Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1

谷氨酸受体 组蛋白脱乙酰基酶2 海马体 代谢型谷氨酸受体 微透析 谷氨酸的 药理学 NMDA受体 神经化学 化学 代谢型谷氨酸受体1 医学 内科学 受体 组蛋白脱乙酰基酶 多巴胺 生物化学 组蛋白 基因
作者
Kai Tao,Qing Cai,Xu Dong Zhang,Lin Zhu,Zhenru Liu,Fei Li,Qiang Wang,Lei Liu,Dayun Feng
出处
期刊:Annals of Translational Medicine [AME Publishing Company]
卷期号:8 (11): 691-691 被引量:17
标识
DOI:10.21037/atm-20-4330
摘要

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.
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