突触囊泡蛋白2A抑制耐药性颞叶癫痫大鼠海马苔藓细胞发生parthanatos缓解癫痫合并认知功能障碍的分子机制

颞叶癫痫常合并广泛的认知功能障碍，海马苔藓细胞(mossy cells, MCs)在认知功能中发挥重要作用，患者海马组织中突触囊泡蛋白2A（SV2A）明显减少的同时伴随大量MCs丢失，但机制不清；我们在预实验中发现，颞叶癫痫模型中SV2A明显降低而PARP1显著增加，且PARP1是Parthanatos死亡的标志物，因此推测，癫痫灶区SV2A减少可能介导海马组织发生parthanatos死亡致使MCs数量丢失，最终出现认知功能障碍，增加SV2A的功能有可能抑制MCs发生parthanatos死亡，从而缓解癫痫合并的认知功能障碍。本研究拟在细胞水平及动物模型水平探讨SV2A对MCs丢失的调控机制，预期结果为上调SV2A可抑制耐药性癫痫大鼠MCs发生parthanatos死亡从而缓解认知功能障碍；该项目的完成有望对耐药性癫痫合并认知功能障碍的发病机制提供新的思路，并有可能提供新的药物治疗靶点。

Temporal lobe epilepsy is commonly complicated with extensive cognitive impairment. Hippocampal mossy cells (MCs) play pivotal roles in cognitive function. Synaptic vesicle protein 2A (SV2A) significantly reduced and a large number of MCs were lost in hippocampal tissues of patients with pharmacoresistant temporal lobe epilepsy. However, the mechanisms underlying the loss of MCs are unclear. Clinically, the ligand of SV2A (Levetiracetam) could significantly inhibit seizures and improve cognitive function. In our preliminary studies, the SV2A significantly decreased in the model of pharmacoresistant temporal lobe epilepsy and the expression of PARP1 significantly increased. Therefore, it was speculated that the reduction of SV2A in the epileptic focus area might mediate the death of parthanatos in the hippocampus, leading to the loss of MCs and eventually cognitive dysfunction. Upregulating SV2A could be possible to inhibit the occurrence of parthanatos death in MCs, thereby inhibiting epileptic seizures and alleviating the combined cognitive impairment. In the present study, the techniques of gene regulation, patch-clamp, rt-PCR, Western blot and other molecular biological techniques are used to further study the regulatory mechanism of SV2A on MCs loss in the levels of cellular experiment and animal model. It is expected that up-regulation of SV2A could inhibit the occurrence of parthanatos death in MCs of pharmacoresistant epileptic rats and alleviate cognitive dysfunction. The completion of the present project is expected to provide new ideas on the pathogenesis of pharmacoresistant epilepsy complicated with cognitive dysfunction, and might provide new therapeutic targets for drugs, which has important scientific significances and clinical values.