Inhibition of IL-1β Signaling Normalizes NMDA-Dependent Neurotransmission and Reduces Seizure Susceptibility in a Mouse Model of Creutzfeldt-Jakob Disease
Inhibition of IL-1β Signaling Normalizes NMDA-Dependent Neurotransmission and Reduces Seizure Susceptibility in a Mouse Model of Creutzfeldt-Jakob Disease
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DOI：
10.1523/jneurosci.1301-17.2017
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发表时间：
2017-10-25
影响因子：
5.3
通讯作者：
Chiesa, Roberto
中科院分区：
文献类型：
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作者：
Bertani, Ilaria;Iori, Valentina;Chiesa, Roberto
CreutzFeldt-Jakob病(CJD)是一种由PrP错误折叠引起的神经退行性疾病，临床上以认知和运动障碍、脑电异常和癫痫发作为特征。其神经生理学基础尚不清楚。为了评估NMDA受体(NMDAR)功能障碍的潜在参与，我们分析了Tg(CJD)小鼠海马片中NMDA依赖的突触可塑性，这是一种遗传形式的CJD模型。由于PrP缺失可能导致NMDAR功能上调，我们也分析了PrP基因敲除(KO)小鼠。在类似100d龄的TG(CJD)小鼠的CA1区，Schaffer侧支-连合突触的长时程增强(LTP)与野生型(WT)对照组相似，但存在化塑性逆转，GluN2B磷酸化增加，这表明NMDAR激活增强。PrP KO小鼠也出现了类似但不太明显的变化。在300d龄时，Tg(CJD)组小鼠LTP的大小增加，而PrP KO组小鼠LTP的大小降低，这表明海马区突触反应性的变化存在差异。TG(CJD)而不是PrP KO小鼠天生比WT对照组更容易受到红藻氨酸诱导的海马局灶性癫痫的影响。Tg(CJD)组大鼠海马区IL-1β阳性星形胶质细胞增多，阻断IL-1受体信号可恢复正常突触反应，降低癫痫敏感性。这些结果表明，甘油三酯(CJD)小鼠依赖NMDA的谷氨酸能传递的改变并不完全依赖PrP功能丧失。此外，星形胶质细胞IL-1β在突触反应增强和癫痫敏感性中发挥作用，提示靶向IL-1β信号可能为CJD提供一种新的对症治疗方法。
Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder caused by prion protein (PrP) misfolding, clinically recognized by cognitive and motor deficits, electroencephalographic abnormalities, and seizures. Its neurophysiological bases are not known. To assess the potential involvement of NMDA receptor (NMDAR) dysfunction, we analyzed NMDA-dependent synaptic plasticity in hippocampal slices from Tg(CJD) mice, which model a genetic form of CJD. Because PrP depletion may result in functional upregulation of NMDARs, we also analyzed PrP knock-out (KO) mice. Long-term potentiation (LTP) at the Schaffer collateral-commissural synapses in the CA1 area of similar to 100-d-old Tg(CJD) mice was comparable to that of wild-type (WT) controls, but there was an inversion of metaplasticity, with increased GluN2B phosphorylation, which is indicative of enhanced NMDAR activation. Similar but less marked changes were seen in PrP KO mice. At similar to 300 d of age, the magnitude of LTP increased in Tg(CJD) mice but decreased in PrP KO mice, indicating divergent changes in hippocampal synaptic responsiveness. Tg(CJD) but not PrP KO mice were intrinsically more susceptible than WT controls to focal hippocampal seizures induced by kainic acid. IL-1 beta-positive astrocytes increased in the Tg(CJD) hippocampus, and blocking IL-1 receptor signaling restored normal synaptic responses and reduced seizure susceptibility. These results indicate that alterations in NMDA-dependent glutamatergic transmission in Tg(CJD) mice do not depend solely on PrP functional loss. Moreover, astrocytic IL-1 beta plays a role in the enhanced synaptic responsiveness and seizure susceptibility, suggesting that targeting IL-1 beta signaling may offer a novel symptomatic treatment for CJD.