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Impaired maturation of cortical GABA(A) receptor expression in pediatric epilepsy.

ABSTRACT: Expression of the protein subunits that make up the ?-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.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.In control cortical samples, ?? and ?? 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, ?? 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.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.

SUBMITTER: Jansen LA

PROVIDER: S-EPMC3243731 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Impaired maturation of cortical GABA(A) receptor expression in pediatric epilepsy.

Jansen Laura A LA Peugh Lindsey D LD Roden William H WH Ojemann Jeffrey G JG

Epilepsia 20100203 8

<h4>Purpose</h4>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.<h4>Methods</h4>Twenty frozen pediatric control and 25 epileptic neocortica ...[more]

PMID: 20132297

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Project description:Epilepsy animal models indicate pronounced changes in the expression and rearrangement of GABAA receptor subunits in the hippocampus and in para-hippocampal areas, including widespread downregulation of the subunits α5 and δ, and upregulation of α4, subunits that mediate tonic inhibition of GABA. In this case-control study, we investigated changes in the expression of subunits α4, α5 and δ in hippocampal specimens of drug resistant temporal lobe epilepsy patients who underwent epilepsy surgery. Using in situ hybridization, immunohistochemistry and α5-specific receptor autoradiography, we characterized expression of the receptor subunits in specimens from patients with and without Ammon's horn sclerosis compared to post-mortem controls. Expression of the α5-subunit was abundant throughout all subfields of the hippocampus, including the dentate gyrus, sectors CA1 and CA3, the subiculum and pre- and parasubiculum. Significant but weaker expression was detected for subunits α4 and δ notably in the granule cell/molecular layer of control specimens, but was faint in the other parts of the hippocampus. Expression of all three subunits was similarly altered in sclerotic and non-sclerotic specimens. Respective mRNA levels were increased by about 50-80% in the granule cell layer compared with post-mortem controls. Subunit α5 mRNA levels and immunoreactivities were also increased in the sector CA3 and in the subiculum. Autoradiography for α5-containing receptors using [3H]L-655,708 as ligand showed significantly increased binding in the molecular layer of the dentate gyrus in non-sclerotic specimens. Increased expression of the α5 and δ subunits is in contrast to the previously observed downregulation of these subunits in different epilepsy models, whereas increased expression of α4 in temporal lobe epilepsy patients is consistent with that in the rodent models. Our findings indicate increased tonic inhibition likely representing an endogenous anticonvulsive mechanism in temporal lobe epilepsy.

Dataset Information

Impaired maturation of cortical GABA(A) receptor expression in pediatric epilepsy.

Publications

Impaired maturation of cortical GABA(A) receptor expression in pediatric epilepsy.

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