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Imbalance between the function of Na(+)-K(+)-2Cl and K(+)-Cl impairs Cl(–) homeostasis in human focal cortical dysplasia

OBJECTIVE: Altered expression patterns of Na(+)-K(+)-2Cl(–) (NKCC1) and K(+)-Cl(–) (KCC2) co-transporters have been implicated in the pathogenesis of epilepsy. Here, we assessed the effects of imbalanced NKCC1 and KCC2 on γ-aminobutyric acidergic (GABAergic) neurotransmission in certain brain region...

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Autores principales: Liu, Ru, Xing, Yue, Zhang, Herui, Wang, Junling, Lai, Huanling, Cheng, Lipeng, Li, Donghong, Yu, Tao, Yan, Xiaoming, Xu, Cuiping, Piao, Yueshan, Zeng, Linghui, Loh, Horace H., Zhang, Guojun, Yang, Xiaofeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9621392/
https://www.ncbi.nlm.nih.gov/pubmed/36324524
http://dx.doi.org/10.3389/fnmol.2022.954167
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author Liu, Ru
Xing, Yue
Zhang, Herui
Wang, Junling
Lai, Huanling
Cheng, Lipeng
Li, Donghong
Yu, Tao
Yan, Xiaoming
Xu, Cuiping
Piao, Yueshan
Zeng, Linghui
Loh, Horace H.
Zhang, Guojun
Yang, Xiaofeng
author_facet Liu, Ru
Xing, Yue
Zhang, Herui
Wang, Junling
Lai, Huanling
Cheng, Lipeng
Li, Donghong
Yu, Tao
Yan, Xiaoming
Xu, Cuiping
Piao, Yueshan
Zeng, Linghui
Loh, Horace H.
Zhang, Guojun
Yang, Xiaofeng
author_sort Liu, Ru
collection PubMed
description OBJECTIVE: Altered expression patterns of Na(+)-K(+)-2Cl(–) (NKCC1) and K(+)-Cl(–) (KCC2) co-transporters have been implicated in the pathogenesis of epilepsy. Here, we assessed the effects of imbalanced NKCC1 and KCC2 on γ-aminobutyric acidergic (GABAergic) neurotransmission in certain brain regions involved in human focal cortical dysplasia (FCD). MATERIALS AND METHODS: We sought to map a micro-macro neuronal network to better understand the epileptogenesis mechanism. In patients with FCD, we resected cortical tissue from the seizure the onset zone (SOZ) and the non-seizure onset zone (non-SOZ) inside the epileptogenic zone (EZ). Additionally, we resected non-epileptic neocortical tissue from the patients with mesial temporal lobe epilepsy (MTLE) as control. All of tissues were analyzed using perforated patch recordings. NKCC1 and KCC2 co-transporters expression and distribution were analyzed by immunohistochemistry and western blotting. RESULTS: Results revealed that depolarized GABAergic signals were observed in pyramidal neurons in the SOZ and non-SOZ groups compared with the control group. The total number of pyramidal neurons showing GABAergic spontaneous postsynaptic currents was 11/14, 7/17, and 0/12 in the SOZ, non-SOZ, and control groups, respectively. The depolarizing GABAergic response was significantly dampened by the specific NKCC1 inhibitor bumetanide (BUM). Patients with FCD exhibited higher expression and internalized distribution of KCC2, particularly in the SOZ group. CONCLUSION: Our results provide evidence of a potential neurocircuit underpinning SOZ epileptogenesis and non-SOZ seizure susceptibility. Imbalanced function of NKCC1 and KCC2 may affect chloride ion homeostasis in neurons and alter GABAergic inhibitory action, thereby contributing to epileptogenesis in FCDs. Maintaining chloride ion homeostasis in the neurons may represent a new avenue for the development of novel anti-seizure medications (ASMs).
