Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy
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 ex...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2023-07-01
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| Series: | ASN Neuro |
| Online Access: | https://doi.org/10.1177/17590914231184072 |
| _version_ | 1797785492838678528 |
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| author | Manolia R. Ghouli Carrie R. Jonak Rajan Sah Todd A. Fiacco Devin K. Binder |
| author_facet | Manolia R. Ghouli Carrie R. Jonak Rajan Sah Todd A. Fiacco Devin K. Binder |
| author_sort | Manolia R. Ghouli |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T00:54:51Z |
| format | Article |
| id | doaj.art-1826b51ec1f2471e8e008f5b5ccf2a45 |
| institution | Directory Open Access Journal |
| issn | 1759-0914 |
| language | English |
| last_indexed | 2024-03-13T00:54:51Z |
| publishDate | 2023-07-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | ASN Neuro |
| spelling | doaj.art-1826b51ec1f2471e8e008f5b5ccf2a452023-07-07T02:33:39ZengSAGE PublishingASN Neuro1759-09142023-07-011510.1177/17590914231184072Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe EpilepsyManolia R. Ghouli0Carrie R. Jonak1Rajan Sah2Todd A. Fiacco3Devin K. Binder4 Center for Glial-Neuronal Interactions, , Riverside, CA, USA Center for Glial-Neuronal Interactions, , Riverside, CA, USA Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA , Riverside, CA, USA Center for Glial-Neuronal Interactions, , Riverside, CA, USAVolume-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.https://doi.org/10.1177/17590914231184072 |
| spellingShingle | Manolia R. Ghouli Carrie R. Jonak Rajan Sah Todd A. Fiacco Devin K. Binder Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy ASN Neuro |
| title | Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy |
| title_full | Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy |
| title_fullStr | Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy |
| title_full_unstemmed | Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy |
| title_short | Regulation of the Volume-Regulated Anion Channel Pore-Forming Subunit LRRC8A in the Intrahippocampal Kainic Acid Model of Mesial Temporal Lobe Epilepsy |
| title_sort | regulation of the volume regulated anion channel pore forming subunit lrrc8a in the intrahippocampal kainic acid model of mesial temporal lobe epilepsy |
| url | https://doi.org/10.1177/17590914231184072 |
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