Murphy D D, Segal M
Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1482-7. doi: 10.1073/pnas.94.4.1482.
While evidence has accumulated in favor of cAMP-associated genomic involvement in long-term synaptic plasticity, the mechanisms downstream of the activated nucleus that underlie these changes in neuronal function remain mostly unknown. Dendritic spines, the locus of excitatory interaction among central neurons, are prime candidates for long-term synaptic modifications. We now present evidence that links phosphorylation of the cAMP response element binding protein (CREB) to formation of new spines; exposure to estradiol doubles the density of dendritic spines in cultured hippocampal neurons, and concomitantly causes a large increase in phosphorylated CREB and in CREB binding protein. Blockade of cAMP-regulated protein kinase A eliminates estradiol-evoked spine formation, as well as the CREB and CREB binding protein responses. A specific antisense oligonucleotide eliminates the phosphorylated CREB response to estradiol as well as the formation of new dendritic spines. These results indicate that CREB phosphorylation is a necessary step in the process leading to generation of new dendritic spines.
尽管已有越来越多的证据支持环磷酸腺苷（cAMP）相关的基因组参与长期突触可塑性，但激活的细胞核下游导致神经元功能这些变化的机制仍大多未知。树突棘是中枢神经元之间兴奋性相互作用的位点，是长期突触修饰的主要候选对象。我们现在提供的证据表明，环磷酸腺苷反应元件结合蛋白（CREB）的磷酸化与新棘突的形成有关；暴露于雌二醇会使培养的海马神经元中树突棘的密度增加一倍，并同时导致磷酸化CREB和CREB结合蛋白大幅增加。阻断cAMP调节的蛋白激酶A可消除雌二醇诱发的棘突形成，以及CREB和CREB结合蛋白反应。一种特异性反义寡核苷酸可消除磷酸化CREB对雌二醇的反应以及新树突棘的形成。这些结果表明，CREB磷酸化是导致新树突棘产生过程中的必要步骤。
