title: Loss of cation-chloride cotransporter expression in preterm infants with white matter lesions: implications for the pathogenesis of epilepsy.
abstract: Epilepsy associated with preterm birth is often refractory to anticonvulsants. Children who are born preterm are also prone to cognitive delay and behavioral problems. Brains from these children often show diffuse abnormalities in cerebral circuitry that is likely caused by disrupted development during critical stages of cortical formation. To test the hypothesis that prenatal injury impairs the developmental switch of gamma-amino butyric acid (GABA)ergic synapses from excitatory to inhibitory, thereby disrupting cortical circuit formation and predisposing to epilepsy, we used immunohistochemistry to compare the expression of cation-chloride transporters that developmentally regulate postsynaptic GABAergic discharges in postmortem cerebral samples from infants born preterm with known white matter injury (n = 11) with that of controls with minimal white matter gliosis (n = 7). Controls showed the expected developmental expression of cation-chloride transporters NKCC1 and KCC2 and ofcalretinin, a marker of a GABAergic neuronal subpopulation. Samples from infants with white matter damage showed a significant loss of expression of both NKCC1 and KCC2 in subplate and white matter. By contrast, there were no significant differences in total cell number or glutamate transporter VGLUT1 expression. Together, these novel findings suggest a molecular mechanism involved in the disruption of a critical stage of cerebral circuit development after brain injury from preterm birth that may predispose to epilepsy.
authors.affiliation: Divisions of Pediatric Neurosurgery, Neurology, Rainbow Babies & Children's Hospital, 11100 Euclid Ave, Cleveland, OH 44106, USA. Shenandoah.robinson@uhhs.com
authors.forename: Shenandoah
authors.initials: S
authors.lastname: Robinson
authors.forename: Irina
authors.initials: I
authors.lastname: Mikolaenko
authors.forename: Ian
authors.initials: I
authors.lastname: Thompson
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cohen
authors.forename: Monisha
authors.initials: M
authors.lastname: Goyal
mesh_terms: D001921:Brain / Q000378:metabolism* / Q000473:pathology; D064032:Calbindin 2; D002452:Cell Count; D005260:Female; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007234:Infant, Premature; D056784:Leukoencephalopathies / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology; D064030:S100 Calcium Binding Protein G / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D064032:Calbindin 2; D064030:S100 Calcium Binding Protein G; D028021:Sodium-Potassium-Chloride Symporters; D027981:Symporters; D000096922:K Cl- Cotransporters
references.citation: Epilepsy Behav. 2006 Sep;9(2):219-35
references.pmid: 16875879
references.citation: Pediatrics. 2006 Feb;117(2):309-16
references.pmid: 16452348
references.citation: Epilepsia. 2007;48 Suppl 5:79-85
references.pmid: 17910585
references.citation: Nat Med. 2005 Nov;11(11):1205-13
references.pmid: 16227993
references.citation: J Neurosci. 2007 Dec 19;27(51):14012-22
references.pmid: 18094240
references.citation: Pediatr Dev Pathol. 2000 Sep-Oct;3(5):419-30
references.pmid: 10890926
references.citation: Biol Neonate. 2003;83(2):85-96
references.pmid: 12576751
references.citation: J Neurosurg. 2006 Jun;104(6 Suppl):396-408
references.pmid: 16776375
references.citation: Prog Brain Res. 2007;160:59-87
references.pmid: 17499109
references.citation: J Neurosci. 2009 May 27;29(21):6982-8
references.pmid: 19474325
references.citation: J Comp Neurol. 2004 Dec 13;480(3):264-80
references.pmid: 15515175
references.citation: Development. 2003 Apr;130(7):1267-80
references.pmid: 12588844
references.citation: Trends Neurosci. 2007 Aug;30(8):382-9
references.pmid: 17590449
references.citation: Natl Vital Stat Rep. 2007 Dec 5;56(6):1-103
references.pmid: 18277471
references.citation: Proc Natl Acad Sci U S A. 2006 May 30;103(22):8465-8
references.pmid: 16709666
references.citation: Neuron. 2009 Mar 26;61(6):820-38
references.pmid: 19323993
references.citation: Lancet Neurol. 2009 Jan;8(1):110-24
references.pmid: 19081519
