Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy

Mesial temporal lobe epilepsy (mTLE) is the most common form of epilepsy, believed to arise in part from compromised GABAergic inhibition. The neuronal specific K+/Cl− co-transporter 2 (KCC2) is a critical determinant of the efficacy of GABAergic inhibition and deficits in its activity are observed...

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Main Authors:	Matt R. Kelley, Ross A. Cardarelli, Joshua L. Smalley, Thomas A. Ollerhead, Peter M. Andrew, Nicholas J. Brandon, Tarek Z. Deeb, Stephen J. Moss
Format:	Article
Language:	English
Published:	Elsevier 2018-06-01
Series:	EBioMedicine
Online Access:	http://www.sciencedirect.com/science/article/pii/S2352396418301944

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spelling	doaj-48778aaa8f3145169b545ba38e5c06bc2020-11-25T02:20:16ZengElsevierEBioMedicine2352-39642018-06-01326271Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe EpilepsyMatt R. Kelley0Ross A. Cardarelli1Joshua L. Smalley2Thomas A. Ollerhead3Peter M. Andrew4Nicholas J. Brandon5Tarek Z. Deeb6Stephen J. Moss7Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USAAstraZeneca-Tufts University Laboratory for Basic and Translational Neuroscience Research, Boston, MA, USADepartment of Neuroscience, Tufts University School of Medicine, Boston, MA, USADepartment of Neuroscience, Tufts University School of Medicine, Boston, MA, USADepartment of Neuroscience, Tufts University School of Medicine, Boston, MA, USAAstraZeneca-Tufts University Laboratory for Basic and Translational Neuroscience Research, Boston, MA, USA; Neuroscience, IMED Biotech Unit, AstraZeneca, Boston, MA, USADepartment of Neuroscience, Tufts University School of Medicine, Boston, MA, USA; AstraZeneca-Tufts University Laboratory for Basic and Translational Neuroscience Research, Boston, MA, USADepartment of Neuroscience, Tufts University School of Medicine, Boston, MA, USA; AstraZeneca-Tufts University Laboratory for Basic and Translational Neuroscience Research, Boston, MA, USA; Neuroscience, IMED Biotech Unit, AstraZeneca, Boston, MA, USA; Department of Neuroscience, Physiology and Pharmacology, University College, London, WC1E, 6BT, UK; Corresponding author at: Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.Mesial temporal lobe epilepsy (mTLE) is the most common form of epilepsy, believed to arise in part from compromised GABAergic inhibition. The neuronal specific K+/Cl− co-transporter 2 (KCC2) is a critical determinant of the efficacy of GABAergic inhibition and deficits in its activity are observed in mTLE patients and animal models of epilepsy. To test if reductions of KCC2 activity directly contribute to the pathophysiology of mTLE, we locally ablated KCC2 expression in a subset of principal neurons within the adult hippocampus. Deletion of KCC2 resulted in compromised GABAergic inhibition and the development of spontaneous, recurrent generalized seizures. Moreover, local ablation of KCC2 activity resulted in hippocampal sclerosis, a key pathological change seen in mTLE. Collectively, our results demonstrate that local deficits in KCC2 activity within the hippocampus are sufficient to precipitate mTLE. Keywords: KCC2, GABA, Epilepsy, Hippocampal sclerosishttp://www.sciencedirect.com/science/article/pii/S2352396418301944
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Matt R. Kelley Ross A. Cardarelli Joshua L. Smalley Thomas A. Ollerhead Peter M. Andrew Nicholas J. Brandon Tarek Z. Deeb Stephen J. Moss
spellingShingle	Matt R. Kelley Ross A. Cardarelli Joshua L. Smalley Thomas A. Ollerhead Peter M. Andrew Nicholas J. Brandon Tarek Z. Deeb Stephen J. Moss Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy EBioMedicine
author_facet	Matt R. Kelley Ross A. Cardarelli Joshua L. Smalley Thomas A. Ollerhead Peter M. Andrew Nicholas J. Brandon Tarek Z. Deeb Stephen J. Moss
author_sort	Matt R. Kelley
title	Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy
title_short	Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy
title_full	Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy
title_fullStr	Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy
title_full_unstemmed	Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy
title_sort	locally reducing kcc2 activity in the hippocampus is sufficient to induce temporal lobe epilepsy
publisher	Elsevier
series	EBioMedicine
issn	2352-3964
publishDate	2018-06-01
description	Mesial temporal lobe epilepsy (mTLE) is the most common form of epilepsy, believed to arise in part from compromised GABAergic inhibition. The neuronal specific K+/Cl− co-transporter 2 (KCC2) is a critical determinant of the efficacy of GABAergic inhibition and deficits in its activity are observed in mTLE patients and animal models of epilepsy. To test if reductions of KCC2 activity directly contribute to the pathophysiology of mTLE, we locally ablated KCC2 expression in a subset of principal neurons within the adult hippocampus. Deletion of KCC2 resulted in compromised GABAergic inhibition and the development of spontaneous, recurrent generalized seizures. Moreover, local ablation of KCC2 activity resulted in hippocampal sclerosis, a key pathological change seen in mTLE. Collectively, our results demonstrate that local deficits in KCC2 activity within the hippocampus are sufficient to precipitate mTLE. Keywords: KCC2, GABA, Epilepsy, Hippocampal sclerosis
url	http://www.sciencedirect.com/science/article/pii/S2352396418301944
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Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy

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