9月22日，《神經(jīng)科學雜志》（The Journal of Neuroscience）發(fā)表了中科院上海生命科學研究院神經(jīng)所熊志奇研究組的最新研究成果——“雷特綜合癥（Rett Syndrome）相關基因CDKL5通過Rac1調(diào)控神經(jīng)元形態(tài)發(fā)育”,。該項工作由博士研究生陳遷和朱永川在熊志奇研究員的指導下共同完成,。
雷特綜合癥是導致女性智力障礙的主要疾病之一。CDKL5基因突變的患者在臨床上表現(xiàn)出雷特綜合癥的特征,，并常常伴有小兒痙攣,。然而，CDKL5在神經(jīng)系統(tǒng)發(fā)育過程中的功能及其突變?nèi)绾螌е屡R床智力障礙等病癥的機制尚不清楚,。
通過結合RNA干擾,、子宮內(nèi)胚胎電轉等技術對神經(jīng)元的發(fā)育進行研究，陳遷和朱永川等證實了在培養(yǎng)神經(jīng)元及在體情況下CDKL5參與神經(jīng)元的形態(tài)發(fā)生,。在皮層神經(jīng)元中,，抑制CDKL5的表達可導致神經(jīng)元樹突的長度和分支明顯減少，提示CDKL5在發(fā)育關鍵期的表達是神經(jīng)元樹突發(fā)育和形態(tài)發(fā)生所必需的,。進一步研究發(fā)現(xiàn),，CDKL5調(diào)節(jié)Rac1活性。鑒于Rac1是控制細胞骨架及神經(jīng)元形態(tài)發(fā)生關鍵分子之一,，這提示了CDKL5通過調(diào)控Rac1信號通路來影響樹突發(fā)育,。因此，CDKL5突變可能通過影響大腦神經(jīng)元樹突的正常發(fā)育而導致早發(fā)癲癇,、重度精神發(fā)育遲緩等一系列臨床表征,。
該工作得到了中國科學院、科技部和國家自然科學基金等項目的資助,。（生物谷Bioon.com）
生物谷推薦英文摘要：
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.
