Brain Advance Access originally published online on July 2, 2009
Brain 2009 132(9):2449-2463; doi:10.1093/brain/awp178
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Selective changes in GABAA receptor subtypes in white matter neurons of patients with focal epilepsy
1 Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland 2 Department of Neurology, University Hospital and Medical School of Geneva, Geneva, Switzerland 3 Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland 4 Department of Neurology, University Hospital Zurich, Zurich, Switzerland
Correspondence to: Dr Jean-Marc Fritschy, Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland E-mail: fritschy{at}pharma.uzh.ch
Mapping the distribution of GABAA receptor subtypes represents a promising approach to characterize alterations in cortical circuitry associated with neurological disorders. We previously reported subtype-selective changes in GABAA receptor expression in the grey matter of patients with focal epilepsy. In the present follow-up study, we focused on the subcortical white matter in the same tissue specimens obtained at surgery from 9 patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis, 12 patients with TLE associated with neocortical lesions and 5 patients with frontal lobe epilepsy; post-mortem tissue from 4 subjects served as controls. The subunit composition and distribution of three major GABAA receptor subtypes were determined immunohistochemically with subunit-specific antibodies. In all cases, a majority of neurons in the white matter was distinctly labelled, allowing detailed visualization of their dendritic arborization and revealing a differential, cell type-specific expression pattern of 
-subunit variants. In controls, 1-subunit staining was most prominent, displaying a gradient that decreased with depth, in parallel with the density of NeuN-positive cells. Subsets of pyramidal cells were 3-subunit-positive, and 2-subunit-labelled neurons were rare. In 19 of the 26 patients with focal epilepsy, no changes were detected as compared with controls. In five patients with TLE, striking changes in the dendritic arborization of a subset of white matter neurons were seen with the 1-subunit antibody. In two further patients with TLE, we observed a disorganized dendritic network immuno-positive for the 1-subunit, cell clusters selectively expressing the 2-subunit and small neuronal aggregates that expressed all subunits and appeared to connect to neighbouring white matter neurons. All seven patients with anomalies in the white matter had a selective reduction in 3-containing GABAA receptors in the superficial layers of the grey matter. These results demonstrate a distinct organization of GABAA receptors in human white matter neurons, consistent with an inhibitory network that is likely to be integrated functionally with the overlying grey matter. The altered dendritic morphology and changes in GABAA receptor expression in the white matter of a subset of patients with focal epilepsy are suggestive for a rewiring of neuronal circuits.
Key Words: cerebral cortex; epilepsy; GABA; human; white matter
Abbreviations: FLE, frontal lobe epilepsy; GAD, glutamic acid decarboxylase; GAT-1, GABA membrane transporter-1; HS, hippocampal sclerosis; MAP2, microtubule-associated protein 2; mMCD, mild malformation of cortical development; NeuN, neuron-specific nuclear protein; PBS, phosphate-buffered saline; TLE, temporal lobe epilepsy
Received March 7, 2009. Revised April 30, 2009. Accepted May 22, 2009.