Zucchini Silvia, Buzzi Andrea, Barbieri Mario, Rodi Donata, Paradiso Beatrice, Binaschi Anna, Coffin J Douglas, Marzola Andrea, Cifelli Pierangelo, Belluzzi Ottorino, Simonato Michele
Section of Pharmacology, Department of Clinical Experimental Medicine, Section of Pathology, National Institute of Neuroscience and Neuroscience Center, University of Ferrara, 44100 Ferrara, Italy.
J Neurosci. 2008 Dec 3;28(49):13112-24. doi: 10.1523/JNEUROSCI.1472-08.2008.
Fibroblast growth factor 2 (FGF-2) has multiple, pleiotropic effects on the nervous system that include neurogenesis, neuroprotection and neuroplasticity. Thus, alteration in FGF-2 expression patterns may have a profound impact in brain function, both in normal physiology and in pathology. Here, we used FGF-2 transgenic mice (TgFGF2) to study the effects of endogenous FGF-2 overexpression on susceptibility to seizures and to the pathological consequences of seizures. TgFGF2 mice display increased FGF-2 expression in hippocampal pyramidal neurons and dentate granule cells. Increased density of glutamatergic synaptic vesicles was observed in the hippocampus of TgFGF2 mice, and electrophysiological data (input/output curves and patch-clamp recordings in CA1) confirmed an increase in excitatory inputs in CA1, suggesting the presence of a latent hyperexcitability. Indeed, TgFGF2 mice displayed increased susceptibility to kainate-induced seizures compared with wild-type (WT) littermates, in that latency to generalized seizure onset was reduced, whereas behavioral seizure scores and lethality were increased. Finally, WT and TgFGF2 mice with similar seizure scores were used for examining seizure-induced cellular consequences. Neurogenesis and mossy fiber sprouting were not significantly different between the two groups. In contrast, cell damage (assessed with Fluoro-Jade B, silver impregnation and anti-caspase 3 immunohistochemistry) was significantly lower in TgFGF2 mice, especially in the areas of overexpression (CA1 and CA3), indicating reduction of seizure-induced necrosis and apoptosis. These data suggest that FGF-2 may be implicated in seizure susceptibility and in seizure-induced plasticity, exerting different, and apparently contrasting effects: favoring ictogenesis but reducing seizure-induced cell death.
成纤维细胞生长因子2（FGF - 2）对神经系统具有多种多效性作用，包括神经发生、神经保护和神经可塑性。因此，FGF - 2表达模式的改变可能对正常生理和病理状态下的脑功能产生深远影响。在此，我们使用FGF - 2转基因小鼠（TgFGF2）来研究内源性FGF - 2过表达对癫痫易感性以及癫痫病理后果的影响。TgFGF2小鼠海马锥体细胞和齿状颗粒细胞中的FGF - 2表达增加。在TgFGF2小鼠的海马中观察到谷氨酸能突触小泡密度增加，电生理数据（CA1区的输入/输出曲线和膜片钳记录）证实CA1区兴奋性输入增加，提示存在潜在的兴奋性过高。事实上，与野生型（WT）同窝小鼠相比，TgFGF2小鼠对海藻酸诱导的癫痫发作易感性增加，表现为全身性癫痫发作开始的潜伏期缩短，而行为性癫痫发作评分和致死率增加。最后，使用癫痫发作评分相似的WT和TgFGF2小鼠来检查癫痫发作诱导的细胞后果。两组之间的神经发生和苔藓纤维发芽没有显著差异。相反，TgFGF2小鼠中的细胞损伤（用Fluoro - Jade B、银浸染和抗半胱天冬酶3免疫组织化学评估）明显更低，尤其是在过表达区域（CA1和CA3），表明癫痫发作诱导的坏死和凋亡减少。这些数据表明，FGF - 2可能与癫痫易感性和癫痫发作诱导的可塑性有关，发挥不同且明显相反的作用：促进癫痫发作但减少癫痫发作诱导的细胞死亡。
