Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy.

IF 3.9 4区 医学 Q2 NEUROSCIENCES ASN NEURO Pub Date : 2023-01-01 DOI:10.1177/17590914231184072
Manolia R Ghouli, Carrie R Jonak, Rajan Sah, Todd A Fiacco, Devin K Binder
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Abstract

Volume-regulated anion channels (VRACs) are a group of ubiquitously expressed outwardly-rectifying anion channels that sense increases in cell volume and act to return cells to baseline volume through an efflux of anions and organic osmolytes, including glutamate. Because cell swelling, increased extracellular glutamate levels, and reduction of the brain extracellular space (ECS) all occur during seizure generation, we set out to determine whether VRACs are dysregulated throughout mesial temporal lobe epilepsy (MTLE), the most common form of adult epilepsy. To accomplish this, we employed the IHKA experimental model of MTLE, and probed for the expression of LRRC8A, the essential pore-forming VRAC subunit, at acute, early-, mid-, and late-epileptogenic time points (1-, 7-, 14-, and 30-days post-IHKA, respectively). Western blot analysis revealed the upregulation of total dorsal hippocampal LRRC8A 14-days post-IHKA in both the ipsilateral and contralateral hippocampus. Immunohistochemical analyses showed an increased LRRC8A signal 7-days post-IHKA in both the ipsilateral and contralateral hippocampus, along with layer-specific changes 1-, 7-, and 30-days post-IHKA bilaterally. LRRC8A upregulation 1 day post-IHKA was observed primarily in astrocytes; however, some upregulation was also observed in neurons. Glutamate-GABA/glutamine cycle enzymes glutamic acid decarboxylase, glutaminase, and glutamine synthetase were also dysregulated at the 7-day timepoint post status epilepticus. The timepoint-dependent upregulation of total hippocampal LRRC8A and the possible subsequent increased efflux of glutamate in the epileptic hippocampus suggest that the dysregulation of astrocytic VRAC may play an important role in the development of epilepsy.

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体积调节阴离子通道成孔亚基LRRC8A在内侧颞叶癫痫海马内凯尼克酸模型中的调控作用。
体积调节阴离子通道(vrac)是一组普遍表达的向外矫正阴离子通道,它们感知细胞体积的增加,并通过阴离子和有机渗透物(包括谷氨酸)的外排使细胞恢复到基线体积。由于细胞肿胀、细胞外谷氨酸水平升高和脑细胞外空间(ECS)减少都发生在癫痫发作期间,我们开始确定VRACs是否在成人癫痫最常见的内侧颞叶癫痫(MTLE)中失调。为此,我们采用了MTLE的IHKA实验模型,并在急性、早期、中期和晚期癫痫发病时间点(分别为IHKA后1、7、14和30天)检测了LRRC8A的表达,LRRC8A是必不可少的成孔VRAC亚基。Western blot分析显示,ihka后14天,同侧和对侧海马总背侧LRRC8A水平均上调。免疫组织化学分析显示,ihka后7天,同侧和对侧海马的LRRC8A信号增加,ihka后1、7和30天,双侧海马的分层特异性变化也有所增加。ihka后1天LRRC8A上调主要出现在星形胶质细胞中;然而,在神经元中也观察到一些上调。谷氨酸- gaba /谷氨酰胺循环酶谷氨酸脱羧酶、谷氨酰胺酶和谷氨酰胺合成酶也在癫痫持续状态后7天出现异常。海马总LRRC8A的时间依赖性上调以及随后可能出现的癫痫海马谷氨酸外排增加提示星形胶质细胞VRAC的失调可能在癫痫的发生中起重要作用。
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来源期刊
ASN NEURO
ASN NEURO NEUROSCIENCES-
CiteScore
7.70
自引率
4.30%
发文量
35
审稿时长
>12 weeks
期刊介绍: ASN NEURO is an open access, peer-reviewed journal uniquely positioned to provide investigators with the most recent advances across the breadth of the cellular and molecular neurosciences. The official journal of the American Society for Neurochemistry, ASN NEURO is dedicated to the promotion, support, and facilitation of communication among cellular and molecular neuroscientists of all specializations.
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