Instituto de Neurociencias de Alicante (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Campus de Sant Joan, 03550 Alicante, Spain.
Cereb Cortex. 2009 Nov;19(11):2535-47. doi: 10.1093/cercor/bhp004. Epub 2009 Feb 12.
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.
环磷酸腺苷反应元件结合蛋白（CREB）通路参与了调节神经元功能的 2 个主要基因表达级联反应。第一个级联反应将 CREB 作为控制神经元可塑性和学习的长时程形式的分子开关的关键组成部分。第二个级联反应与 CREB 相关神经元的存活和保护。为了研究 CREB 依赖性基因表达在体内神经元可塑性和存活中的作用，我们生成了表达 A-CREB 的双转基因小鼠，A-CREB 是一种对 CREB 家族具有强而广泛抑制作用的人工肽，以可调节的方式在大脑前神经元中表达。在海马神经元中表达 A-CREB 会损害 L-LTP，降低内在兴奋性和诱导性癫痫发作的易感性，并改变基础和活性驱动的基因表达。从长远来看，CREB 功能的慢性抑制会导致 CA1 亚区以及其他脑区的神经元严重丢失。我们的实验证实了 CREB 缺失突变体中的先前发现，并揭示了海马体中 CREB 依赖性基因表达的新方面，支持 CREB 依赖性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。
