Department of Biotechnology and Life Sciences and Center of Neuroscience, University of Insubria, 21052 Busto Arsizio, Italy.
Department of Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy.
Hum Mol Genet. 2018 Jun 15;27(12):2052-2063. doi: 10.1093/hmg/ddy108.
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a complex neurological disorder, characterized by infantile seizures, impairment of cognitive and motor skills and autistic features. Loss of Cdkl5 in mice affects dendritic spine maturation and dynamics but the underlying molecular mechanisms are still far from fully understood. Here we show that Cdkl5 deficiency in primary hippocampal neurons leads to deranged expression of the alpha-amino-3-hydroxy-5-methyl-4-iso-xazole propionic acid receptors (AMPA-R). In particular, a dramatic reduction of expression of the GluA2 subunit occurs concomitantly with its hyper-phosphorylation on Serine 880 and increased ubiquitination. Consequently, Cdkl5 silencing skews the composition of membrane-inserted AMPA-Rs towards the GluA2-lacking calcium-permeable form. Such derangement is likely to contribute, at least in part, to the altered synaptic functions and cognitive impairment linked to loss of Cdkl5. Importantly, we find that tianeptine, a cognitive enhancer and antidepressant drug, known to recruit and stabilise AMPA-Rs at the synaptic sites, can normalise the expression of membrane inserted AMPA-Rs as well as the number of PSD-95 clusters, suggesting its therapeutic potential for patients with mutations in CDKL5.
X 连锁周期蛋白依赖性激酶样 5（CDKL5）基因突变导致一种复杂的神经发育障碍，其特征为婴儿期癫痫发作、认知和运动技能受损以及自闭症特征。小鼠中 Cdkl5 的缺失会影响树突棘的成熟和动态，但潜在的分子机制仍远未完全理解。在这里，我们显示在原代海马神经元中 Cdkl5 的缺乏会导致 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPA-R）的表达失调。特别是 GluA2 亚基的表达显著降低，同时其丝氨酸 880 发生过度磷酸化和泛素化增加。因此，Cdkl5 沉默使插入到细胞膜中的 AMPA-R 组成偏向于缺乏 GluA2 的钙通透性形式。这种失调可能至少部分导致与 Cdkl5 缺失相关的突触功能改变和认知障碍。重要的是，我们发现噻奈普汀，一种认知增强剂和抗抑郁药物，已知可以募集和稳定突触部位的 AMPA-R，可以使插入到细胞膜中的 AMPA-R 的表达以及 PSD-95 簇的数量正常化，这表明它对 CDKL5 基因突变患者具有治疗潜力。
