Impaired maturation of cortical GABA_A receptor expression in pediatric epilepsy

Abstract

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.

Functional and structural correlates of the aging brain: Relating visual cortex (V1) gamma band responses to age‐related structural change

“…(Sowell et al, 2003). In addition to synaptic density, age-dependent neurochemical processes are also known to change with development and maturation (Jansen et al, 2010). …”

“…However, both the subunit composition neuronal GABA a receptors and functional role changes during prenatal and postnatal development in humans (Andersen et al, 2002; Brooks-Kayal and Pritchett 1993; Kanaumi, et al, 2006; Reichelt et al, 1991). Due to elevated intracellular Cl- concentrations in immature neurons, GABA signaling in neonatal brain acts as an excitatory neurotransmitter – which switches to an inhibitory neurotransmitter after about the first 2 years of life (Jansen et al, 2010). In addition, GABA a receptor α1 and γ 2 subunit expression are known to increase over the first 5–6 years of life before reaching a plateau, whereas α4 subunit expression decreases during this same time period (Jansen, et al 2010).…”

Altered GABAA receptor subunit expression and pharmacology in human Angelman syndrome cortex

“…Other details regarding these antibodies are provided in Supplemental Table 1. Frozen cortical tissue specimens (100–200 mg) were processed to isolate the membrane fraction and subjected to Western blot analysis as detailed in [14]. Infrared fluorescence was used for signal detection and quantitation (Odyssey Infrared Imaging System, LI-COR Biosciences).…”

Examining the GABA_A receptor alpha-subunits in the neonatal pig brain: changes across development and the effect of seizures after hypoxic-ischaemic brain injury

“…We have shown that neonatal seizures that arise by 24 h after HI are associated with similar alterations to GABAAR subunit changes that have previously been observed following SE and in chronic epilepsy (Lauren et al 2005, Wasterlain et al 2009, Jansen et al 2010. In HI-Sz animals we observed a significant reduction of GABAAR α3…”