Altered expression of a3-containing GABAA receptors in the neocortex of patients with focal epilepsy

Impaired transmission in GABAergic circuits is thought to contribute to the pathogenesis of epilepsy. Although it is well established that major reorganization of GABAA receptor subtypes occurs in the hippocampus of patients with medically refractory temporal lobe epilepsy (TLE), it is unclear whether this disorder is also associated with alterations in GABAA receptor subtypes in the neocortex. Here we have investigated immunohistochemically the subunit composition and neocortical distribution of three major GABAA receptor subtypes using antibodies specifically recognizing the subunits a1, a2, a3, b2/3 and g2. Cortical tissue was obtained at surgery from patients with TLE and hippocampal sclerosis (HS; n = 9), TLE associated with neocortical lesions (non-HS; n = 12) and frontal lobe epilepsy (FLE; n = 5), with post-mortem samples serving as controls (n = 4). A distinct laminar and neuronal expression pattern of the a-subunit variants was found across the neocortical regions examined in the temporal and frontal lobes in both control and patient tissue samples. In the five patients with FLE, GABAA receptor subunit staining was unchanged as compared to controls. In patients with TLE we observed a marked decrease in a3-subunit staining in the superficial neocortical layers (I–III), but no change in the deep layers (V and VI) or in the expression pattern of the a1 and a2-subunits. Reduced expression in a3-containing GABAA receptors was detected in six out of nine patients of the HS group and four out of twelve patients of the non-HS group. Histopathological changes were present in eight out of the ten patients with decreased a3-subunit staining. The selective reduction in a3-containing GABAA receptors was confirmed using semiquantitative measurements of optical density (OD). The specific changes unique to a3-subunit expression in the superficial neocortical layers of patients with TLE suggest that this subtype is of particular significance in the reorganization of cortical GABAergic systems in focal epilepsy.