基于NIPBL基因剔除致Cornelia de Lange综合征的认知障碍机制研究

Cornelia de Lange syndrome (CdLS) is a genetic disease with severe cognitive impairment. The mutation in the NIPBL gene is the cause of CdLS in autosomal dominant patients, which leads to an abnormal gene expression. However, the neurobiological mechanism of NIPBL is still unclear. In a NIPBL gene knockout mouse model established in our previous study, we found decreased expressions of synapses and NR2 subunit of the N-methyl-D-aspartate (NMDA) receptor, and lowered in learning and memory abilities. NMDA and alpha-amino-3-hydroxy-5-methyl-4-oxazole propionic acid (AMPA) receptors of glutamate considered to play an crucial role in the formation and maintnance of synapses and long-term potentiation (LTP), which is the structural and electrophysiological basis of cognitive function. Herein, we plan to clarify the effects and mechanisms of NIPBL gene on cognitive impairment in CdLS by investigating the role of the NIPBL gene on synaptic remodeling, LTP formation, as well as NMDA receptors expression and function using animal models, molecular biology, electrophysiology, and behavioral methods. It will help us to understand the neurobiological function of the NIPBL gene and the CdLS pathogenesis, also provides new insights into the diagnosis and intervention of CdLS.

Cornelia de Lange综合征(CdLS)是一种伴有严重认知障碍的遗传病，NIPBL基因是其常染色体显性遗传病例的致病基因，其突变导致调控基因的表达异常。然而NIPBL导致CdLS认知障碍的神经生物学机制并不清楚。通过对项目组前期建立的NIPBL基因剔除小鼠模型的研究,发现NIPBL基因剔除小鼠海马突触减少、谷氨酸NMDA受体NR2亚基表达下降，及学习记忆功能低下。谷氨酸NMDA和AMPA受体被认为与突触和长时程效应（LTP）形成和维持密切相关，是认知的结构和电生理基础。本课题拟在前期研究基础上，综合动物模型、分子生物学、电生理学和行为学等方法，通过研究NIPBL基因对突触重塑和LTP形成和NMDA受体表达和功能，及学习记忆的影响，阐明NIPBL基因在CdLS认知障碍中的作用和可能机制。这有助于了解NIPBL基因的神经生物学功能及CdLS发病机制，为其诊疗提供新策略。

NIPBL中的突变与Cornelia de Lange综合征的大多数和最严重的表现相关联，Cornelia de Lange综合征是包括智力障碍和癫痫发作在内的几种神经缺陷的发育障碍。除了其负载粘附素到染色体上的作用之外，NIPBL还被证明涉及基因表达，基因组构象配置和基因组完整性的维持。 Nipbl如何影响出生后的大脑发育仍有待探索。在这里，我们在锥体神经元中产生具有NIPBL条件敲除的小鼠模型。 NIPBL-cKO小鼠表现出生长缺陷和神经行为迟缓。这些生长缺陷和神经行为迟缓与海马突触密度降低有关。因此，据我们所知，我们首次报道正常的有丝分裂后神经发育需要足够的NIPBL，而NIPBL-cKO小鼠为理解Nipbl在出生后大脑发育的遗传调节中的作用提供了有用的工具。