Laboratory of Molecular and Systemic Neuromorphology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
Laboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
PLoS One. 2021 Jun 4;16(6):e0239111. doi: 10.1371/journal.pone.0239111. eCollection 2021.
The Brain-Derived Neurotrophic Factor is one of the most important trophic proteins in the brain. The role of this growth factor in neuronal plasticity, in health and disease, has been extensively studied. However, mechanisms of epigenetic regulation of Bdnf gene expression in epilepsy are still elusive. In our previous work, using a rat model of neuronal activation upon kainate-induced seizures, we observed a repositioning of Bdnf alleles from the nuclear periphery towards the nuclear center. This change of Bdnf intranuclear position was associated with transcriptional gene activity. In the present study, using the same neuronal activation model, we analyzed the relation between the percentage of the Bdnf allele at the nuclear periphery and clinical and morphological traits of epilepsy. We observed that the decrease of the percentage of the Bdnf allele at the nuclear periphery correlates with stronger mossy fiber sprouting-an aberrant form of excitatory circuits formation. Moreover, using in vitro hippocampal cultures we showed that Bdnf repositioning is a consequence of transcriptional activity. Inhibition of RNA polymerase II activity in primary cultured neurons with Actinomycin D completely blocked Bdnf gene transcription and repositioning occurring after neuronal excitation. Interestingly, we observed that histone deacetylases inhibition with Trichostatin A induced a slight increase of Bdnf gene transcription and its repositioning even in the absence of neuronal excitation. Presented results provide novel insight into the role of BDNF in epileptogenesis. Moreover, they strengthen the statement that this particular gene is a good candidate to search for a new generation of antiepileptic therapies.
脑源性神经营养因子是大脑中最重要的营养蛋白之一。该生长因子在神经元可塑性、健康和疾病中的作用已经得到了广泛的研究。然而，BDNF 基因表达的表观遗传调控机制在癫痫中的作用仍不清楚。在我们之前的工作中，使用红藻氨酸诱导癫痫发作的大鼠模型，我们观察到 Bdnf 等位基因从核周向核中心重新定位。BDNF 核内位置的这种变化与转录基因活性有关。在本研究中，我们使用相同的神经元激活模型，分析了 Bdnf 等位基因在核周的百分比与癫痫的临床和形态特征之间的关系。我们观察到，Bdnf 等位基因在核周的百分比下降与苔藓纤维发芽（一种异常的兴奋性回路形成形式）的增强有关。此外，我们通过体外海马培养实验表明，BDNF 重定位是转录活性的结果。用放线菌素 D 抑制原代培养神经元中的 RNA 聚合酶 II 活性完全阻断了 Bdnf 基因转录和神经元兴奋后发生的重定位。有趣的是，我们观察到组蛋白去乙酰化酶抑制剂 Trichostatin A 即使在没有神经元兴奋的情况下，也能轻微增加 Bdnf 基因的转录和重定位。目前的结果为 BDNF 在癫痫发生中的作用提供了新的见解。此外，它们还加强了这样一种观点，即该特定基因是寻找新一代抗癫痫治疗方法的良好候选基因。
