title: Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition.
abstract: Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis). Epileptogenesis was induced by infusing the irreversible GS blocker methionine sulfoximine (MSO) unilaterally into the hippocampal formation of rats. We then used continuous video-intracranial electroencephalogram (EEG) monitoring and c-Fos immunohistochemistry to determine the type of seizures and spatial distribution of neuronal activation early (1-5days postinfusion) and late (16-43days postinfusion) in epileptogenesis. Early in epileptogenesis, seizures were preferentially mild (stage 1-2), activating neurons in the entorhinal-hippocampal area, the basolateral amygdala, the piriform cortex, the midline thalamus, and the anterior olfactory area. Late in epileptogenesis, the seizures were generally more severe (stages 4-5) with neuronal activation extending to the neocortex, the bed nucleus of the stria terminalis, the mediodorsal thalamu\s, and the central nucleus of the amygdala. Our findings demonstrate that inhibition of GS focally in the hippocampal formation triggers a process of epileptogenesis characterized by gradual worsening of seizure severity and involvement of progressively larger neuronal populations over a period of several weeks. Knowledge about the underlying mechanism of epileptogenesis is important because such knowledge may result in more specific and efficacious treatments of MTLE by moving away from large and poorly specific surgical resections to highly targeted surgical or pharmacological interventions of the epileptogenic process.
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Benjamin
authors: B
authors: Albright
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Roni
authors: R
authors: Dhaher
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Helen
authors: H
authors: Wang
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Roa
authors: R
authors: Harb
authors: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Tih-Shih W
authors: TW
authors: Lee
authors: Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Hitten
authors: H
authors: Zaveri
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: tore.eid@yale.edu.
authors: Tore
authors: T
authors: Eid
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004827:Epilepsy / Q000139:chemically induced*; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008717:Methionine Sulfoximine / Q000633:toxicity*; D018721:Muscarinic Agonists / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014741:Video Recording
chemical_list: D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D010862:Pilocarpine; D008717:Methionine Sulfoximine; D005974:Glutamate-Ammonia Ligase
keywords: Entorhinal cortex; Epileptogenesis; Hippocampus; Limbic structures; c-Fos