.2008

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Cellular/Molecular
BHLHB2 Controls Bdnf Promoter 4 Activity and Neuronal Excitability

Xueying Jiang,¹ Feng Tian,¹ Yang Du,³ Neal G. Copeland,³ Nancy A. Jenkins,³ Lino Tessarollo,³ Xuan Wu,⁴ Hongna Pan,⁴ Xian-Zhang Hu,¹ Ke Xu,² Heather Kenney,¹ Sean E. Egan,^5,6 Helen Turley,⁷ Adrian L. Harris,⁷ Ann M. Marini,⁴ and Robert H. Lipsky¹

¹Section on Molecular Genetics, ²Section on Human Genetics, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, ³Mouse Cancer Genetics Program, National Cancer Institute, Center for Cancer Research, Frederick, Maryland 21702, ⁴Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, ⁵Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8, ⁶Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and ⁷Laboratory of Molecular Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom

Correspondence should be addressed to Robert H. Lipsky, 5625 Fishers Lane, Room 3S32, MSC 9412, Bethesda, MD 20892-9412. Email: rlipsky{at}mail.nih.gov

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.

Key words: brain-derived neurotrophic factor; BDNF; neuronal excitability; BHLHB2; DEC1/Sharp2/Stra13; transcription

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Received May 17, 2007; revised Nov. 15, 2007; accepted Dec. 10, 2007.

Correspondence should be addressed to Robert H. Lipsky, 5625 Fishers Lane, Room 3S32, MSC 9412, Bethesda, MD 20892-9412. Email: rlipsky{at}mail.nih.gov

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