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spelling pubmed-96213922022-11-01 Imbalance between the function of Na(+)-K(+)-2Cl and K(+)-Cl impairs Cl(–) homeostasis in human focal cortical dysplasia Liu, Ru Xing, Yue Zhang, Herui Wang, Junling Lai, Huanling Cheng, Lipeng Li, Donghong Yu, Tao Yan, Xiaoming Xu, Cuiping Piao, Yueshan Zeng, Linghui Loh, Horace H. Zhang, Guojun Yang, Xiaofeng Front Mol Neurosci Neuroscience OBJECTIVE: Altered expression patterns of Na(+)-K(+)-2Cl(–) (NKCC1) and K(+)-Cl(–) (KCC2) co-transporters have been implicated in the pathogenesis of epilepsy. Here, we assessed the effects of imbalanced NKCC1 and KCC2 on γ-aminobutyric acidergic (GABAergic) neurotransmission in certain brain regions involved in human focal cortical dysplasia (FCD). MATERIALS AND METHODS: We sought to map a micro-macro neuronal network to better understand the epileptogenesis mechanism. In patients with FCD, we resected cortical tissue from the seizure the onset zone (SOZ) and the non-seizure onset zone (non-SOZ) inside the epileptogenic zone (EZ). Additionally, we resected non-epileptic neocortical tissue from the patients with mesial temporal lobe epilepsy (MTLE) as control. All of tissues were analyzed using perforated patch recordings. NKCC1 and KCC2 co-transporters expression and distribution were analyzed by immunohistochemistry and western blotting. RESULTS: Results revealed that depolarized GABAergic signals were observed in pyramidal neurons in the SOZ and non-SOZ groups compared with the control group. The total number of pyramidal neurons showing GABAergic spontaneous postsynaptic currents was 11/14, 7/17, and 0/12 in the SOZ, non-SOZ, and control groups, respectively. The depolarizing GABAergic response was significantly dampened by the specific NKCC1 inhibitor bumetanide (BUM). Patients with FCD exhibited higher expression and internalized distribution of KCC2, particularly in the SOZ group. CONCLUSION: Our results provide evidence of a potential neurocircuit underpinning SOZ epileptogenesis and non-SOZ seizure susceptibility. Imbalanced function of NKCC1 and KCC2 may affect chloride ion homeostasis in neurons and alter GABAergic inhibitory action, thereby contributing to epileptogenesis in FCDs. Maintaining chloride ion homeostasis in the neurons may represent a new avenue for the development of novel anti-seizure medications (ASMs). Frontiers Media S.A. 2022-10-17 /pmc/articles/PMC9621392/ /pubmed/36324524 http://dx.doi.org/10.3389/fnmol.2022.954167 Text en Copyright © 2022 Liu, Xing, Zhang, Wang, Lai, Cheng, Li, Yu, Yan, Xu, Piao, Zeng, Loh, Zhang and Yang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Liu, Ru
Xing, Yue
Zhang, Herui
Wang, Junling
Lai, Huanling
Cheng, Lipeng
Li, Donghong
Yu, Tao
Yan, Xiaoming
Xu, Cuiping
Piao, Yueshan
Zeng, Linghui
Loh, Horace H.
Zhang, Guojun
Yang, Xiaofeng
Imbalance between the function of Na(+)-K(+)-2Cl and K(+)-Cl impairs Cl(–) homeostasis in human focal cortical dysplasia
title Imbalance between the function of Na(+)-K(+)-2Cl and K(+)-Cl impairs Cl(–) homeostasis in human focal cortical dysplasia
title_full Imbalance between the function of Na(+)-K(+)-2Cl and K(+)-Cl impairs Cl(–) homeostasis in human focal cortical dysplasia
title_fullStr Imbalance between the function of Na(+)-K(+)-2Cl and K(+)-Cl impairs Cl(–) homeostasis in human focal cortical dysplasia
title_full_unstemmed Imbalance between the function of Na(+)-K(+)-2Cl and K(+)-Cl impairs Cl(–) homeostasis in human focal cortical dysplasia
title_short Imbalance between the function of Na(+)-K(+)-2Cl and K(+)-Cl impairs Cl(–) homeostasis in human focal cortical dysplasia
title_sort imbalance between the function of na(+)-k(+)-2cl and k(+)-cl impairs cl(–) homeostasis in human focal cortical dysplasia
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9621392/
https://www.ncbi.nlm.nih.gov/pubmed/36324524
http://dx.doi.org/10.3389/fnmol.2022.954167
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