Institut für Zelluläre und Molekulare Anatomie (Anatomie III), Universitätsklinikum, Theodor-Stern-Kai 7, 60590, Frankfurt/Main, Germany.
Mol Neurobiol. 2018 May;55(5):4492-4503. doi: 10.1007/s12035-017-0665-5. Epub 2017 Jul 6.
Epileptic seizures are generally associated with pathological changes in the hippocampus such as astrogliosis, mossy fiber sprouting, and neuronal damage. However, more than 30% of temporal lobe epilepsy in humans shows neither neuronal damage nor mossy fiber sprouting despite chronic epileptic seizures. A similar situation exists in certain commonly used strains of mice, specifically C57BL/6 and BALB/c, which exhibit epileptic seizures, but no neuronal damage upon kainic acid administration. This suggests that intrinsic factors may influence the pathological manifestations of epilepsy. Mechanisms which are behind the resistance of hippocampal cells to KA-induced neuronal death are unknown. Autophagy seems to be involved in the pathogenesis of many brain insults and to have a dual nature in neuroprotection and cell death. This study addresses the role of autophagy upon status epilepticus (SE) that has been induced by kainic acid (KA) in the C57BL/6 strain which is classified as seizure resistant. We analyzed the dynamics in the expression of autophagic and cell death markers in the hippocampus upon SE. Immunofluorescence data show that KA did not induce neuronal death in the hippocampal CA1-CA3 subfields; however, it leads to an exclusive activation of caspase-3 in the mossy fibers. We also found alterations in the expression of core proteins of the autophagic machinery. Levels of MAP1LC3, phospho-mTOR/mTOR, and Beclin 1 were significantly increased after induction of seizures. However, levels of Atg3, Atg14, Atg5-Atg12, Atg7, BAG3, Hsp70, and LAMP1 showed no significant alterations compared to controls. Although KA did not induce neuronal death, this study provides morphological and biochemical evidence that status epilepticus induced by KA activates caspase-3 in mossy fibers and induces autophagy in the C57BL/6 hippocampus. These data indicate that autophagic factors may modulate the sensitivity of pyramidal cells to KA and that autophagy may constitute a part of an endogenous neuroprotective arsenal which might be behind the resistance of C57BL/6-hippocampal cells to KA-induced neuronal death.
癫痫发作通常与海马体的病理变化有关，如星形胶质细胞增生、苔藓纤维发芽和神经元损伤。然而，尽管存在慢性癫痫发作，人类超过 30%的颞叶癫痫既没有神经元损伤也没有苔藓纤维发芽。在某些常用的小鼠品系中也存在类似的情况，特别是 C57BL/6 和 BALB/c，它们表现出癫痫发作，但在给予海人酸后没有神经元损伤。这表明内在因素可能影响癫痫的病理表现。海马细胞对 KA 诱导的神经元死亡的抗性背后的机制尚不清楚。自噬似乎参与了许多脑损伤的发病机制，并具有神经保护和细胞死亡的双重性质。本研究探讨了自噬在 C57BL/6 品系（被归类为癫痫发作抗性）中由海人酸（KA）诱导的癫痫持续状态（SE）中的作用。我们分析了 SE 后海马体中自噬和细胞死亡标志物表达的动态变化。免疫荧光数据显示，KA 不会在海马 CA1-CA3 亚区诱导神经元死亡；然而，它会导致苔藓纤维中 caspase-3 的特异性激活。我们还发现自噬机制的核心蛋白表达发生了改变。在诱导癫痫发作后，MAP1LC3、磷酸化 mTOR/mTOR 和 Beclin 1 的水平显著增加。然而，与对照组相比，Atg3、Atg14、Atg5-Atg12、Atg7、BAG3、Hsp70 和 LAMP1 的水平没有明显变化。尽管 KA 没有诱导神经元死亡，但本研究提供了形态学和生物化学证据，表明 KA 诱导的癫痫持续状态激活了苔藓纤维中的 caspase-3，并在 C57BL/6 海马体中诱导了自噬。这些数据表明，自噬因子可能调节锥体细胞对 KA 的敏感性，自噬可能构成内源性神经保护武器库的一部分，这可能是 C57BL/6 海马体细胞对 KA 诱导的神经元死亡产生抗性的原因。
