Impaired maturation of cortical GABA(A) receptor expression in pediatric epilepsy.
OBJECTIVE
Expression of the protein subunits that make up the γ-aminobutyric acid (GABA)(A) receptor pentamer is known to change during postnatal brain development in animal models. In the present study, analysis of cortical GABA(A) subunit expression was performed in control human tissue obtained from infancy through adolescence, and was compared to that from similarly aged children with intractable focal epilepsy.


METHODS
Twenty frozen pediatric control and 25 epileptic neocortical specimens were collected. The membrane fractions were isolated and subjected to quantitative western blot analysis. Subunit expression was correlated with clinical factors including age, pathology, and medication exposure.


RESULTS
In control cortical samples, α₁ and γ₂ GABA(A) receptor subunits exhibited low expression in infancy, which increased over the first several years of life and then stabilized through adolescence. In contrast, α₄ subunit expression was higher in infants than in older children. The level of the chloride transporter KCC2 increased markedly with age, whereas that of NKCC1 decreased. These patterns were absent in the children with epilepsy, both in those with focal cortical dysplasia and in those with cortical gliosis. Although there was marked variability in GABA(A) receptor subunit expression among the children with epilepsy, identifiable patterns of subunit expression were found in each individual child.


CONCLUSIONS
Maturation of cortical GABA(A) receptor subunit expression continues over the first several years of postnatal human development. Intractable focal epilepsy in children is associated with disruption of this normal developmental pattern. These findings have significant implications for the treatment of children with medications that modulate GABA(A) receptor function.
Jansen
Laura A
LA
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA. laura.jansen@seattlechildrens.org
Peugh
Lindsey D
LD
Roden
William H
WH
Ojemann
Jeffrey G
JG
D000293:Adolescent; D000367:Age Factors; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000150:complications / Q000473:pathology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D054220:Malformations of Cortical Development / Q000209:etiology / Q000473:pathology; D010372:Pediatrics; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D064506:Solute Carrier Family 12, Member 2; D013223:Statistics as Topic; D055815:Young Adult
D021122:Protein Subunits; D011963:Receptors, GABA-A; C578714:SLC12A1 protein, human; C578877:SLC12A2 protein, human; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064506:Solute Carrier Family 12, Member 2