references.citation: Nat Neurosci. 2007 Apr;10(4):400-2
references.pmid: 17387326
references.citation: Neuron. 2009 Apr 16;62(1):53-71
references.pmid: 19376067
references.citation: Neuron. 2006 Sep 7;51(5):627-38
references.pmid: 16950160
references.citation: J Neurochem. 2007 Aug;102(3):957-66
references.pmid: 17630987
references.citation: J Neurosci. 2001 Nov 1;21(21):8339-47
references.pmid: 11606621
references.citation: Brain Pathol. 2005 Jul;15(3):250-60
references.pmid: 16196392
references.citation: J Neurosci. 2005 Jun 1;25(22):5280-9
references.pmid: 15930375
references.citation: J Neurosci. 2009 Mar 18;29(11):3419-30
references.pmid: 19295148
references.citation: J Neurosci. 2006 Oct 11;26(41):10407-19
references.pmid: 17035525
references.citation: Neuropediatrics. 1999 Feb;30(1):14-8
references.pmid: 10222455
references.citation: J Neurosci. 2003 May 15;23(10):4134-45
references.pmid: 12764101
references.citation: Epilepsia. 2007 Apr;48(4):663-73
references.pmid: 17319917
references.citation: J Comp Neurol. 2006 Nov 1;499(1):132-43
references.pmid: 16958091
references.citation: Lancet. 2008 Jan 19;371(9608):261-9
references.pmid: 18207020
references.citation: J Neurochem. 2009 Oct;111(2):321-31
references.pmid: 19686239
references.citation: Neuron. 2007 Dec 20;56(6):1019-33
references.pmid: 18093524
references.citation: Biochem Biophys Res Commun. 2009 Apr 10;381(3):388-92
references.pmid: 19232517
references.citation: Science. 2002 Nov 15;298(5597):1418-21
references.pmid: 12434059
references.citation: J Physiol. 2005 Jan 1;562(Pt 1):27-36
references.pmid: 15528236
references.citation: Nature. 2006 Feb 2;439(7076):589-93
references.pmid: 16341203
references.citation: Nat Rev Neurosci. 2002 Sep;3(9):728-39
references.pmid: 12209121
references.citation: Neurobiol Dis. 2007 Jan;25(1):163-9
references.pmid: 17045484
references.citation: J Physiol. 2004 Jun 15;557(Pt 3):829-41
references.pmid: 15090604
references.citation: J Neurosci. 2003 May 1;23(9):3826-36
references.pmid: 12736353
references.citation: Nat Neurosci. 2007 Apr;10(4):453-61
references.pmid: 17351636
references.citation: J Neurosci. 2003 Apr 15;23(8):3308-15
references.pmid: 12716938
references.citation: Neurology. 1999 Jan 15;52(2):341-5
references.pmid: 9932954
references.citation: Pediatrics. 1996 Jan;97(1):112-3
references.pmid: 8545202
references.citation: Pediatrics. 2005 Apr;115(4):997-1003
references.pmid: 15805376
references.citation: J Biol Chem. 2009 Oct 9;284(41):27980-27988
references.pmid: 19679663
references.citation: Eur J Neurosci. 2005 Mar;21(5):1327-37
references.pmid: 15813942
references.citation: J Physiol. 2008 Feb 15;586(4):1059-75
references.pmid: 18096599
references.citation: J Neurophysiol. 2005 Apr;93(4):2117-26
references.pmid: 15774713
references.citation: Dev Med Child Neurol. 2006 May;48(5):388-93
references.pmid: 16608549
references.citation: Neuroscience. 2008 Jun 23;154(2):677-89
references.pmid: 18472345
references.citation: Ann Neurol. 2008 Feb;63(2):222-35
references.pmid: 17918265
references.citation: Nature. 1999 Jan 21;397(6716):251-5
references.pmid: 9930699
references.citation: J Int Neuropsychol Soc. 2007 Jul;13(4):571-81
references.pmid: 17521479
references.citation: Epilepsy Res. 2007 May;74(2-3):220-7
references.pmid: 17344024
references.citation: J Neurosci. 2009 Aug 12;29(32):9943-54
references.pmid: 19675228
references.citation: J Neurosci. 2007 Feb 14;27(7):1642-50
references.pmid: 17301172
references.citation: Pediatrics. 2004 Oct;114(4):932-40
references.pmid: 15466087
references.citation: Neurosci Res. 2007 Nov;59(3):288-95
references.pmid: 17904674
references.citation: Neuroscience. 2007 Mar 2;145(1):185-96
references.pmid: 17207578
references.citation: Epilepsia. 2007 Apr;48(4):837-44
references.pmid: 17284302
references.citation: Adv Neurol. 2000;84:153-72
references.pmid: 11091865
references.citation: Schizophr Res. 2005 Mar 1;73(2-3):159-72
references.pmid: 15653259
references.citation: J Neurosci. 2007 Sep 12;27(37):9866-73
references.pmid: 17855601
references.citation: BJOG. 2005 Mar;112 Suppl 1:10-5
references.pmid: 15715587
references.citation: Synapse. 2007 Mar;61(3):138-49
references.pmid: 17146765