CBP is required for establishing adaptive gene programs in the adult brain [p300]

We investigated the impact in transcription, chromatin acetylation and behavior of eliminating either CBP or p300 in excitatory neurons of the adult forebrain. The elimination of CBP reduced the expression of plasticity genes. The importance of CBP became more prominent in paradigms that involved a chronic or recurrent change in transcription, including kindling and neuroadaptation to environmental enrichment, in which CBP loss interfered with the establishment of activity-induced transcriptional and epigenetic adaptive changes in response to stimulus or experience. Comparative analyses in mice lacking CBP’s paralog p300 underscored the specificity of CBP function. Total RNA from hippocampi from 3- to 6-month-old mice. The recombination of floxed alleles was induced by 5 intragastrical administrations of tamoxifen (Sigma Aldrich, 20 mg/mL dissolved in corn oil) on alternate days (Fiorenza et al., 2016). In all our experiments with ifKOs, we used CaMKIIα-creERT2- littermates treated with tamoxifen as controls.

本研究探究了在成年前脑兴奋性神经元中敲除CBP或p300对转录 (transcription)、染色质乙酰化 (chromatin acetylation) 以及行为表型的影响。敲除CBP会降低可塑性相关基因的表达水平。在涉及慢性或反复性转录改变的实验范式（包括点燃模型与环境富集诱导的神经适应）中，CBP的重要性更为凸显：此时CBP缺失会干扰由神经元活动诱导的、响应外界刺激或个体经历的转录与表观遗传 (epigenetic) 适应性改变的建立过程。对CBP的旁系同源基因p300敲除小鼠开展的对比分析，进一步证实了CBP功能的特异性。本实验所用样本为3至6月龄小鼠的海马体总RNA。通过隔日灌胃给予他莫昔芬 (tamoxifen，西格玛奥德里奇，Sigma Aldrich，20 mg/mL，溶于玉米油) 共5次，可诱导两侧带有loxP位点的等位基因 (floxed alleles) 发生重组（Fiorenza等，2016）。在所有诱导型敲除实验中，我们均以经他莫昔芬处理的CaMKIIα-creERT2同窝小鼠作为对照。