Astrocytic NKCC1 inhibits seizures by buffering Cl- and antagonizing neuronal NKCC1 at GABAergic synapses

Nguyen, Trong Dao

doi:https://doi.org/10.1111/epi.17784

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Astrocytic NKCC1 inhibits seizures by buffering Cl- and antagonizing neuronal NKCC1 at GABAergic synapses

http://hdl.handle.net/10271/0002000205

名前 / ファイル	ライセンス	アクション
論文本文 (10.2 MB)

Item type

学位論文 / Thesis or Dissertation(1)

公開日

2024-09-05

タイトル

Astrocytic NKCC1 inhibits seizures by buffering Cl- and antagonizing neuronal NKCC1 at GABAergic synapses

言語

eng

資源タイプ

資源タイプ識別子

http://purl.org/coar/resource_type/c_db06

資源タイプ

doctoral thesis

アクセス権

open access

アクセス権URI

http://purl.org/coar/access_right/c_abf2

その他のタイトル

アストロサイトNKCC1はGABA作動性シナプスにおけるCl-緩衝作用で神経細胞NKCC1とは拮抗的に痙攣発作を抑制する

著者

Nguyen, Trong Dao

書誌情報

en : Epilepsia

巻 64, 号 12, p. 3389-3403, 発行日 2023-12-12

出版者

John Wiley and Sons

言語

権利

言語

権利情報

This is the peer reviewed version of the following article: "Astrocytic NKCC1 inhibits seizures by buffering Cl⁻ and antagonizing neuronal NKCC1 at GABAergic synapses, 64(12), pp2491, c2023", which has been published in final form at https://doi.org/10.1111/epi.17784. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

抄録

内容記述タイプ

Abstract

内容記述

A pathological excitatory action of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been observed in epilepsy. Blocking the Cl⁻ importer NKCCl with bumetanide is expected to reduce the neuronal intracellular Cl⁻ concentration ([Cl⁻]i) and thereby attenuate the excitatory GABA response. Accordingly, several clinical trials of bumetanide for epilepsy are currently ongoing. Although NKCCl is expressed in both neurons and glial cells, an involvement of glial NKCCl in seizures has not yet been reported. Astrocytes maintain high [Cl⁻]i with NKCCl, and this gradient promotes Cl⁻ efflux via the astrocytic GABAA receptor (GABAAR). This Cl⁻ efflux buffers the synaptic cleft Cl⁻ concentration ([Cl⁻]o) to maintain the postsynaptic Cl⁻ gradient during intense firing of GABAergic neurons, thereby sustaining its inhibitory action during epilepsy. In this study, we investigated the function of astrocytic NKCCl in modulating the postsynaptic action of GABA in acute seizure models. We used the astrocyte-specific NKCCl knockout (AstroNKCClKO) mice. Seizure-like events (SLEs) in CAI pyramidal neurons in vitro and in the in vivo pilocarpine-induced seizure model were evaluated. The AstroNKCClKO mice were prone to seizures with lower threshold and longer duration of SLEs and larger GABAAR-mediated depolarization underlying the SLEs, accompanied by higher Racine-scored seizures. Bumetanide reduced these indicators of seizure in AstroNKCClKO mice (which still express neuronal NKCCl), but not in the WT, both in vitro and in vivo. Thus, astrocytic NKCCl inhibits excitatory GABA-mediated seizures, whereas neuronal NKCCl has the converse effect, suggesting opposing actions of bumetanide on these cells.

言語

学位名

博士（医学）

学位の区分

内容記述

doctoral

学位の分野

内容記述

医学系研究科

学位授与機関

学位授与機関識別子Scheme

kakenhi

学位授与機関識別子

13802

学位授与機関名

浜松医科大学

学位授与年月日

2023-09-22

学位授与番号

甲第959号

ISSN

収録物識別子タイプ

PISSN

収録物識別子

0013-9580

EISSN

収録物識別子タイプ

EISSN

収録物識別子

1528-1167

NII書誌ID

収録物識別子タイプ

NCID

収録物識別子

AA00180597

PubMed番号

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2024-09-05 06:56:08.944873

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Astrocytic NKCC1 inhibits seizures by buffering Cl- and antagonizing neuronal NKCC1 at GABAergic synapses

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