Inhibition of cAMP Response Element-Binding Protein Reduces Neuronal Excitability and Plasticity, and Triggers Neurodegeneration
Inhibition of cAMP Response Element-Binding Protein Reduces Neuronal Excitability and Plasticity, and Triggers Neurodegeneration
复制标题
DOI：
10.1093/cercor/bhp004
复制
发表时间：
2009-11-01
期刊：
影响因子：
3.7
通讯作者：
Barco, Angel
中科院分区：
文献类型：
--
作者：
Jancic, Dragana;Lopez de Armentia, Mikel;Barco, Angel
cAMP-responsive element-binding protein (CREB) pathway参与了基因表达调控神经元功能的两个主要级联反应。第一篇文章将CREB描述为控制神经元可塑性和学习的长期形式的分子开关的关键组成部分。第二个是将CREB与神经元存活和保护联系起来。为了研究CREB依赖性基因表达在神经元可塑性和体内存活中的作用，我们在前脑神经元中以可调节的方式表达a -CREB，这是一种对CREB家族具有强而广泛抑制作用的人工肽。海马神经元A-CREB的表达损害了L-LTP，降低了内在兴奋性和诱发癫痫的易感性，并改变了基础和活动驱动基因的表达。从长期来看，CREB功能的慢性抑制导致CA1亚区以及其他脑区神经元的严重损失。我们的实验证实了之前在creb缺陷突变体中的发现，并揭示了海马中creb依赖基因表达的新方面，支持creb依赖基因表达调节内在和突触可塑性以及促进神经元存活的双重作用。
The cAMP-responsive element-binding protein (CREB) pathway has been involved in 2 major cascades of gene expression regulating neuronal function. The first one presents CREB as a critical component of the molecular switch that controls long-lasting forms of neuronal plasticity and learning. The second one relates CREB to neuronal survival and protection. To investigate the role of CREB-dependent gene expression in neuronal plasticity and survival in vivo, we generated bitransgenic mice expressing A-CREB, an artificial peptide with strong and broad inhibitory effect on the CREB family, in forebrain neurons in a regulatable manner. The expression of A-CREB in hippocampal neurons impaired L-LTP, reduced intrinsic excitability and the susceptibility to induced seizures, and altered both basal and activity-driven gene expression. In the long-term, the chronic inhibition of CREB function caused severe loss of neurons in the CA1 subfield as well as in other brain regions. Our experiments confirmed previous findings in CREB-deficient mutants and revealed new aspects of CREB-dependent gene expression in the hippocampus supporting a dual role for CREB-dependent gene expression regulating intrinsic and synaptic plasticity and promoting neuronal survival.