c-Jun N-terminal kinase activation responses induced by hippocampal kindling are mediated by reactive astrocytes
c-Jun N-terminal kinase activation responses induced by hippocampal kindling are mediated by reactive astrocytes
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DOI：
10.1523/jneurosci.1986-05.2006
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发表时间：
2006-08-09
影响因子：
5.3
通讯作者：
Bazan, Nicolas G.
中科院分区：
文献类型：
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作者：
Cole-Edwards, Kasie K.;Musto, Alberto E.;Bazan, Nicolas G.
海马区点燃是内侧颞叶癫痫的一种模型，通过重复刺激海马区而发展起来，并导致EEG测量的后放电增加和持久的癫痫易发状态。新蛋白质的合成被认为是癫痫持续诱发的突触重组和神经细胞凋亡/坏死性死亡的生理和/或病理改变的基础。在这里，我们研究了点燃对刺激诱导的c-Junn末端激酶(JNK)和p38磷酸化的影响，这些事件被认为是癫痫诱导的基因转录变化的上游事件。我们发现，刺激诱导的JNK的磷酸化，而不是p38的磷酸化，在点燃的动物中比在海马区CA1亚区的幼稚动物显著增强。免疫荧光染色证实了JNK激活的这种区域特异性模式，并揭示了反应性星形胶质细胞介导了这一效应。点燃后4d，星形胶质细胞增殖肥大，Vimentin蛋白水平升高，这是星形胶质细胞增生症的常见标志。此外，荧光素B和反活性caspase-3染色显示，这种反应性星形胶质细胞增生与神经元死亡有关。刺激诱导的JNK底物paxlin的磷酸化在点燃动物中增强，但对c-jun的磷酸化无影响。此外，针对MAPK/CDK(丝裂原活化蛋白激酶/细胞周期依赖性激酶)底物的泛抗体表明，胞浆、膜和细胞核中存在磷酸化蛋白。这些磷酸化事件的后果尚不完全清楚，但这些发现表明，星形胶质细胞对异常突触活动的选择性信号反应，信号可能调节点燃进程和/或神经元死亡。
Hippocampal kindling, a model of mesial temporal lobe epilepsy, is developed through repetitive stimulation of the hippocampus and leads to increased after-discharges as measured by EEG and an enduring seizure-prone state. Synthesis of new proteins is thought to form the basis for sustained seizure-induced physiological and/or pathological changes in synaptic reorganization and apoptotic/necrotic neuronal death. Here we examined the effect of kindling on stimulus-induced c-JunN-terminal kinase (JNK) and p38 phosphorylation, events postulated to lie upstream of seizure-induced changes in gene transcription. We found that stimulus-induced phosphorylation of JNK, but not of p38, is significantly enhanced in kindled animals compared with their naive counterparts in the CA1 subregion of the hippocampus. Immunofluorescent staining confirmed this region-specific pattern of JNK activation and revealed that reactive astrocytes mediate this effect. Astrocyte proliferation and hypertrophy, as well as upregulation of vimentin protein levels, common markers of astrogliosis, were present after 4 d of kindling. Moreover, this reactive astrogliosis was associated with neuronal death as visualized with Fluoro-jade B and anti-active caspase-3 staining. Stimulus-induced phosphorylation of the JNK substrate paxillin was enhanced in kindled animals, but not that of c-Jun. Moreover, a pan-antibody against MAPK/CDK (mitogen-activated protein kinases/cyclindependent kinase) substrates indicated the presence of phosphorylated proteins in cytosolic, membrane, and nuclear fractions. The consequence of these phosphorylation events is not completely understood, but these findings suggest a selective astrocytic signaling response to aberrant synaptic activity, signaling that may modulate kindling progression and/or neuronal death.