An excess of extracellular
glutamate in the hippocampus has been linked to the generation of recurrent
seizures and brain pathology in patients with medically intractable mesial
temporal lobe epilepsy (MTLE). However, the mechanism which results in
glutamate excess in MTLE remains unknown. We recently reported that the
glutamate-metabolizing
enzyme glutamine synthetase is deficient in the hippocampus in patients with MTLE, and we postulated that this deficiency is critically involved in the pathophysiology of the disease. To further explore the role of
glutamine synthetase in MTLE we created a novel animal model of hippocampal
glutamine synthetase deficiency by continuous (approximately 28 days) microinfusion of
methionine sulfoximine (MSO: 0.625 to 2.5 microg/h) unilaterally into the hippocampus in rats. This treatment led to a deficiency in hippocampal
glutamine synthetase activity by 82-97% versus saline. The majority (>95%) of the MSO-treated animals exhibited recurrent
seizures that continued for several weeks. Some of the MSO-treated animals exhibited neuropathological features that were similar to
mesial temporal sclerosis, such as hippocampal
atrophy and patterned loss of hippocampal neurons. However, many MSO-treated animals displayed only minimal injury to the hippocampus, with no clear evidence of
mesial temporal sclerosis. These findings support the hypothesis that a deficiency in hippocampal
glutamine synthetase causes recurrent
seizures, even in the absence of classical
mesial temporal sclerosis, and that restoration of
glutamine synthetase may represent a novel approach to therapeutic intervention in this disease.