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Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1
BACKGROUND: Delayed cognitive impairment (DCI) after subarachnoid hemorrhage (SAH) is one of the most common sequelae in patients. This study aimed to investigate the characteristics of the course and glutamatergic pathogenesis of DCI after SAH in mice. METHODS: A SAH mouse model of internal carotid...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AME Publishing Company
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327310/ https://www.ncbi.nlm.nih.gov/pubmed/32617311 http://dx.doi.org/10.21037/atm-20-4330 |
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author | Tao, Kai Cai, Qing Zhang, Xudong Zhu, Lin Liu, Zhenru Li, Fei Wang, Qiang Liu, Lei Feng, Dayun |
author_facet | Tao, Kai Cai, Qing Zhang, Xudong Zhu, Lin Liu, Zhenru Li, Fei Wang, Qiang Liu, Lei Feng, Dayun |
author_sort | Tao, Kai |
collection | PubMed |
description | BACKGROUND: Delayed cognitive impairment (DCI) after subarachnoid hemorrhage (SAH) is one of the most common sequelae in patients. This study aimed to investigate the characteristics of the course and glutamatergic pathogenesis of DCI after SAH in mice. METHODS: A SAH mouse model of internal carotid puncture was used. Depressive and cognitive behaviors were detected by forced swimming and sucrose preference tests and Morris water maze test, respectively. Microdialysis and high-performance liquid chromatography (HPLC) were used to detect the interstitial glutamate. The expressions of histone deacetylases (HDACs), glutamate transporters, and glutamate receptors were examined. Primary astrocytes magnetically sorted from adult mice were cultured for glutamate uptake assay and protein and mRNA detection. Selective HDAC2 inhibitor and glutamate transporter-1 (GLT-1) inhibitor administered via were intraperitoneal injection to evaluate their effects on DCI in SAH mice. RESULTS: Depression and memory impairment lasted for more than 12 weeks and peaked at 8 weeks after SAH. Interstitial glutamate accumulation in the hippocampus and impaired glutamate uptake in astrocytes of the SAH mice were found during DCI, which could be explained by there being a significant decrease in GLT-1 expression but not in glutamate and aspartate transporter (GLAST) in hippocampal astrocytes. Meanwhile, the phosphorylation level of excitatory glutamate receptors (GluN2B and GluA1) in the hippocampus was significantly reduced, although there was no significant change in the expression of the receptors. Importantly, the expression of HDAC2 increased most significantly in astrocytes after SAH compared with that of other subtypes of HDACs. Inhibition of HDAC2 markedly rescued the decrease in GLT-1 expression after SAH through transcriptional regulation. Behavioral results showed that a selective HDAC2 inhibitor effectively improved DCI in SAH mice, but this effect could be weakened by GLT-1 inhibition. CONCLUSIONS: In summary, our study suggests that the dysfunction of GLT-1-mediated glutamate uptake in astrocytes may be a key pathological mechanism of DCI after SAH, and that a specific inhibitor of HDAC2 may exert a potential therapy. |
format | Online Article Text |
id | pubmed-7327310 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-73273102020-07-01 Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1 Tao, Kai Cai, Qing Zhang, Xudong Zhu, Lin Liu, Zhenru Li, Fei Wang, Qiang Liu, Lei Feng, Dayun Ann Transl Med Original Article BACKGROUND: Delayed cognitive impairment (DCI) after subarachnoid hemorrhage (SAH) is one of the most common sequelae in patients. This study aimed to investigate the characteristics of the course and glutamatergic pathogenesis of DCI after SAH in mice. METHODS: A SAH mouse model of internal carotid puncture was used. Depressive and cognitive behaviors were detected by forced swimming and sucrose preference tests and Morris water maze test, respectively. Microdialysis and high-performance liquid chromatography (HPLC) were used to detect the interstitial glutamate. The expressions of histone deacetylases (HDACs), glutamate transporters, and glutamate receptors were examined. Primary astrocytes magnetically sorted from adult mice were cultured for glutamate uptake assay and protein and mRNA detection. Selective HDAC2 inhibitor and glutamate transporter-1 (GLT-1) inhibitor administered via were intraperitoneal injection to evaluate their effects on DCI in SAH mice. RESULTS: Depression and memory impairment lasted for more than 12 weeks and peaked at 8 weeks after SAH. Interstitial glutamate accumulation in the hippocampus and impaired glutamate uptake in astrocytes of the SAH mice were found during DCI, which could be explained by there being a significant decrease in GLT-1 expression but not in glutamate and aspartate transporter (GLAST) in hippocampal astrocytes. Meanwhile, the phosphorylation level of excitatory glutamate receptors (GluN2B and GluA1) in the hippocampus was significantly reduced, although there was no significant change in the expression of the receptors. Importantly, the expression of HDAC2 increased most significantly in astrocytes after SAH compared with that of other subtypes of HDACs. Inhibition of HDAC2 markedly rescued the decrease in GLT-1 expression after SAH through transcriptional regulation. Behavioral results showed that a selective HDAC2 inhibitor effectively improved DCI in SAH mice, but this effect could be weakened by GLT-1 inhibition. CONCLUSIONS: In summary, our study suggests that the dysfunction of GLT-1-mediated glutamate uptake in astrocytes may be a key pathological mechanism of DCI after SAH, and that a specific inhibitor of HDAC2 may exert a potential therapy. AME Publishing Company 2020-06 /pmc/articles/PMC7327310/ /pubmed/32617311 http://dx.doi.org/10.21037/atm-20-4330 Text en 2020 Annals of Translational Medicine. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Original Article Tao, Kai Cai, Qing Zhang, Xudong Zhu, Lin Liu, Zhenru Li, Fei Wang, Qiang Liu, Lei Feng, Dayun Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1 |
title | Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1 |
title_full | Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1 |
title_fullStr | Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1 |
title_full_unstemmed | Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1 |
title_short | Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1 |
title_sort | astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1 |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327310/ https://www.ncbi.nlm.nih.gov/pubmed/32617311 http://dx.doi.org/10.21037/atm-20-4330 |
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