Neurogranin, Encoded by the Schizophrenia Risk Gene NRGN, Bidirectionally Modulates Synaptic Plasticity via Calmodulin-Dependent Regulation of the Neuronal Phosphoproteome.
Neurogranin, Encoded by the Schizophrenia Risk Gene NRGN, Bidirectionally Modulates Synaptic Plasticity via Calmodulin-Dependent Regulation of the Neuronal Phosphoproteome.
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由精神分裂症危险基因NRGN编码的Neurogranin，双向通过钙调蛋白依赖性调节神经元磷酸蛋白酶调节突触可塑性。
DOI：
10.1016/j.biopsych.2020.07.014
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发表时间：
2021-02-01
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
神经颗粒蛋白（Ng）是由精神分裂症风险基因NRGN编码的一种钙调素结合蛋白，在突触后区室中富集，并且其在精神分裂症患者死后脑中的表达减少。Ng的经验依赖性翻译是编码背景记忆的关键，Ng在关键期调节初级视皮层的发育可塑性。然而，Ng对调节突触可塑性的神经元信号传导的总体影响是未知的。在小鼠中通过病毒介导的基因操作实现改变的Ng表达。对长时程增强（LTP）的影响使用尖峰时间依赖性可塑性协议进行评估。定量磷酸化蛋白质组学分析导致了重要磷酸化靶点的发现。一个确定的候选人进行了检查与高通量平面膜片钳，并验证与药理学操作。Ng双向调节海马LTP。降低Ng水平显著影响突触后密度蛋白的磷酸化模式，包括谷氨酸受体、GTP酶、激酶、RNA结合蛋白、选择性离子通道和离子转运蛋白，其中一些突出了精神分裂症和自闭症相关基因的簇。NMDAR亚基Grin2A（一个重要的磷酸化靶点）的低磷酸化导致NMDAR电流的加速衰减。阻断蛋白磷酸酶PP2B活性可挽救NMDAR电流衰减的加速和Ng敲低介导的LTP损伤，这暗示了突触PP2B活性对这些缺陷的要求。改变的Ng水平影响神经元蛋白的磷酸化景观。PP2B活性是介导由降低Ng水平引起的突触可塑性缺陷所必需的，揭示了精神分裂症风险基因与认知缺陷的新机制联系。
Neurogranin (Ng), encoded by the schizophrenia risk gene NRGN, is a calmodulin-binding protein enriched in the postsynaptic compartments, and its expression is reduced in the post-mortem brains of schizophrenic patients. Experience-dependent translation of Ng is critical for encoding contextual memory, and Ng regulates the developmental plasticity in the primary visual cortex during the critical period. However, the overall impact of Ng on the neuronal signaling that regulates synaptic plasticity is unknown. Altered Ng expression was achieved via virus-mediated gene manipulation in mice. The effect on long-term potentiation (LTP) was accessed using spike-timing-dependent plasticity protocols. Quantitative phosphoproteomics analyses led to discoveries in significant phospho-targets. An identified candidate was examined with high-throughput planar patch clamp, and validated with pharmacological manipulation. Ng bidirectionally modulated LTP in the hippocampus. Decreasing Ng levels significantly affected the phosphorylation pattern of postsynaptic density proteins, including glutamate receptors, GTPases, kinases, RNA binding proteins, selective ion channels and ionic transporters, some of which highlighted the clusters of schizophrenia- and autism-related genes. Hypo-phosphorylation of NMDAR subunit Grin2A, one significant phospho-target, resulted in accelerated decay of NMDAR currents. Blocking protein phosphatase PP2B activity rescued the accelerated NMDAR current decay and the impairment of LTP mediated by Ng knockdown, implicating the requirement of synaptic PP2B activity for the deficits. Altered Ng levels affect the phosphorylation landscape of neuronal proteins. PP2B activity is required for mediating the deficit in synaptic plasticity caused by decreasing Ng levels, revealing a novel mechanistic link of a schizophrenia risk gene to cognitive deficits.
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