Abnormal expression of cerebrospinal fluid cation chloride cotransporters in patients with Rett syndrome

PLoS One. 2013 Jul 19;8(7):e68851. doi: 10.1371/journal.pone.0068851. Print 2013.


Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Female
  • Gene Expression Regulation
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Rett Syndrome / cerebrospinal fluid*
  • Rett Syndrome / genetics
  • Solute Carrier Family 12, Member 2 / cerebrospinal fluid*
  • Solute Carrier Family 12, Member 2 / genetics
  • Symporters / cerebrospinal fluid*
  • Symporters / genetics
  • Young Adult


  • Solute Carrier Family 12, Member 2
  • Symporters
  • potassium-chloride symporters

Grant support

This study was funded by “Real Patronato” (Spanish Ministry of Health and Social Policy), Tecnifar Epilepsy Research grant and FIS PS09/01132. Dr. Sofia T. Duarte has received a research grant from Portuguese League Against Epilepsy and from Tecnifar S.A. (Epilepsy research grant). Currently, Dr. Sofia Duarte integrates the Portuguese Programme for Advanced Medical Education, sponsored by Calouste Gulbenkian Foundation and Portuguese Foundation for Science and Technology. Dr. Carlos Ortez was supported by a grant from Caja Navarra. Dr. Mercedes Pineda is funded by a grant from “Real Patronato”, Spanish Ministry of Social Politics. Dr. Angels Garcia-Cazorla is funded by the grant FIS PS09/01132. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.