TY - JOUR
T1 - Persistent aberrant cortical phase–amplitude coupling following seizure treatment in absence epilepsy models
AU - Maheshwari, Atul
AU - Akbar, Abraham
AU - Wang, Mai
AU - Marks, Rachel L.
AU - Yu, Katherine
AU - Park, Suhyeorn
AU - Foster, Brett L.
AU - Noebels, Jeffrey L.
N1 - Publisher Copyright:
© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Key points: In two monogenic models of absence epilepsy, interictal beta/gamma power is augmented in homozygous stargazer (stg/stg) but not homozygous tottering (tg/tg) mice. There are distinct gene-linked patterns of aberrant phase–amplitude coupling in the interictal EEG of both stg/stg and tg/tg mice, compared to +/+ and stg/+ mice. Treatment with ethosuximide significantly blocks seizures in both genotypes, but the abnormal phase–amplitude coupling remains. Seizure-free stg/+ mice have normal power and phase–amplitude coupling, but beta/gamma power is significantly reduced with NMDA receptor blockade, revealing a latent cortical network phenotype that is separable from, and therefore not a result of, seizures. Altogether, these findings reveal gene-linked quantitative electrographic biomarkers free from epileptiform activity, and provide a potential network correlate for persistent cognitive deficits in absence epilepsy despite effective treatment. 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.
AB - Key points: In two monogenic models of absence epilepsy, interictal beta/gamma power is augmented in homozygous stargazer (stg/stg) but not homozygous tottering (tg/tg) mice. There are distinct gene-linked patterns of aberrant phase–amplitude coupling in the interictal EEG of both stg/stg and tg/tg mice, compared to +/+ and stg/+ mice. Treatment with ethosuximide significantly blocks seizures in both genotypes, but the abnormal phase–amplitude coupling remains. Seizure-free stg/+ mice have normal power and phase–amplitude coupling, but beta/gamma power is significantly reduced with NMDA receptor blockade, revealing a latent cortical network phenotype that is separable from, and therefore not a result of, seizures. Altogether, these findings reveal gene-linked quantitative electrographic biomarkers free from epileptiform activity, and provide a potential network correlate for persistent cognitive deficits in absence epilepsy despite effective treatment. 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.
KW - comodulogram
KW - stargazer
KW - tottering
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U2 - 10.1113/JP274696
DO - 10.1113/JP274696
M3 - Article
C2 - 28901011
AN - SCOPUS:85030239757
SN - 0022-3751
VL - 595
SP - 7249
EP - 7260
JO - Journal of Physiology
JF - Journal of Physiology
IS - 23
ER -