SUMMARY
Purpose
Expression of the protein subunits that make up the GABAA receptor pentamer is known to change during postnatal brain development in animal models. In the present study, analysis of cortical GABAA 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 GABAA 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, while that of NKCC1 decreased. These patterns were absent in the epileptic children, both in those with focal cortical dysplasia and in those with cortical gliosis. While there was marked variability in GABAA receptor subunit expression amongst the epileptic children, identifiable patterns of subunit expression were found in each individual child.
Discussion
Maturation of cortical GABAA 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 GABAA receptor function.