Interneurons, GABAA currents, and subunit composition of the GABAA receptor in type I and type II cortical dysplasia

Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
Epilepsia (Impact Factor: 4.57). 07/2010; 51 Suppl 3(s3):166-70. DOI: 10.1111/j.1528-1167.2010.02634.x
Source: PubMed


Interneurons, gamma-aminobutyric acid (GABA)(A) receptor density, and subunit composition determine inhibitory function in pyramidal neurons and control excitability in cortex. Abnormalities in GABAergic cells or GABA(A) receptors could contribute to seizures in malformations of cortical development. Herein we review data obtained in resected cortex from pediatric epilepsy surgery patients with type I and type II cortical dysplasia (CD) and non-CD pathologies. Our studies found fewer interneurons immunolabeled for glutamic acid decarboxylase (GAD) in type II CD, whereas there were no changes in tissue from type I CD. GAD-labeled neurons had larger somata, and GABA transporter (VGAT and GAT1) staining showed a dense plexus surrounding cytomegalic neurons in type II CD. Functionally, neurons from type I CD tissue showed GABA currents with increased half maximal effective concentration compared to cells from the other groups. In type II CD, cytomegalic pyramidal neurons showed alterations in GABA currents, decreased sensitivity to zolpidem and zinc, and increased sensitivity to bretazenil. In addition, pyramidal neurons from type II CD displayed higher frequency of spontaneous inhibitory post synaptic currents. The GABAergic system is therefore, altered differently in cortex from type I and type II CD patients. Alterations in zolpidem, zinc, and bretazenil sensitivity and spontaneous inhibitory postsynaptic currents (IPSCs) suggest that type II CD neurons have altered GABA(A) receptor subunit composition and receive dense GABA inputs. These findings support the hypothesis that patients with type I and type II CD will respond differently to GABA receptor-mediated antiepileptic drugs and that cytomegalic neurons have features similar to immature neurons.

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    • "Furthermore, a number of studies have suggested that failure to remove regions of dysplasia results in continued seizure occurrence (Wagner et al., 2011). Slice electrophysiologic investigations have been carried out on regions of cortical dysplasia removed at surgery, and investigators have suggested that these tissue samples are hyperexcitable (and may generate spontaneous epileptiform events) (Avoli et al., 1999; D'Antuono et al., 2004; Calcagnotto et al., 2005; Andre et al., 2010). However, recordings from individual neurons that appear to have aberrant morphologic characteristics (as seen with intracellular staining) suggest that the most abnormal-appearing cells are relatively silent, and unlikely to serve as a basis for seizure generation. "
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