Molecular Genetics of Brain Derived Neurotrophic Factor (BDNF)

脑源性神经营养因子（BDNF）通过激活TrkB受体介导脑中从神经元存活到突触可塑性的重要生理功能，并且已经涉及神经退行性疾病的病理生理学。 虽然BDNF基因（BDNF）的转录调控已被广泛研究，但仍有许多有待了解。 我们在Bdnf启动子4中发现了一个序列，该序列与碱性螺旋-环-螺旋蛋白BHLHB 2结合，并且是BHLHB 2介导的转录抑制的靶标。 N-甲基-D-天冬氨酸（NMDA）受体激活去抑制启动子4介导的转录，并与BHLHB 2在培养的海马神经元中的启动子占用减少相关。Bhlhb 2基因-/-小鼠表现出增加海马外显子4特异性BDNF mRNA水平相比，+/+同窝出生的基础和活动依赖性条件。 BHLHB 2基因敲除小鼠也表现出癫痫持续状态易感性增加，表明BHLHB 2改变神经元兴奋性。总之，这些结果支持BHLHB 2作为BDNF转录和神经元兴奋性的新调节剂的作用。

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.