9月22日,《神经科学杂志》(The Journal of Neuroscience)发表了中科院上海生命科学研究院神经所熊志奇研究组的最新研究成果——“雷特综合症(Rett Syndrome)相关基因CDKL5通过Rac1调控神经元形态发育”。该项工作由博士研究生陈迁和朱永川在熊志奇研究员的指导下共同完成。
雷特综合症是导致女性智力障碍的主要疾病之一。CDKL5基因突变的患者在临床上表现出雷特综合症的特征,并常常伴有小儿痉挛。然而,CDKL5在神经系统发育过程中的功能及其突变如何导致临床智力障碍等病症的机制尚不清楚。
通过结合RNA干扰、子宫内胚胎电转等技术对神经元的发育进行研究,陈迁和朱永川等证实了在培养神经元及在体情况下CDKL5参与神经元的形态发生。在皮层神经元中,抑制CDKL5的表达可导致神经元树突的长度和分支明显减少,提示CDKL5在发育关键期的表达是神经元树突发育和形态发生所必需的。进一步研究发现,CDKL5调节Rac1活性。鉴于Rac1是控制细胞骨架及神经元形态发生关键分子之一,这提示了CDKL5通过调控Rac1信号通路来影响树突发育。因此,CDKL5突变可能通过影响大脑神经元树突的正常发育而导致早发癫痫、重度精神发育迟缓等一系列临床表征。
该工作得到了中国科学院、科技部和国家自然科学基金等项目的资助。(生物谷Bioon.com)
生物谷推荐英文摘要:
The Journal of Neuroscience doi:10.1523/JNEUROSCI.2623-05.2006
Learning and Memory and Synaptic Plasticity Are Impaired in a Mouse Model of Rett Syndrome
Paolo Moretti,1,2 Jonathan M. Levenson,3 Fortunato Battaglia,7 Richard Atkinson,1 Ryan Teague,1 Barbara Antalffy,4 Dawna Armstrong,4 Ottavio Arancio,7 J. David Sweatt,3 and Huda Y. Zoghbi1,2,3,5,6
Departments of 1Molecular and Human Genetics, 2Neurology, 3Neuroscience, 4Pathology, and 5Pediatrics, and 6Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, and 7Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research–New York University, Orangeburg, New York 10962
Loss-of-function mutations or abnormal expression of the X-linked gene encoding methyl CpG binding protein 2 (MeCP2) cause a spectrum of postnatal neurodevelopmental disorders including Rett syndrome (RTT), nonsyndromic mental retardation, learning disability, and autism. Mice expressing a truncated allele of Mecp2 (Mecp2308) reproduce the motor and social behavior abnormalities of RTT; however, it is not known whether learning deficits are present in these animals. We investigated learning and memory, neuronal morphology, and synaptic function in Mecp2308 mice. Hippocampus-dependent spatial memory, contextual fear memory, and social memory were significantly impaired in Mecp2308 mutant males (Mecp2308/Y). The morphology of dendritic arborizations, the biochemical composition of synaptosomes and postsynaptic densities, and brain-derived neurotrophic factor expression were not altered in these mice. However, reduced postsynaptic density cross-sectional length was identified in asymmetric synapses of area CA1 of the hippocampus. In the hippocampus of symptomatic Mecp2308/Y mice, Schaffer-collateral synapses exhibited enhanced basal synaptic transmission and decreased paired-pulse facilitation, suggesting that neurotransmitter release was enhanced. Schaffer-collateral long-term potentiation (LTP) was impaired. LTP was also reduced in the motor and sensory regions of the neocortex. Finally, very early symptomatic Mecp2308/Y mice had increased basal synaptic transmission and deficits in the induction of long-term depression. These data demonstrate a requirement for MeCP2 in learning and memory and suggest that functional and ultrastructural synaptic dysfunction is an early event in the pathogenesis of RTT.