HDAC2 (Histone deacetylase 2): A critical factor in environmental enrichment-mediated stroke recovery
HDAC2 (Histone deacetylase 2): A critical factor in environmental enrichment-mediated stroke recovery
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HDAC2（组蛋白脱乙酰酶 2）：环境富集介导的中风恢复的关键因素
DOI：
10.1111/jnc.15043
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发表时间：
2020-06-29
影响因子：
4.7
通讯作者：
Zhu, Dong-Ya
中科院分区：
文献类型：
--
作者：
Lin, Yu-Hui;Yao, Meng-Cheng;Zhu, Dong-Ya
环境丰富(EE)是一种普遍接受的促进卒中康复的策略，其有益效果与神经可塑性呈正相关。然而，其背后的机制仍然难以捉摸。组蛋白脱乙酰酶2(HDAC2)是一种神经可塑性的负调节因子，在中风后表达上调。因此，我们假设HDAC2可能参与EE介导的卒中恢复。在这项研究中，局灶性卒中是由暴露在EE或标准住房(SH)条件下的雄性小鼠的光血栓形成引起的。在卒中前3天将重组病毒载体Ad-HDAC2-Flag、AAV-CAG-EGFP-CRE、LV-shHDAC2或其对照注射到运动皮质内。通过网格行走和圆柱体任务评估运动功能。Western印迹和免疫染色用于揭示EE介导的卒中恢复的机制。我们发现，EE暴露逆转了卒中诱导的HDAC2上调，暗示HDAC2参与了EE介导的功能恢复。重要的是，EE依赖的中风恢复被过度表达的HDAC2所抵消，HDAC2基因敲除促进中风后功能恢复的程度与EE暴露的程度相似。此外，HDAC2基因的敲除在表观遗传学上增强了神经营养因子和神经可塑性相关蛋白的表达，其效果与EE相似，因此，整个大脑和皮质脊髓束(CST)重新连接。综上所述，我们的发现表明，HDAC2对于EE依赖的功能恢复至关重要。精确靶向HDAC2可能模仿EE，并作为中风康复的一种新的治疗策略。
Environmental enrichment (EE) is a generally accepted strategy to promote stroke recovery and its beneficial effect is positively correlated with neuroplasticity. However, the mechanisms underlying it remain elusive. Histone deacetylase 2 (HDAC2), a negative regulator of neuroplasticity, is up-regulated after stroke. Thus, we hypothesized that HDAC2 may participate in EE-mediated stroke recovery. In this study, focal stroke was induced by photothrombosis in male mice exposing to EE or standard housing (SH) conditions. Recombinant virus vectors, including Ad-HDAC2-Flag, AAV-CAG-EGFP-Cre, LV-shHDAC2, or their controls were microinjected into the motor cortex at 3 days before stroke. Grid-walking and cylinder tasks were conducted to assess motor function. Western blot and immunostaining were used to uncover the mechanisms underlying EE-mediated stroke recovery. We found that EE exposure reversed stroke-induced HDAC2 up-regulation, implicating HDAC2 in EE-mediated functional recovery. Importantly, EE-dependent stroke recovery was counteracted by over-expressing HDAC2, and HDAC2 knockdown promoted functional recovery from stroke to the similar extent as EE exposure. Moreover, the knockdown of HDAC2 epigenetically enhanced expressions of neurotrophins and neuroplasticity-related proteins, with similar effects as EE, and consequently, whole brain and corticospinal tract (CST) rewiring. Together, our findings indicate that HDAC2 is critical for EE-dependent functional restoration. Precisely targeting HDAC2 may mimic EE and serve as a novel therapeutic strategy for stroke recovery.