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Persistent aberrant cortical phase-amplitude coupling following seizure treatment in absence epilepsy models.

Authors
  • Maheshwari, Atul1
  • Akbar, Abraham1
  • Wang, Mai1, 2
  • Marks, Rachel L1
  • Yu, Katherine1, 2
  • Park, Suhyeorn1
  • Foster, Brett L3, 4
  • Noebels, Jeffrey L1, 4, 5
  • 1 Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
  • 2 Rice University, Houston, TX, USA.
  • 3 Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
  • 4 Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
  • 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Type
Published Article
Journal
The Journal of Physiology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Dec 01, 2017
Volume
595
Issue
23
Pages
7249–7260
Identifiers
DOI: 10.1113/JP274696
PMID: 28901011
Source
Medline
Keywords
License
Unknown

Abstract

In childhood absence epilepsy, cortical seizures are brief and intermittent; however there are extended periods without behavioural or electrographic ictal events. This genetic disorder is associated with variable degrees of cognitive dysfunction, but no consistent functional biomarkers that might provide insight into interictal cortical function have been described. Previous work in monogenic mouse models of absence epilepsy have shown that the interictal EEG displays augmented beta/gamma power in homozygous stargazer (stg/stg) mice bearing a presynaptic AMPA receptor defect, but not homozygous tottering (tg/tg) mice with a P/Q type calcium channel mutation. To further evaluate the interictal EEG, we quantified phase-amplitude coupling (PAC) in stg/stg, stg/+, tg/tg and wild-type (+/+) mice. We found distinct gene-linked patterns of aberrant PAC in stg/stg and tg/tg mice compared to +/+ and stg/+ mice. Treatment with ethosuximide significantly blocks seizures in both stg/stg and tg/tg, but the abnormal PAC remains. Stg/+ mice are seizure free with normal baseline beta/gamma power and normal theta-gamma PAC, but like stg/stg mice, beta/gamma power is significantly reduced by NMDA receptor blockade, a treatment that paradoxically enhances seizures in stg/stg mice. Stg/+ mice, therefore, have a latent cortical network phenotype that is veiled by NMDA-mediated neurotransmission. Altogether, these findings reveal gene-linked quantitative electrographic biomarkers in the absence of epileptiform activity and provide a potential network correlate for persistent cognitive deficits in absence epilepsy despite effective treatment.

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