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Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition.

Publication ,  Journal Article
Albright, B; Dhaher, R; Wang, H; Harb, R; Lee, T-SW; Zaveri, H; Eid, T
Published in: Exp Neurol
February 2017

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.

Duke Scholars

Published In

Exp Neurol

DOI

EISSN

1090-2430

Publication Date

February 2017

Volume

288

Start / End Page

122 / 133

Location

United States

Related Subject Headings

  • Video Recording
  • Rats, Sprague-Dawley
  • Rats
  • Pilocarpine
  • Neurons
  • Neurology & Neurosurgery
  • Muscarinic Agonists
  • Methionine Sulfoximine
  • Male
  • Hippocampus
 

Citation

APA
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Albright, B., Dhaher, R., Wang, H., Harb, R., Lee, T.-S., Zaveri, H., & Eid, T. (2017). Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition. Exp Neurol, 288, 122–133. https://doi.org/10.1016/j.expneurol.2016.10.007
Albright, Benjamin, Roni Dhaher, Helen Wang, Roa Harb, Tih-Shih W. Lee, Hitten Zaveri, and Tore Eid. “Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition.Exp Neurol 288 (February 2017): 122–33. https://doi.org/10.1016/j.expneurol.2016.10.007.
Albright B, Dhaher R, Wang H, Harb R, Lee T-SW, Zaveri H, et al. Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition. Exp Neurol. 2017 Feb;288:122–33.
Albright, Benjamin, et al. “Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition.Exp Neurol, vol. 288, Feb. 2017, pp. 122–33. Pubmed, doi:10.1016/j.expneurol.2016.10.007.
Albright B, Dhaher R, Wang H, Harb R, Lee T-SW, Zaveri H, Eid T. Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition. Exp Neurol. 2017 Feb;288:122–133.
Journal cover image

Published In

Exp Neurol

DOI

EISSN

1090-2430

Publication Date

February 2017

Volume

288

Start / End Page

122 / 133

Location

United States

Related Subject Headings

  • Video Recording
  • Rats, Sprague-Dawley
  • Rats
  • Pilocarpine
  • Neurons
  • Neurology & Neurosurgery
  • Muscarinic Agonists
  • Methionine Sulfoximine
  • Male
  • Hippocampus