Dysregulation and restoration of homeostatic network plasticity in fragile X syndrome mice.
Dysregulation and restoration of homeostatic network plasticity in fragile X syndrome mice.
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DOI：
10.1016/j.neuropharm.2018.06.011
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发表时间：
2018-08
影响因子：
4.7
通讯作者：
Tsai NP
中科院分区：
文献类型：
--
作者：
Jewett KA;Lee KY;Eagleman DE;Soriano S;Tsai NP
神经元中的慢性活动扰动通过调节突触强度或其他内在特性来诱导稳态可塑性，以维持兴奋性的正确生理范围。虽然类似的可塑性也可以发生在人口水平上，但涉及的分子机制仍不清楚。在目前的研究中，我们利用多电极阵列（MEA）记录系统来评估原代小鼠皮层神经元培养的稳态神经网络活动。我们证明，通过抑制GABA（A）受体，神经元活动的慢性升高，可使神经网络活动同步化，并使自发神经网络尖峰的振幅稳态降低。我们随后发现，这种现象是由肿瘤抑制基因p53的泛素化介导的，这是由小鼠双微体2（Mdm 2）触发的。使用小鼠模型脆性X综合征，其中脆性X智力低下蛋白（FMRP）是不存在的（Fmr 1敲除），我们发现，Mdm 2-p53信号，网络同步，和网络尖峰幅度的减少后，慢性活动刺激都受损。在药理学上用匹非林-α抑制p53或在基因上使用p53杂合小鼠在Fmr 1敲除培养物中强制p53失活，可恢复慢性活动刺激后神经网络活动的同步性，并部分纠正神经网络峰电位幅度的稳态降低。总之，我们的研究结果揭示了Fmr 1和Mdm 2-p53信号在神经网络活动的稳态调节中的作用，并提供了对Fmr 1受损时（如脆性X综合征）兴奋性稳态缺陷的深入了解。
Chronic activity perturbations in neurons induce homeostatic plasticity through modulation of synaptic strength or other intrinsic properties to maintain the correct physiological range of excitability. Although similar plasticity can also occur at the population level, what molecular mechanisms are involved remain unclear. In the current study, we utilized a multielectrode array (MEA) recording system to evaluate homeostatic neural network activity of primary mouse cortical neuron cultures. We demonstrated that chronic elevation of neuronal activity through the inhibition of GABA(A) receptors elicits synchronization of neural network activity and homeostatic reduction of the amplitude of spontaneous neural network spikes. We subsequently showed that this phenomenon is mediated by the ubiquitination of tumor suppressor p53, which is triggered by murine double minute-2 (Mdm2). Using a mouse model of fragile X syndrome, in which fragile X mental retardation protein (FMRP) is absent (Fmr1 knockout), we found that Mdm2-p53 signaling, network synchronization, and the reduction of network spike amplitude upon chronic activity stimulation were all impaired. Pharmacologically inhibiting p53 with Pifithrin-α or genetically employing p53 heterozygous mice to enforce the inactivation of p53 in Fmr1 knockout cultures restored the synchronization of neural network activity after chronic activity stimulation and partially corrects the homeostatic reduction of neural network spike amplitude. Together, our findings reveal the roles of both Fmr1 and Mdm2-p53 signaling in the homeostatic regulation of neural network activity and provide insight into the deficits of excitability homeostasis seen when Fmr1 is compromised, such as occurs with fragile X syndrome.
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DOI：
10.1016/j.tig.2017.07.008
发表时间：
2017-10
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Davis JK;Broadie K
通讯作者：
Broadie K
影响因子：
25
作者：
Chang, Michael C.;Park, Joo Min;Pelkey, Kenneth A.;Grabenstatter, Heidi L.;Xu, Desheng;Linden, David J.;Sutula, Thomas P.;McBain, Chris J.;Worley, Paul F.
通讯作者：
Worley, Paul F.
影响因子：
16.2
作者：
Hengen KB;Lambo ME;Van Hooser SD;Katz DB;Turrigiano GG
通讯作者：
Turrigiano GG
影响因子：
2.5
作者：
Brennan, F. X.;Albeck, D. S.;Paylor, R.
通讯作者：
Paylor, R.
影响因子：
4.8
作者：
Fraser, Jennifer A.;Madhumalar, Arumugam;Hupp, Ted R.
通讯作者：
Hupp, Ted R.