Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology.
Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Hum Mol Genet. 2018 Aug 15;27(16):2805-2816. doi: 10.1093/hmg/ddy189.
Synaptic scaling allows neurons to homeostatically readjust synaptic strength upon chronic neural activity perturbations. Although altered synaptic scaling has been implicated to underlie imbalanced brain excitability in neurological disorders such as autism spectrum disorders and epilepsy, the molecular dysregulation and restoration of synaptic scaling in those diseases have not been demonstrated. Here, we showed that the homeostatic synaptic downscaling is absent in the hippocampal neurons of Fmr1 KO mice, the mouse model of the most common inherited autism, fragile X syndrome (FXS). We found that the impaired homeostatic synaptic downscaling in Fmr1 KO neurons is caused by loss-of-function dephosphorylation of an epilepsy-associated ubiquitin E3 ligase, neural precursor cell expressed developmentally down-regulated gene 4-2, Nedd4-2. Such dephosphorylation of Nedd4-2 is surprisingly caused by abnormally stable tumor suppressor p53 and subsequently destabilized kinase Akt. Dephosphorylated Nedd4-2 fails to elicit 14-3-3-dependent ubiquitination and down-regulation of the GluA1 subunit of AMPA receptor, and therefore impairs synaptic downscaling. Most importantly, using a pharmacological inhibitor of p53, Nedd4-2 phosphorylation, GluA1 ubiquitination and synaptic downscaling are all restored in Fmr1 KO neurons. Together, our results discover a novel cellular mechanism underlying synaptic downscaling, and demonstrate the dysregulation and successful restoration of this mechanism in the FXS mouse model.
突触缩放允许神经元在慢性神经活动扰动后进行自我平衡调整突触强度。尽管改变的突触缩放已被暗示为神经退行性疾病（如自闭症谱系障碍和癫痫）中大脑兴奋性失衡的基础，但这些疾病中的突触缩放的分子失调和恢复尚未得到证明。在这里，我们发现最常见的遗传性自闭症脆性 X 综合征（FXS）的小鼠模型 Fmr1 KO 小鼠的海马神经元中不存在稳态突触缩小。我们发现 Fmr1 KO 神经元中稳态突触缩小受损是由癫痫相关泛素 E3 连接酶、神经前体细胞表达的发育下调基因 4-2（Nedd4-2）的功能丧失性去磷酸化引起的。令人惊讶的是，Nedd4-2 的这种去磷酸化是由异常稳定的肿瘤抑制因子 p53 引起的，随后导致激酶 Akt 不稳定。去磷酸化的 Nedd4-2 无法引发 14-3-3 依赖性泛素化和 AMPA 受体 GluA1 亚基的下调，因此损害了突触缩小。最重要的是，使用 p53 的药理学抑制剂，Nedd4-2 磷酸化、GluA1 泛素化和突触缩小都在 Fmr1 KO 神经元中得到恢复。总之，我们的研究结果揭示了突触缩小的一种新的细胞机制，并证明了该机制在 FXS 小鼠模型中的失调和成功恢复。
