THE ROLE OF GABAb RECEPTORS IN TEMPORAL LOBE EPILEPSY

Temporal lobe epilepsy is the most common partial epilepsy syndrome seen in adult humans. The hippocampus is a key structure in the evolution of temporal lobe seizures. The axons of the dentate granule cells, the mossy fibres, constitute a major hippocampal excitatory input. Inhibitory phenomena at mossy fibre synapses may therefore prevent seizure propagation through the hippocampus. One such inhibitory phenomenon is heterosynaptic depression. In this thesis I studied the role of GABAb receptors in temporal lobe epilepsy. In particular I studied changes in GABAb receptor-mediated heterosynaptic depression at the mossy fibre synapse following status epilepticus. I have shown that status epilepticus, triggered by either perforant path stimulation or pilocarpine administration, was followed 24 hours later by a loss of GABAb receptor-mediated heterosynaptic depression among populations of mossy fibres. This was accompanied by a decrease in the sensitivity of mossy fibre transmission to the exogenous GABAb receptor agonist baclofen. Autoradiography revealed a reduction in GABAb receptor binding in stratum lucidum after status epilepticus. I then addressed the question: what is the source of the GABA that mediates heterosynaptic depression? I have also shown that the GABAb receptor agonist baclofen has antiepileptic properties. In addition, GABAb receptors do not appear to be involved in the function of the antiepileptic drug tiagabine. Failure of GABAb receptor-mediated modulation of mossy fibre transmission may contribute to the development of spontaneous seizures after status epilepticus. The GABAb receptor may be useful as a target for antiepileptic drugs.