Journal Article

Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats

Tore Eid, Arko Ghosh, Yue Wang, Henning Beckström, Hitten P. Zaveri, Tih-Shih W. Lee, James C. K. Lai, Gauri H. Malthankar-Phatak and Nihal C. de Lanerolle

in Brain

Published on behalf of The Guarantors of Brain

Volume 131, issue 8, pages 2061-2070
Published in print August 2008 | ISSN: 0006-8950
Published online July 2008 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awn133
Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats

Show Summary Details

Preview

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.

Keywords: astrocyte; epileptiform EEG discharges; animal models; glutamate; temporal lobes

Journal Article.  6052 words.  Illustrated.

Subjects: Neurology ; Neuroscience

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.