Vascular cognitive impairment (VCI) due to chronic cerebral hypoperfusion (CCH), is the second leading cause of dementia. Although synaptic impairment plays a critical role in VCI, its exact mechanism remains unknown. Our previous research revealed that remote ischemic conditioning (RIC) could alleviate cognitive decline resulting from CCH, however, its effects on synaptic impairment remain unclear. In this study, we confirmed that RIC alleviated both cognitive decline and its associated synaptic dysfunction caused by CCH. RNA sequencing revealed that CCH increased in miR-218a-5p expression, which was decreased by RIC. Elevated miR-218a-5p levels limited the benefits of RIC, however, inhibiting miR-218a-5p in hippocampal CA1 neurons rescued synaptic dysfunction. Additionally, we found that SHANK2 is a downstream target of miR-218a-5p, and inhibiting SHANK2 expression reduced the alleviation caused by hypoxic conditioning in synaptic impairment in vitro. In conclusion, our results suggested that RIC alleviated synaptic impairment via the miR-218a-5p/SHANK2 pathway, which could be a potential biomarker or therapeutic target for cognitive impairment caused by CCH.

慢性脑灌注不足（CCH）导致的血管性认知障碍（VCI）是痴呆症的第二大原因。尽管突触损伤在 VCI 中发挥着关键作用，但其确切机制仍不清楚。我们之前的研究表明，远程缺血调节（RIC）可以缓解 CCH 引起的认知能力下降，但其对突触损伤的影响仍不清楚。在这项研究中，我们证实 RIC 可以缓解 CCH 引起的认知能力下降及其相关的突触功能障碍。RNA 测序显示，CCH 的 miR-218a-5p 表达增加，而 RIC 则降低了这种表达。miR-218a-5p 水平升高限制了 RIC 的益处，然而，抑制海马 CA1 神经元中的 miR-218a-5p 可挽救突触功能障碍。此外，我们发现 SHANK2 是 miR-218a-5p 的下游靶标，抑制 SHANK2 表达可减轻体外缺氧条件引起的突触损伤的缓解。总之，我们的结果表明，RIC 通过 miR-218a-5p/SHANK2 通路减轻突触损伤，这可能是 CCH 引起的认知障碍的潜在生物标志物或治疗靶点。