Loss of cation-chloride cotransporter expression in preterm infants with white matter lesions: implications for the pathogenesis of epilepsy.
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.
Robinson
Shenandoah
S
Divisions of Pediatric Neurosurgery, Neurology, Rainbow Babies & Children's Hospital, 11100 Euclid Ave, Cleveland, OH 44106, USA. Shenandoah.robinson@uhhs.com
Mikolaenko
Irina
I
Thompson
Ian
I
Cohen
Mark L
ML
Goyal
Monisha
M
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
D064032:Calbindin 2; D064030:S100 Calcium Binding Protein G; D028021:Sodium-Potassium-Chloride Symporters; D027981:Symporters; D000096922:K Cl- Cotransporters
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