Department of Neurology, Hospital Sant Joan de Déu (HSJD), Barcelona, Spain.
PLoS One. 2013 Jul 19;8(7):e68851. doi: 10.1371/journal.pone.0068851. Print 2013.
Rett Syndrome is a progressive neurodevelopmental disorder caused mainly by mutations in the gene encoding methyl-CpG-binding protein 2. The relevance of MeCP2 for GABAergic function was previously documented in animal models. In these models, animals show deficits in brain-derived neurotrophic factor, which is thought to contribute to the pathogenesis of this disease. Neuronal Cation Chloride Cotransporters (CCCs) play a key role in GABAergic neuronal maturation, and brain-derived neurotrophic factor is implicated in the regulation of CCCs expression during development. Our aim was to analyse the expression of two relevant CCCs, NKCC1 and KCC2, in the cerebrospinal fluid of Rett syndrome patients and compare it with a normal control group.
The presence of bumetanide sensitive NKCC1 and KCC2 was analysed in cerebrospinal fluid samples from a control pediatric population (1 day to 14 years of life) and from Rett syndrome patients (2 to 19 years of life), by immunoblot analysis.
Both proteins were detected in the cerebrospinal fluid and their levels are higher in the early postnatal period. However, Rett syndrome patients showed significantly reduced levels of KCC2 and KCC2/NKCC1 ratio when compared to the control group.
Reduced KCC2/NKCC1 ratio in the cerebrospinal fluid of Rett Syndrome patients suggests a disturbed process of GABAergic neuronal maturation and open up a new therapeutic perspective.
雷特综合征是一种进行性神经发育障碍，主要由编码甲基-CpG 结合蛋白 2 的基因突变引起。先前在动物模型中证明了 MeCP2 与 GABA 能功能有关。在这些模型中，动物表现出脑源性神经营养因子的缺乏，这被认为是导致这种疾病的发病机制之一。神经元阳离子氯离子共转运蛋白（CCCs）在 GABA 能神经元成熟中起着关键作用，脑源性神经营养因子被认为在发育过程中调节 CCCs 的表达。我们的目的是分析雷特综合征患者脑脊液中两种相关 CCCs（NKCC1 和 KCC2）的表达，并将其与正常对照组进行比较。
通过免疫印迹分析，检测来自对照组儿科人群（1 天至 14 岁）和雷特综合征患者（2 至 19 岁）脑脊液样本中布美他尼敏感 NKCC1 和 KCC2 的存在。
两种蛋白均在脑脊液中检测到，其水平在新生儿期后较高。然而，与对照组相比，雷特综合征患者的 KCC2 水平和 KCC2/NKCC1 比值显著降低。
雷特综合征患者脑脊液中 KCC2/NKCC1 比值降低表明 GABA 能神经元成熟过程受损，并为新的治疗提供了新的视角。
