Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy

Summary: Loss of function mutations of the WW domain-containing oxidoreductase (WWOX) gene are associated with severe and fatal drug-resistant pediatric epileptic encephalopathy. Epileptic seizures are typically characterized by neuronal hyperexcitability; however, the specific contribution of WWOX...

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Autores principales:	Vanessa L. Breton, Mark S. Aquilino, Srinivasarao Repudi, Afifa Saleem, Shanthini Mylvaganam, Sara Abu-Swai, Berj L. Bardakjian, Rami I. Aqeilan, Peter L. Carlen
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	WWOX Epilepsy Electrophysiology NMDA Coupling Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/19d57401746a48c2a8e58b0768dc74d1
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spelling	oai:doaj.org-article:19d57401746a48c2a8e58b0768dc74d12021-11-12T04:26:09ZAltered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy1095-953X10.1016/j.nbd.2021.105529https://doaj.org/article/19d57401746a48c2a8e58b0768dc74d12021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0969996121002783https://doaj.org/toc/1095-953XSummary: Loss of function mutations of the WW domain-containing oxidoreductase (WWOX) gene are associated with severe and fatal drug-resistant pediatric epileptic encephalopathy. Epileptic seizures are typically characterized by neuronal hyperexcitability; however, the specific contribution of WWOX to that hyperexcitability has yet to be investigated. Using a mouse model of neuronal Wwox-deletion that exhibit spontaneous seizures, in vitro whole-cell and field potential electrophysiological characterization identified spontaneous bursting activity in the neocortex, a marker of the underlying network hyperexcitability. Spectral analysis of the neocortical bursting events highlighted increased phase-amplitude coupling, and a propagation from layer II/III to layer V. These bursts were NMDAR and gap junction dependent. In layer II/III pyramidal neurons, Wwox knockout mice demonstrated elevated amplitude of excitatory post-synaptic currents, whereas the frequency and amplitude of inhibitory post-synaptic currents were reduced, as compared to heterozygote and wild-type littermate controls. Furthermore, these neurons were depolarized and demonstrated increased action potential frequency, sag current, and post-inhibitory rebound. These findings suggest WWOX plays an essential role in balancing neocortical excitability and provide insight towards developing therapeutics for those suffering from WWOX disorders.Vanessa L. BretonMark S. AquilinoSrinivasarao RepudiAfifa SaleemShanthini MylvaganamSara Abu-SwaiBerj L. BardakjianRami I. AqeilanPeter L. CarlenElsevierarticleWWOXEpilepsyElectrophysiologyNMDACouplingNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENNeurobiology of Disease, Vol 160, Iss , Pp 105529- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	WWOX Epilepsy Electrophysiology NMDA Coupling Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	WWOX Epilepsy Electrophysiology NMDA Coupling Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Vanessa L. Breton Mark S. Aquilino Srinivasarao Repudi Afifa Saleem Shanthini Mylvaganam Sara Abu-Swai Berj L. Bardakjian Rami I. Aqeilan Peter L. Carlen Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy
description	Summary: Loss of function mutations of the WW domain-containing oxidoreductase (WWOX) gene are associated with severe and fatal drug-resistant pediatric epileptic encephalopathy. Epileptic seizures are typically characterized by neuronal hyperexcitability; however, the specific contribution of WWOX to that hyperexcitability has yet to be investigated. Using a mouse model of neuronal Wwox-deletion that exhibit spontaneous seizures, in vitro whole-cell and field potential electrophysiological characterization identified spontaneous bursting activity in the neocortex, a marker of the underlying network hyperexcitability. Spectral analysis of the neocortical bursting events highlighted increased phase-amplitude coupling, and a propagation from layer II/III to layer V. These bursts were NMDAR and gap junction dependent. In layer II/III pyramidal neurons, Wwox knockout mice demonstrated elevated amplitude of excitatory post-synaptic currents, whereas the frequency and amplitude of inhibitory post-synaptic currents were reduced, as compared to heterozygote and wild-type littermate controls. Furthermore, these neurons were depolarized and demonstrated increased action potential frequency, sag current, and post-inhibitory rebound. These findings suggest WWOX plays an essential role in balancing neocortical excitability and provide insight towards developing therapeutics for those suffering from WWOX disorders.
format	article
author	Vanessa L. Breton Mark S. Aquilino Srinivasarao Repudi Afifa Saleem Shanthini Mylvaganam Sara Abu-Swai Berj L. Bardakjian Rami I. Aqeilan Peter L. Carlen
author_facet	Vanessa L. Breton Mark S. Aquilino Srinivasarao Repudi Afifa Saleem Shanthini Mylvaganam Sara Abu-Swai Berj L. Bardakjian Rami I. Aqeilan Peter L. Carlen
author_sort	Vanessa L. Breton
title	Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy
title_short	Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy
title_full	Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy
title_fullStr	Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy
title_full_unstemmed	Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy
title_sort	altered neocortical oscillations and cellular excitability in an in vitro wwox knockout mouse model of epileptic encephalopathy
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/19d57401746a48c2a8e58b0768dc74d1
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Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy

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