Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, Second Hospital of Jilin University, Changchun, People's Republic of China.
Department of Medical Research Centar, Second Hospital of Jilin University, Changchun, People's Republic of China.
J Cell Mol Med. 2024 Sep;28(17):e18578. doi: 10.1111/jcmm.18578.
Kruppel-like factor 4 (Klf4) is a transcription factor that is involved in neuronal regeneration and the development of glutamatergic systems. However, it is unknown whether Klf4 is involved in acute seizure. To investigate the potential role of Klf4 in pentylenetetrazol (PTZ)-induced seizure, western blotting, immunofluorescence, behaviour test and electrophysiology were conducted in this study. We found that Klf4 protein and mRNA expression were increased in both the hippocampus (HP) and prefrontal cortex (PFC) after PTZ-induced seizure in mice. HP-specific knockout (KO) of Klf4 in mice decreased protein expression of Klf4 and the down-stream Klf4 target tumour protein 53 (TP53/P53). These molecular changes are accompanied by increased seizure latency, reduced immobility time in the forced swimming test and tail suspension test. Reduced hippocampal protein levels for synaptic proteins, including glutamate receptor 1 (GRIA1/GLUA1) and postsynaptic density protein 95 (DLG4/PSD95), were also observed after Klf4-KO, while increased mRNA levels of complement proteins were observed for complement component 1q subcomponent A (C1qa), complement component 1q subcomponent B (C1qb), complement component 1q subcomponent C (C1qc), complement component 3 (C3), complement component 4A (C4a) and complement component 4B (C4b). Moreover, c-Fos expression induced by PTZ was reduced by hippocampal conditional KO of Klf4. Electrophysiology showed that PTZ-induced action potential frequency was decreased by overexpression of Klf4. In conclusion, these findings suggest that Klf4 plays an important role in regulating PTZ-induced seizures and therefore constitutes a new molecular target that should be explored for the development of antiepileptic drugs.
Kruppel 样因子 4（Klf4）是一种参与神经元再生和谷氨酸能系统发育的转录因子。然而，Klf4 是否参与急性癫痫发作尚不清楚。为了研究 Klf4 在戊四氮（PTZ）诱导的癫痫发作中的潜在作用，本研究进行了 Western blot、免疫荧光、行为测试和电生理学检测。我们发现，PTZ 诱导的癫痫发作后，小鼠海马（HP）和前额叶皮层（PFC）中的 Klf4 蛋白和 mRNA 表达增加。在小鼠中特异性敲除（KO）HP 中的 Klf4 会降低 Klf4 及其下游 Klf4 靶标肿瘤蛋白 53（TP53/P53）的蛋白表达。这些分子变化伴随着癫痫潜伏期的延长、强迫游泳试验和悬尾试验中不动时间的减少。在 Klf4-KO 后，还观察到海马突触蛋白谷氨酸受体 1（GRIA1/GLUA1）和突触后密度蛋白 95（DLG4/PSD95）的蛋白水平降低，而补体蛋白的 mRNA 水平升高，包括补体成分 1q 亚成分 A（C1qa）、补体成分 1q 亚成分 B（C1qb）、补体成分 1q 亚成分 C（C1qc）、补体成分 3（C3）、补体成分 4A（C4a）和补体成分 4B（C4b）。此外，PTZ 诱导的 c-Fos 表达也因 Klf4 海马条件性 KO 而减少。电生理学显示，Klf4 的过表达降低了 PTZ 诱导的动作电位频率。总之，这些发现表明 Klf4 在调节 PTZ 诱导的癫痫发作中起着重要作用，因此构成了开发抗癫痫药物的新分子靶点。
