GABAA Receptors in Human Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) is a form of focal epilepsy, which is particularly resistant to medical treatment. It is, however, established that patients with TLE and HS respond favorably to surgery. Accumulating evidence indicates that TLE is associated with impairment in synaptic signaling via GABA (γ-aminobutyric acid), the main inhibitory neurotransmitter in the brain. GABAA receptors, which mediate the fast synaptic inhibitory action of GABA, are also targets for several medications used in treating seizures, including benzodiazepines or barbiturates. Nineteen genes have been identified coding for distinct subunits, which assemble into a functional GABAA receptor composed of a combination of five of these subunits. This heterogeneity is reflected in the multitude of structurally distinct GABAA receptor subtypes expressed in various brain regions. A comparative analysis based on immunohistochemical techniques revealed significant changes in the distribution and expression of three major GABAA receptor subtypes in hippocampal tissue removed during surgery from TLE patients with HS versus tissue from autopsy controls. In TLE with HS, which is characterized by neuronal loss and gliosis in the hippocampus, we found first that, although GABAA receptor subunit staining was decreased in areas of extensive cell death, surviving neurons of the dentate gyrus had more GABAA receptors, in particular the α2-subtype. Second, we observed changes in numbers and morphology of interneurons expressing the α1-subtype. These results, demonstrating marked reorganization of specific GABAA receptor subtypes in surviving hippocampal neurons, provide new insights into the role of inhibitory mechanisms in the pathophysiology of focal epilepsy.