ER stress-induced modulation of neural activity and seizure susceptibility is impaired in a fragile X syndrome mouse model.
ER stress-induced modulation of neural activity and seizure susceptibility is impaired in a fragile X syndrome mouse model.
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DOI：
10.1016/j.nbd.2021.105450
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发表时间：
2021-10
影响因子：
6.1
通讯作者：
Tsai NP
中科院分区：
文献类型：
--
作者：
Liu DC;Lee KY;Lizarazo S;Cook JK;Tsai NP
神经元兴奋性稳态失衡常见于脆性 X 综合征 (FXS) 患者和 FXS 动物模型（Fmr1 KO）中。虽然 FXS 稳态时神经元内在兴奋性和突触活动的改变被认为会导致这种缺陷，并最终增加 FXS 中癫痫发作的易感性，但目前仍不清楚 FXS 中外部挑战后神经元兴奋性的稳态反应是否以及如何被破坏。我们之前的工作表明，诱导内质网（ER）应激后的急性反应可以降低神经活动和癫痫易感性。由于许多与 ER 应激反应相关的信号通路都是由 Fmr1 介导的，因此我们想知道 FXS 中急性 ER 应激诱导的神经活动减少和癫痫易感性是否发生改变。我们的结果首先表明，在野生型小鼠中，急性内质网应激可以在体外触发依赖于蛋白质合成的神经网络同步预防，并在体内降低对红藻氨酸诱导的癫痫发作的易感性，但在 Fmr1 KO 小鼠中则不然。从机制上讲，我们发现急性内质网应激诱导的小鼠双分钟-2 (Mdm2) 激活、p53 泛素化以及随后的瞬时蛋白质合成在 Fmr1 KO 神经元中均受到损害。使用 p53 抑制剂 Pifithrin-α 来模拟 p53 失活，我们能够抑制 Fmr1 KO 小鼠在 ER 应激诱导后神经网络同步的增加并降低癫痫易感性。总之，我们的数据揭示了 Fmr1 KO 小鼠中的一种新的细胞缺陷，并表明对常见外部挑战的反应受损可能导致 FXS 中神经元兴奋性稳态失衡。
Imbalanced neuronal excitability homeostasis is commonly observed in patients with fragile X syndrome (FXS) and the animal model of FXS, the Fmr1 KO. While alterations of neuronal intrinsic excitability and synaptic activity at the steady state in FXS have been suggested to contribute to such a deficit and ultimately the increased susceptibility to seizures in FXS, it remains largely unclear whether and how the homeostatic response of neuronal excitability following extrinsic challenges is disrupted in FXS. Our previous work has shown that the acute response following induction of endoplasmic reticulum (ER) stress can reduce neural activity and seizure susceptibility. Because many signaling pathways associated with ER stress response are mediated by Fmr1, we asked whether acute ER stress–induced reduction of neural activity and seizure susceptibility are altered in FXS. Our results first revealed that acute ER stress can trigger a protein synthesis–dependent prevention of neural network synchronization in vitro and a reduction of susceptibility to kainic acid–induced seizures in vivo in wild-type but not in Fmr1 KO mice. Mechanistically, we found that acute ER stress–induced activation of murine double minute-2 (Mdm2), ubiquitination of p53, and the subsequent transient protein synthesis are all impaired in Fmr1 KO neurons. Employing a p53 inhibitor, Pifithrin-α, to mimic p53 inactivation, we were able to blunt the increase in neural network synchronization and reduce the seizure susceptibility in Fmr1 KO mice following ER stress induction. In summary, our data revealed a novel cellular defect in Fmr1 KO mice and suggest that an impaired response to common extrinsic challenges may contribute to imbalanced neuronal excitability homeostasis in FXS.
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