【作者】 苏岩；

【导师】 赵春杰；

【作者基本信息】 东南大学 ， 生物学， 2019， 博士

【摘要】 智力障碍（Intellectual disability,ID）属于神经发育障碍,其主要临床特征表现为认知能力低下和社会适应功能缺陷。研究表明,智力障碍的病因复杂,具体的发病机制尚不明了。研究报道BRPF1（bromodomain and PHD finger-containing protein 1）与组蛋白乙酰化转移酶形成复合体,调控组蛋白的乙酰化,在表观遗传转录调控中至关重要。临床研究表明,BRPF1剂量不足的患者多表现出智力障碍,提示Brpf1的单倍剂量效应在大脑发育过程中发挥重要调控作用,但目前其具体的调控作用和分子机制并不清晰。在本课题中,我们通过Emx1-cre小鼠与Brpf1^fl/fl小鼠交配后获得Brpf1杂合敲除小鼠,用于模拟BRPF1基因突变的病人。我们发现,Brpf1杂合缺失导致神经元树突复杂性下降,在海马颗粒细胞以及皮层锥体神经元中均观察到此现象。同时我们也发现Brpf1杂合敲除导致神经元树突棘密度下降,形态受损,以及突触形态明显改变受损。电生理的结果显示Brpf1单倍剂量导致神经环路中mEPSCs的频率和幅度都明显下调,小鼠表现出行为上的异常,包括焦虑水平降低,学习和记忆能力的受损。我们的结果提示Brpf1基因的单倍剂量效应在神经元树突分枝、树突棘形态发生过程中发挥重要调控作用,为进一步解析BRPF1基因相关的智力障碍疾病的致病机理提供了新的线索。更多还原

【Abstract】 Intellectual disability is a common neurodevelopmental disorder characterized by impaired intellectual and adaptive functioning.Both environmental insults and genetic defects contribute to the etiology of intellectual disability.Bromodomain and PHD finger-containing protein 1(BRPF1)has been demonstrated to act as a multivalent chromatin reader,forming complexes with histone acetyltransferases,to stimulate acetyltransferase activity.Haploinsufficiency of BRPF1 gene causes intellectual disability(ID),however,the neurological basis for ID and the neurological function of BRPF1 dosage in the brain remain unclear.Here,by crossing Emx1-cre mice with Brpf1~fl/fll/fl mice,we generated Brpf1 heterozygous mice to model BRPF1-related ID.Brpf1 heterozygotes showed reduced dendritic complexity in both hippocampal granule cells and cortical pyramidal neurons,accompanied by reduced spine density and altered spine and synapse morphology.An in vitro study of Brpf1haploinsufficiency also demonstrated decreased frequency and amplitude of miniature EPSCs that may subsequently contribute to abnormal behaviors,including decreased anxiety levels and defective learning and memory.Our results demonstrate a critical role for Brpf1 dosage in neuron dendrite arborization,spine morphogenesis and behavior and provide insight into the pathogenesis of BRPF1-related ID.更多还原