Functional expression of recombinant GABAA receptor channels in L929 fibroblasts.

While GABAergic inhibition plays a major role in the regulation of neuronal excitability, a role for altered GABAergic inhibition in the pathogenesis of epilepsy remains to be proven. The demonstration that GABAA receptors are composed of multiple subunits and that the properties and pharmacology of GABAA receptors are different for different subunit combinations, suggests that GABAA receptor heterogeneity may be of importance in determining the properties of GABAergic inhibition in different regions of the nervous system. While it is clear that GABAA receptor heterogeneity is present in the nervous system, a role for receptor heterogeneity in the pathogenesis of epilepsy remains uncertain. GABAA receptor heterogeneity may have implications for the treatment of epilepsy. It is quite possible that drugs which regulate GABAergic function may have variable efficacy in different regions of the nervous system due to expression of receptors with subunits that have different sensitivity to allosteric regulators. In situ hybridization studies indicate the colocalization of alpha 1 beta 1 gamma 2L and delta subunit mRNAs in hippocampal dentate gyrus granule cells while only the alpha 1, beta 1 and gamma 2L and not the delta subunit mRNAs colocalize in the pyramidal cells of the hippocampus. The reduced rate of acute desensitization and the slow recovery of GABA-evoked currents typical of delta-containing subunit combinations could generate tonic inhibition via long-lasting IPSPs in the dentate gyrus and thus play a role in preventing seizures. By the same rationale, a reduction in the level of expression of the delta subunit mRNA in the dentate gyrus or its absence as in the hippocampal pyramidal cells could be associated with a reduced seizure threshold. Furthermore, it is likely that there are developmental changes in the stoichiometry or subunit composition of GABAA receptors rendering the developing nervous system more or less sensitive to the effects of GABAergic anticonvulsant drugs. In addition to the heterogeneous expression of GABAA receptors, other issues concerning the regulation of GABAergic function are of potential importance. The regulatory events that control the expression of specific receptor subtypes and levels of GABA receptors are unknown. To understand the role of GABAA receptor heterogeneity in the pathogenesis of epilepsy will require the combination of biophysical and molecular biological techniques. It will be important to determine not only whether the properties of GABAA receptors have been altered in a specific form of epilepsy but also whether gene expression has been altered.