Connectivity and Neurotransmission in Experimental Epileptogenesis

This thesis summarizes the research performed by Pieter van Eijsden on two important aspects of the development of temporal lobe epilepsy: changes in white matter connectivity and hippocampal neurotransmitter imbalance. A major theme in this thesis is the characterization of changes that occur before the onset of spontaneous seizures in order to distinguish these from changes that occur due to spontaneous seizures. Connectivity: While epilepsy is historically viewed as a disease of grey matter, the research in this thesis shows that white matter tracts are also affected, and even before epilepsy manifests itself. A single epileptogenic event, in this case status epilepticus induced by lithium and pilocarpine, will induce chronic changes in the myelin component of the white matter. Some of these changes may contribute to epileptogenesis, others are probably merely an epiphenomenon. Neurotransmission: Previous research has shown an imbalance between excitatory glutamate and inhibitory GABA in the hippocampus of TLE patients. This thesis expands this finding to the pre-epileptic period, confirming that this is probably a cause and not (only) a consequence of seizures. It is shown that weeks before spontaneous seizures start, the imbalance is present, and that this is partially attributable to selective GABAergic cell death, but also due to an inability of the surviving GABAergic cells to turn over normal amounts of GABA. In addition, a reduction of glutamine synthetase activity is shown, which is hypothesized to be a consequence of the accumulation of glutamine, the precursor of GABA and glutamate. We propose that this represents an important step towards the development of epilepsy.