Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China; Wannan Medical College, Wuhu 241002, China.
Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
Exp Neurol. 2024 Oct;380:114906. doi: 10.1016/j.expneurol.2024.114906. Epub 2024 Jul 28.
Post-stroke anxiety (PSA) seriously affects the prognosis of patients, which is an urgent clinical problem to be addressed. However, the pathological mechanism of PSA is largely unclear. Here, we found that neuronal HIPK2 expression was upregulated in the ischemic lesion after stroke. The upregulation of HIPK2 promotes Drp1 oligomerization through the HDAC3-dependent pathway, leading to excessive mitochondrial damage. This subsequently triggers the release of cellular cytokines such as IL-18 from neurons under ischemic stress. Microglia are capable of responding to IL-18, which promotes their activation and enhances their phagocytosis, ultimately resulting in the loss of synapses and neurons, thereby exacerbating the pathological progression of PSA. HIPK2 knockdown or inhibition suppresses excessive pruning of neuronal synapses by activated microglia in the contralateral vCA1 region to compromise inactivated anxiolytic pBLA-vCA1 circuit, relieving anxiety-like behavior after stroke. Furthermore, we discovered that early remimazolam administration can remodel HIPK2-HDAC3 axis, ameliorating the progression of PSA. In conclusion, our study revealed that the neuronal HIPK2-HDAC3 axis in the ischemic focus regulates mitochondrial fragmentation to balance inflammation stress reservoir to participate in anxiety susceptibility after stroke.
卒中后焦虑（PSA）严重影响患者的预后，是亟待解决的临床问题。然而，PSA 的病理机制在很大程度上尚不清楚。在这里，我们发现卒中后缺血性损伤中神经元 HIPK2 表达上调。HIPK2 的上调通过依赖于 HDAC3 的途径促进 Drp1 寡聚化，导致线粒体过度损伤。这随后触发细胞因子如神经元在缺血应激下释放 IL-18。小胶质细胞能够对 IL-18 作出反应，促进其激活并增强其吞噬作用，最终导致突触和神经元丢失，从而加重 PSA 的病理进展。HIPK2 敲低或抑制通过抑制激活的小胶质细胞对同侧 vCA1 区神经元突触的过度修剪，破坏失活的抗焦虑 pBLA-vCA1 回路，从而缓解卒中后的焦虑样行为。此外，我们发现早期 remimazolam 给药可以重塑 HIPK2-HDAC3 轴，改善 PSA 的进展。总之，我们的研究表明，缺血灶中的神经元 HIPK2-HDAC3 轴通过调节线粒体片段化来平衡炎症应激库，从而参与卒中后的焦虑易感性。
