title: Effects of site-specific infusions of methionine sulfoximine on the temporal progression of seizures in a rat model of mesial temporal lobe epilepsy.
abstract: Glutamine synthetase (GS) in astrocytes is critical for metabolism of glutamate and ammonia in the brain, and perturbations in the anatomical distribution and activity of the enzyme are likely to adversely affect synaptic transmission. GS is deficient in discrete regions of the hippocampal formation in patients with mesial temporal lobe epilepsy (MTLE), a disorder characterized by brain glutamate excess and recurrent seizures. To investigate the role of site-specific inhibition of GS in MTLE, we chronically infused the GS inhibitor methionine sulfoximine (MSO) into one of the following areas of adult laboratory rats: (1) the angular bundle, n=6; (2) the deep entorhinal cortex (EC), n=7; (3) the stratum lacunosum-moleculare of CA1, n=7; (4) the molecular layer of the subiculum, n=10; (5) the hilus of the dentate gyrus, n=6; and (6) the lateral ventricle, n=6. Twelve animals were infused with phosphate buffered saline (PBS) into the same areas to serve as controls. All infusions were unilateral, and animals were monitored by continuous video-intracranial EEG recordings for 3 weeks to capture seizure activity. All animals infused with MSO into the entorhinal-hippocampal area exhibited recurrent seizures that were particularly frequent during the first 3 days of infusion and that continued to recur for the entire 3 week recording period. Only a fraction of animals infused with MSO into the lateral ventricle had recurrent seizures, which occurred at a lower frequency compared with the other MSO infused group. Infusion of MSO into the hilus of the dentate gyrus resulted in the highest total number of seizures over the 3-week recording period. Infusion of MSO into all brain regions studied, with the exception of the lateral ventricle, led to a change in the composition of seizure severity over time. Low-grade (stages 1-3) seizures were more prevalent early during infusion, while severe (stages 4-5) seizures were more prevalent later. Thus, the site of GS inhibition within the brain determines the pattern and temporal evolution of recurrent seizures in the MSO model of MTLE.
authors.affiliation: Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., PO Box 208083, New Haven, CT 06520-8035, USA.
authors.forename: Roni
authors.initials: R
authors.lastname: Dhaher
authors.affiliation: Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., PO Box 208083, New Haven, CT 06520-8035, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., PO Box 208083, New Haven, CT 06520-8035, USA.
authors.forename: Shaun E
authors.initials: SE
authors.lastname: Gruenbaum
authors.affiliation: Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., PO Box 208083, New Haven, CT 06520-8035, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Tu
authors.affiliation: Department of Psychiatry Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Tih-Shih W
authors.initials: TS
authors.lastname: Lee
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hitten P
authors.initials: HP
authors.lastname: Zaveri
authors.affiliation: Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., PO Box 208083, New Haven, CT 06520-8035, USA. Electronic address: tore.eid@yale.edu.
authors.forename: Tore
authors.initials: T
authors.lastname: Eid
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000201:enzymology*; D004195:Disease Models, Animal; D018450:Disease Progression; D000069280:Electrocorticography; D004833:Epilepsy, Temporal Lobe / Q000201:enzymology*; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057967:Infusions, Intraventricular; D007263:Infusions, Parenteral; D008297:Male; D008717:Methionine Sulfoximine / Q000008:administration & dosage; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000201:enzymology; D014741:Video Recording
chemical_list: D008717:Methionine Sulfoximine; D005974:Glutamate-Ammonia Ligase
keywords: Astrocytes; Glutamate; Glutamine synthetase; Metabolism; Plasticity