The role of the GABA B receptors in absence epilepsy

Identification of the GABA B-receptor in the thalamus, that is involved in seizure genesis will allow for therapeutic targeting of the appropriate receptor subtype in the treatment of absence epilepsy. Epilepsy is a common condition affecting over 70 000 people alone in Austria. The epileptic seizure is a manifest of an abnormal discharge of cerebral neurons. The diagnosis "epilepsy" is a symptomativ definition, that occurs with a wide variety of cerebral pathologies. It is proposed, that absence epilepsy -as a special form of epilepsy- may result from disruption of the normal sleep rhythm, which causes hypersynchrony. Neuronal rhythmic activities within thalamo-cortical circuits range from partially synchronous oscillations during normal sleep to hypersynchrony associated with absence epilepsy. It has been proposed that recurrent inhibition within the thalamic reticular nucleus (nRt) serves to reduce synchrony and thus prevents seizures. Gamma-aminobutyric acid (GABA) represents the major inhibitory neurotransmitter in the brain. Of particular interest is the finding that the efficacy of intra-nRt inhibition is down-regulated through activation of GABA B-receptors via endogenous GABA release, especially during epileptiform activity. We hypothesize that the GABABR 1b specific receptor mediates the intra- nRt inhibition and that we might be able to antagonize this receptor to produce therapeutic anti-epileptic actions. AIM:1.The assessment of the function of the GABA B receptor in absence epilepsy seizure genesis 2.The development of anti-epileptic actions through antagonism of the GABABR 1b receptor. METHODE: Design of specific genproducts for subtypes of the GABA B receptor (antisense technique), which will be administered intracerebrally. After confirmation of functional knockdown of the receptor we will test for altered thalamic excitability (GABA B-receptor response).