Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy

Patients harboring mutations in the PI3K-AKT-MTOR pathway-encoding genes often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion remains unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critic...

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Autores principales:	Achira Roy, Victor Z. Han, Angela M. Bard, Devin T. Wehle, Stephen E. P. Smith, Jan-Marino Ramirez, Franck Kalume, Kathleen J. Millen
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	PI3K epilepsy mouse model electrophysiology hippocampus BKM120 (buparlisib) Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/2d9e75212ff44739a7d5a2363a17616b
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spelling	oai:doaj.org-article:2d9e75212ff44739a7d5a2363a17616b2021-12-01T08:00:53ZNon-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy1662-509910.3389/fnmol.2021.772847https://doaj.org/article/2d9e75212ff44739a7d5a2363a17616b2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnmol.2021.772847/fullhttps://doaj.org/toc/1662-5099Patients harboring mutations in the PI3K-AKT-MTOR pathway-encoding genes often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion remains unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critical for molecularly targeted therapies. We previously determined that mouse models expressing a patient-related activating mutation in PIK3CA, encoding the p110α catalytic subunit of phosphoinositide-3-kinase (PI3K), are epileptic and acutely treatable by PI3K inhibition, irrespective of dysmorphology. Here we report the physiological mechanisms underlying this dysregulated neuronal excitability. In vivo, we demonstrate epileptiform events in the Pik3ca mutant hippocampus. By ex vivo analyses, we show that Pik3ca-driven hyperactivation of hippocampal pyramidal neurons is mediated by changes in multiple non-synaptic, cell-intrinsic properties. Finally, we report that acute inhibition of PI3K or AKT, but not MTOR activity, suppresses the intrinsic hyperactivity of the mutant neurons. These acute mechanisms are distinct from those causing neuronal hyperactivity in other AKT-MTOR epileptic models and define parameters to facilitate the development of new molecularly rational therapeutic interventions for intractable epilepsy.Achira RoyVictor Z. HanVictor Z. HanAngela M. BardDevin T. WehleDevin T. WehleStephen E. P. SmithStephen E. P. SmithJan-Marino RamirezJan-Marino RamirezJan-Marino RamirezJan-Marino RamirezFranck KalumeFranck KalumeFranck KalumeKathleen J. MillenKathleen J. MillenFrontiers Media S.A.articlePI3Kepilepsymouse modelelectrophysiologyhippocampusBKM120 (buparlisib)Neurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Molecular Neuroscience, Vol 14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	PI3K epilepsy mouse model electrophysiology hippocampus BKM120 (buparlisib) Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	PI3K epilepsy mouse model electrophysiology hippocampus BKM120 (buparlisib) Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Achira Roy Victor Z. Han Victor Z. Han Angela M. Bard Devin T. Wehle Devin T. Wehle Stephen E. P. Smith Stephen E. P. Smith Jan-Marino Ramirez Jan-Marino Ramirez Jan-Marino Ramirez Jan-Marino Ramirez Franck Kalume Franck Kalume Franck Kalume Kathleen J. Millen Kathleen J. Millen Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy
description	Patients harboring mutations in the PI3K-AKT-MTOR pathway-encoding genes often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion remains unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critical for molecularly targeted therapies. We previously determined that mouse models expressing a patient-related activating mutation in PIK3CA, encoding the p110α catalytic subunit of phosphoinositide-3-kinase (PI3K), are epileptic and acutely treatable by PI3K inhibition, irrespective of dysmorphology. Here we report the physiological mechanisms underlying this dysregulated neuronal excitability. In vivo, we demonstrate epileptiform events in the Pik3ca mutant hippocampus. By ex vivo analyses, we show that Pik3ca-driven hyperactivation of hippocampal pyramidal neurons is mediated by changes in multiple non-synaptic, cell-intrinsic properties. Finally, we report that acute inhibition of PI3K or AKT, but not MTOR activity, suppresses the intrinsic hyperactivity of the mutant neurons. These acute mechanisms are distinct from those causing neuronal hyperactivity in other AKT-MTOR epileptic models and define parameters to facilitate the development of new molecularly rational therapeutic interventions for intractable epilepsy.
format	article
author	Achira Roy Victor Z. Han Victor Z. Han Angela M. Bard Devin T. Wehle Devin T. Wehle Stephen E. P. Smith Stephen E. P. Smith Jan-Marino Ramirez Jan-Marino Ramirez Jan-Marino Ramirez Jan-Marino Ramirez Franck Kalume Franck Kalume Franck Kalume Kathleen J. Millen Kathleen J. Millen
author_facet	Achira Roy Victor Z. Han Victor Z. Han Angela M. Bard Devin T. Wehle Devin T. Wehle Stephen E. P. Smith Stephen E. P. Smith Jan-Marino Ramirez Jan-Marino Ramirez Jan-Marino Ramirez Jan-Marino Ramirez Franck Kalume Franck Kalume Franck Kalume Kathleen J. Millen Kathleen J. Millen
author_sort	Achira Roy
title	Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy
title_short	Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy
title_full	Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy
title_fullStr	Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy
title_full_unstemmed	Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy
title_sort	non-synaptic cell-autonomous mechanisms underlie neuronal hyperactivity in a genetic model of pik3ca-driven intractable epilepsy
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/2d9e75212ff44739a7d5a2363a17616b
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Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy

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