目的 探讨微小RNA（miRNA, miR）‑17‑5p通过调控低氧诱导因子‑1α（hypoxia‑inducible factor‑1α, HIF‑1α）/Bcl‑2/腺病毒E1B 19 kDa蛋白相互作用蛋白3（Bcl‑2/adenovirus E1B 19 kDa interacting protein 3, BNIP3）通路对癫痫小鼠认知功能及海马突触可塑性的影响。 方法 采用戊四唑（pentylenetetrazol, PTZ）腹腔注射法构建小鼠癫痫模型，将无特定病原体级BALB/c小鼠随机分为正常对照组、PTZ组、miR‑17‑5p激动剂对照组（PTZ+激动剂阴性对照）、miR‑17‑5p激动剂组（PTZ+miR‑17‑5p激动剂）、miR‑17‑5p激动剂+pcDNA组（PTZ+miR‑17‑5p激动剂+空载体）、miR‑17‑5p激动剂+pc‑HIF‑1α组（PTZ+miR‑17‑5p激动剂+HIF‑1α过表达质粒）和miR‑17‑5p激动剂+pc‑BNIP3组（PTZ+miR‑17‑5p激动剂+BNIP3过表达质粒），每组12只。采用Morris水迷宫实验评估认知功能；采用场电位记录法检测海马CA1区兴奋性突触后电位（field excitatory postsynaptic potential, fEPSP）水平，采用透射电子显微镜观察突触超微结构；采用实时荧光定量反转录PCR和Western blot分别检测海马组织中miR‑17‑5p、HIF‑1α、BNIP3及突触相关蛋白（突触后密度蛋白95、突触结合蛋白1、突触小体相关蛋白25、桥尾蛋白）的表达水平；采用双荧光素酶报告基因实验验证miR‑17‑5p与HIF‑1α的靶向关系。 结果 与正常对照组比较，PTZ组小鼠认知功能受损（逃避潜伏期延长、目标象限停留时间缩短、穿越原平台次数减少），海马突触结构破坏（突触间隙增宽、突触后致密物质厚度变薄）、突触可塑性下降（fEPSP最大振幅降低、高频刺激诱导后1 h fEPSP斜率增幅减小），miR‑17‑5p及突触相关蛋白（突触后密度蛋白95、突触结合蛋白1、突触小体相关蛋白25、桥尾蛋白）表达下调，HIF‑1α、BNIP3表达上调（P<0.05）。与PTZ组比较，miR‑17‑5p激动剂组小鼠上述病理改变得到逆转（P<0.05）。过表达HIF‑1α或BNIP3可拮抗miR‑17‑5p的保护作用，使除miR‑17‑5p外的各项指标恢复至接近PTZ组水平（P<0.05）。双荧光素酶实验证实miR‑17‑5p可直接靶向结合HIF‑1α的3'‑UTR。 结论 miR‑17‑5p可直接靶向抑制HIF‑1α/BNIP3通路，上调突触相关蛋白表达，修复海马突触超微结构、增强突触可塑性，从而改善癫痫小鼠认知功能，为癫痫相关认知损伤的治疗提供潜在靶点。

Objective To investigate the effects of microRNA (miR)-17-5p regulation of the hypoxia-inducible factor-1α (HIF-1α)/Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) pathway on cognitive function and hippocampal synaptic plasticity in epileptic mice. Methods A mouse epilepsy model was established by intraperitoneal injection of pentylenetetrazol (PTZ). Specific pathogen-free BALB/c mice were randomly assigned to seven groups (n=12 each): normal control, PTZ, miR‑17‑5p agomir control (PTZ + agomir negative control), miR‑17‑5p agomir (PTZ + miR‑17‑5p agomir), miR‑17‑5p agomir + pcDNA (PTZ + miR‑17‑5p agomir + empty vector), miR‑17‑5p agomir + pc-HIF‑1α (PTZ + miR‑17‑5p agomir + HIF‑1α overexpression plasmid), and miR‑17‑5p agomir + pc-BNIP3 (PTZ + miR‑17‑5p agomir + BNIP3 overexpression plasmid). Cognitive function was evaluated by the Morris water maze test. Field potential recording was used to measure field excitatory postsynaptic potentials (fEPSPs) in the hippocampal CA1 region. Transmission electron microscopy was used to observe synaptic ultrastructure. Quantitative real-time reverse transcription polymerase chain reaction and Western blot were employed to detect miR‑17‑5p, HIF‑1α, BNIP3, and synapse-related proteins [postsynaptic density protein 95 (PSD95), synaptotagmin-1 (Syt1), synaptosome-associated protein 25 (SNAP25), and gephyrin] in the hippocampus. A dual-luciferase reporter assay was used to verify whether miR-17-5p directly targets HIF-1α. Results Compared with the normal control group, the PTZ group showed significant cognitive impairment (prolonged escape latency, reduced time in the target quadrant, and fewer platform crossings), damage to hippocampal synaptic structure (widened synaptic cleft and thinner postsynaptic density), reduced synaptic plasticity (a decreased maximum amplitude of fEPSPs and a reduced increase in the fEPSP slope 1 hour after high-frequency stimulation), downregulation of miR‑17‑5p and synapse-related proteins (PSD95, Syt1, SNAP25, and gephyrin), and upregulation of HIF‑1α and BNIP3 (P<0.05). In the miR-17-5p agomir group, these pathological changes were significantly reversed compared with the PTZ group (P<0.05). Overexpression of HIF‑1α or BNIP3 antagonized the protective effects of miR‑17‑5p, restoring all indicators except miR-17-5p to levels close to those of the PTZ group (P<0.05). The dual-luciferase assay confirmed that miR‑17‑5p could directly bind to the 3′-UTR of HIF‑1α. Conclusions miR‑17‑5p can directly target and inhibit the HIF‑1α/BNIP3 pathway, upregulate the expression of synapse-related proteins, repair hippocampal synaptic ultrastructure, enhance synaptic plasticity, and thereby improve cognitive function in epileptic mice, providing a potential therapeutic target for epilepsy-related cognitive impairment.