RGD Reference Report - Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats. - Rat Genome Database

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

Authors: Eid, T  Ghosh, A  Wang, Y  Beckstrom, H  Zaveri, HP  Lee, TS  Lai, JC  Malthankar-Phatak, GH  De Lanerolle, NC 
Citation: Eid T, etal., Brain. 2008 Aug;131(Pt 8):2061-70. Epub 2008 Jul 6.
RGD ID: 2301554
Pubmed: PMID:18669513   (View Abstract at PubMed)
PMCID: PMC2724901   (View Article at PubMed Central)
DOI: DOI:10.1093/brain/awn133   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
temporal lobe epilepsy  ISOGlul (Rattus norvegicus)2301554; 2301554 RGD 
temporal lobe epilepsy  IDA 2301554inhibition results in recurrent seizuresRGD 

Objects Annotated

Genes (Rattus norvegicus)
Glul  (glutamate-ammonia ligase)

Genes (Mus musculus)
Glul  (glutamate-ammonia ligase)

Genes (Homo sapiens)
GLUL  (glutamate-ammonia ligase)


Additional Information