Brain Advance Access published online on July 6, 2008
Brain, doi:10.1093/brain/awn133
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Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats
1Department of Laboratory Medicine, 2Department of Neurosurgery, 3Department of Neurology and 4Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA, 5Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway and 6Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy and Idaho State University Biomedical Research Institute, Idaho State University, Pocatello, ID, USA
Correspondence to:
Tore Eid, MD, PhD, Department of Laboratory Medicine, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208035, New Haven, CT 06520-8035, USA E-mail: tore.eid{at}yale.edu
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 (
28 days) microinfusion of methionine sulfoximine (MSO: 0.625 to 2.5 µg/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.
Key Words: astrocyte; epileptiform EEG discharges; animal models; glutamate; temporal lobes
Abbreviations: CA1-3, cornu ammonis subfields 1–3 of the hippocampus; MSO, methionine sulfoximine; MTLE, mesial temporal lobe epilepsy
Received March 10, 2008. Revised May 30, 2008. Accepted June 2, 2008.