SWI/SNF复合体组分ARID1A在海马发育和认知中的调控作用及机制研究

Learning and memory are the most important intellectual functions of the brain. It has been conclusively demonstrated that neurogenesis in the hippocampus is critical for learning and memory. However, the molecular and cellular mechanisms underlying neurogenesis, learning and memory have been remained elusive. Recent studies have shown a link between aberrant SWI/SNF complex and intellectual disability. This proposed project will focus on the functions of one of SWI/SNF complex gene ARID1A (AT rich interactive domain l A) in hippocampus development and neurogenesis and cognition. Our preliminary data show that deletion of ARID1A in the developing brain led to abnormalities of hippocampus structures. In the Morris water maze and barnes maze tests, deletion of ARID1A in the adult hippocampus displayed the lower ability to locate the platform, indicating impaired spatial learning and memory abilities. Based on our data, we will characterize the deficits of neurogenesis, especially neuronal migration, neuronal maturation, underlying the loss of ARID1A in the hippocampus. We will identify key downstream targets of ARID1A that play critical roles in regulating hippocampus development, neuronal migration, neuronal maturation, learning and memory. Finally, we will evaluate the therapeutic potentials of key downstream molecules of ARID1A in treating cognition deficits in ARID1A conditional knockout mice. This project will provide evidences for determining the roles of ARID1A in neuronal maturation, neuronal migration, learning and memory, and also provide clues to therapeutic strategies for treating intelligence disorders.

学习记忆是大脑最基本也是最重要的高级神经功能之一。虽然海马神经发生被认为在调节学习和记忆等认知过程中起着至关重要的作用，但其背后的分子调控机理，尤其表观遗传调控机制尚待深入揭示。近期一些临床数据显示染色质重塑复合物SWI/SNF参与认知的调控，我们前期的工作证实染色质重塑复合物SWI/SNF中的组分ARID1A在大脑中缺失后引起海马发育异常、学习记忆能力下降。因此本课题主要以ARID1A为研究对象，利用条件敲除小鼠模型，分析其在海马发育、神经干细胞增殖与分化、神经元迁移、新生神经元成熟及大脑认知中的功能，寻找其调控海马发育与认知的细胞基础，探索其作用的关键信号通路，并评测关键靶点能否改善由于ARID1A基因缺失引起的认知能力改变的表型。本研究将为染色质重塑复合物SWI/SNF在海马神经发生，海马结构、大脑认知功能中的调控提供充实的理论和实验依据，为治疗认知功能障碍疾病开创新的突破口。

Arid1a, 作为SWI/SNF染色质重塑复合体的组分之一，在癌症中通常发生突变，被认为肿瘤抑制因子。最近，Arid1a基因突变已被证明会导致智力残疾;然而，这一现象的神经生物学机制尚不清楚。我们构建了Arid1a条件敲除小鼠，并研究了Arid1a在中枢神经系统中的功能。我们首次发现，破坏Arid1a在小鼠前脑导致齿状回(DG)内神经干细胞数量的损失，显著增加围产和出生后的细胞凋亡，导致海马体积减小。此外，详细的分析表明，Arid1a对DG区神经祖细胞的维持和有丝分裂后神经元的成熟和存活是必要的。成年小鼠海马中Arid1a的急性缺失或前脑中Arid1a的单倍性不足导致小鼠学习记忆功能障碍。转录组分析数据显示，ARID1A调控多个基因，包括Prox1参与调节DG神经元成熟。过表达下游靶点之一Prox1可修复神经元形态缺陷和记忆损伤。总的来说，我们的研究结果证明了Arid1a在海马体发育中的关键作用，也可能为智力障碍(如Coffin-Siris综合征)的遗传基础提供了新见解。