Glutamine synthetase is deficient in astrocytes in the epileptogenic hippocampus in human mesial
temporal lobe epilepsy (MTLE). To explore the role of this deficiency in the pathophysiology of MTLE, rats were continuously infused with the
glutamine synthetase inhibitor
methionine sulfoximine (MSO, 0.625 microg/h) or
0.9% NaCl (saline control) unilaterally into the hippocampus. The
seizures caused by MSO were assessed by video-intracranial electroencephalogram (EEG) monitoring. All (28 of 28) of the MSO-treated animals and none (0 of 12) of the saline-treated animals developed recurrent
seizures. Most recurrent
seizures appeared in clusters of 2 days' duration (median; range, 1 to 12 days). The first cluster was characterized by frequent, predominantly stage I
seizures, which presented after the first 9.5 h of infusion (median; range, 5.5 to 31.7 h). Subsequent clusters of less-frequent, mainly
partial seizures occurred after a clinically silent interval of 7.1 days (median; range, 1.8 to 16.2 days). The ictal intracranial EEGs shared several characteristics with recordings of
partial seizures in humans, such as a distinct evolution of the amplitude and frequency of the EEG signal. The neuropathology caused by MSO had similarities to
hippocampal sclerosis in 23.1% of cases, whereas 26.9% of the animals had minimal neuronal loss in the hippocampus. Moderate to severe diffuse neuronal loss was observed in 50% of the animals. In conclusion, the model of intrahippocampal MSO infusion replicates key features of human MTLE and may represent a useful tool for further studies of the cellular, molecular and electrophysiological mechanisms of this disorder.