title: Abnormal expression of cerebrospinal fluid cation chloride cotransporters in patients with Rett syndrome.
abstract: 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.
authors.affiliation: Department of Neurology, Hospital Sant Joan de Déu (HSJD), Barcelona, Spain. sofia.duarte22@hotmail.com
authors.forename: Sofia Temudo
authors.initials: ST
authors.lastname: Duarte
authors.forename: Judith
authors.initials: J
authors.lastname: Armstrong
authors.forename: Ana
authors.initials: A
authors.lastname: Roche
authors.forename: Carlos
authors.initials: C
authors.lastname: Ortez
authors.forename: Ana
authors.initials: A
authors.lastname: Pérez
authors.forename: Maria del Mar
authors.initials: Mdel M
authors.lastname: O'Callaghan
authors.forename: Antonina
authors.initials: A
authors.lastname: Pereira
authors.forename: Francesc
authors.initials: F
authors.lastname: Sanmartí
authors.forename: Aida
authors.initials: A
authors.lastname: Ormazábal
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.forename: Mercedes
authors.initials: M
authors.lastname: Pineda
authors.forename: Angels
authors.initials: A
authors.lastname: García-Cazorla
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015518:Rett Syndrome / Q000134:cerebrospinal fluid* / Q000235:genetics; D064506:Solute Carrier Family 12, Member 2 / Q000134:cerebrospinal fluid* / Q000235:genetics; D027981:Symporters / Q000134:cerebrospinal fluid* / Q000235:genetics; D055815:Young Adult; D000096922:K Cl- Cotransporters
chemical_list: D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D000096922:K Cl- Cotransporters
references.citation: Ann Neurol. 2010 Dec;68(6):944-50
references.pmid: 21154482
references.citation: J Neurosci. 2010 Apr 14;30(15):5303-10
references.pmid: 20392952
references.citation: Epilepsy Res. 2008 Aug;80(2-3):99-113
references.pmid: 18524541
references.citation: J Neurosci. 2006 Oct 18;26(42):10911-5
references.pmid: 17050729
references.citation: Ann Neurol. 1983 Oct;14(4):471-9
references.pmid: 6638958
references.citation: Ann Neurol. 1993 Aug;34(2):227-34
references.pmid: 8338347
references.citation: Hippocampus. 2008;18(3):294-309
references.pmid: 18058824
references.citation: Cereb Cortex. 2006 Jan;16(1):47-63
references.pmid: 15829735
references.citation: Neuron. 2007 Oct 4;56(1):58-65
references.pmid: 17920015
references.citation: J Neurosci. 2012 Oct 3;32(40):13860-72
references.pmid: 23035095
references.citation: Hum Mol Genet. 2007 Mar 15;16(6):640-50
references.pmid: 17309881
references.citation: Development. 2003 Apr;130(7):1267-80
references.pmid: 12588844
references.citation: Front Synaptic Neurosci. 2010 Aug 06;2:28
references.pmid: 21423514
references.citation: Neuron. 2009 Mar 26;61(6):820-38
references.pmid: 19323993
references.citation: J Neurobiol. 1997 Nov 20;33(6):781-95
references.pmid: 9369151
references.citation: J Proteome Res. 2008 Oct;7(10):4409-21
references.pmid: 18774838
references.citation: Biol Psychiatry. 2009 Feb 1;65(3):204-10
references.pmid: 19058783
references.citation: Cerebrospinal Fluid Res. 2009 Sep 07;6:10
references.pmid: 19735572
references.citation: Transl Psychiatry. 2012 Dec 11;2:e202
references.pmid: 23233021
references.citation: Science. 2004 Feb 13;303(5660):1007-10
references.pmid: 14963329
references.citation: Nat Med. 2005 Nov;11(11):1205-13
references.pmid: 16227993
references.citation: Clin Chem. 2000 Mar;46(3):399-403
references.pmid: 10702528
references.citation: Hippocampus. 2006;16(12):1032-60
references.pmid: 17094147
references.citation: J Child Neurol. 2009 May;24(5):572-6
references.pmid: 19406757
references.citation: Epilepsia. 2007 Apr;48(4):663-73
references.pmid: 17319917
references.citation: Ann Neurol. 2012 Apr;71(4):539-51
references.pmid: 22447678
references.citation: J Neurophysiol. 2008 Jan;99(1):112-21
references.pmid: 18032561
references.citation: J Inherit Metab Dis. 2011 Apr;34(2):523-8
references.pmid: 21229320
references.citation: Nature. 2010 Nov 11;468(7321):263-9
references.pmid: 21068835
references.citation: Hippocampus. 2002;12(2):258-68
references.pmid: 12000122
references.citation: Acta Neuropathol. 1988;76(2):142-58
references.pmid: 2900587
references.citation: J Neurosci Methods. 2005 Mar 15;142(1):153-8
references.pmid: 15652629
references.citation: Curr Neuropharmacol. 2008 Mar;6(1):1-20
references.pmid: 19305785
references.citation: Epilepsia. 2010 Jul;51(7):1252-8
references.pmid: 20491871