CBP is required for environmental enrichment-induced neurogenesis and cognitive enhancement

The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CBP, a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioral adaptations to environmental enrichment (EE). Morphological and behavioral analyses demonstrated that EE ameliorates deficits associated to CBP-deficiency. However, CBP-deficient mice also showed a strong defect in environment-induced neurogenesis and impaired EE-enhanced spatial navigation and patter separation ability. These defects correlated with an attenuation of the transcriptional program induced in response to EE and with deficits in histone acetylation at the promoters of EE-regulated, neurogenesis-related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment-induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics. To identify those genes whose expression was altered in the hippocampus of cbp heterozygous mice both under basal conditions and after 2 weeks of exposure to environmental enrichment, we performed a gene profiling analysis of hippocampal tissue using high-density oligonucleotide microarrays. We obtained quintuplicate (standard housing) and triplicate (environmental enrichment) samples containing total RNA from the hippocampi of four 3-month old females of either genotype (in total 32 cbp+/- mice and 32 wild type littermates were used in the experiment).染色质的表观遗传改变（epigenetic changes）是适应外界环境的理想分子底物。本研究探讨了CBP——一种与智力障碍相关的组蛋白乙酰转移酶（histone acetyltransferase）——在环境丰富化（Environmental Enrichment, EE）诱导的长期系统性与行为适应性的发生与维持过程中的作用。形态学与行为学分析结果显示，环境丰富化可改善CBP缺陷相关的功能缺损。然而，CBP缺陷小鼠同时表现出严重的环境诱导成年神经发生（adult neurogenesis）缺陷，且EE增强的空间导航与模式分离能力也出现受损。上述缺损与EE诱导的转录程序减弱、EE调控的神经发生相关基因启动子（promoters）处的组蛋白乙酰化（histone acetylation）水平降低密切相关。针对CBP限制性与诱导性基因敲除小鼠（knockout mice）的补充实验表明，环境诱导的成年神经发生由成熟颗粒细胞中的CBP功能进行外源调控。综上，本研究证实外界环境可通过作用于表观基因组修饰相关的活性来改变基因表达，并确定依赖CBP的转录神经适应是EE诱导益处的重要介导因子，这一发现对智力障碍治疗具有重要的借鉴意义。为鉴定在基础条件与环境丰富化暴露2周后，cbp杂合小鼠海马体（hippocampus）内表达发生改变的基因，我们采用高密度寡核苷酸微阵列（oligonucleotide microarrays）对海马组织进行了基因表达谱分析。我们获取了标准饲养组的5份重复样本与环境丰富化组的3份重复样本，每份样本均提取自两种基因型各4只3月龄雌性同窝仔鼠的海马总RNA（total RNA）；本实验共使用32只cbp+/-小鼠与32只野生型同窝仔鼠（wild type littermates）。