The gamma-aminobutyric acid B receptor (GABABR) is a metabotropic receptor in heteromultimer structure with three subunits (R1a, R1b and R2) that mediates slow and sustained inhibitory responses via G-protein mediated K+ channels members of the K channel tetramerisation domain-containing (KCTD). When administered in experimental models of typical absence seizures, GABABR agonists exacerbate, while GABABR antagonists suppress the seizures. This unique pharmacology also is characteristic of both the AY-9944 and the transgenic GABABR models of atypical absence seizures of Lennox-Gastaut syndrome. AY-9944 is a cholesterol synthesis inhibitor that has been shown to induce spontaneous, recurrent atypical absence seizures via over-expression of the GABABR in forebrain. A more pronounced atypical absence seizure phenotype results from the over-expression of the R1a; hence the severity of the atypical absence phenotype in the GABABR transgenic mouse model is GABABR subunit specific. The absence seizure phenotype is circuitry-dependent. Spike-wave discharge that is constrained within thalamocortical circuitry results in a typical absence seizure phenotype as opposed to atypical absence seizures that result from entrainment of thalamocortical-hippocampal circuitry. The involvement of hippocampal circuitry in atypical absence seizures likely is responsible for the cognitive impairment in that disorder. GABABR antagonists can reverse both the seizures and the impairment in cognition in experimental atypical absence seizures, raising the possibility of the therapeutic utility of these compounds in the Lennox-Gastaut syndrome.
Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.