Oligodendrocyte-myelin glycoprotein and Nogo negatively regulate activity-dependent synaptic plasticity.
Oligodendrocyte-myelin glycoprotein and Nogo negatively regulate activity-dependent synaptic plasticity.
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DOI：
10.1523/jneurosci.0895-10.2010
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发表时间：
2010-09-15
期刊：
影响因子：
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通讯作者：
Giger RJ
中科院分区：
文献类型：
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作者：
Raiker SJ;Lee H;Baldwin KT;Duan Y;Shrager P;Giger RJ
在成年哺乳动物CNS中，生长抑制剂少突胶质细胞-髓鞘糖蛋白（OMgp）和网状蛋白RTN 4（Nogo）在少突胶质细胞和神经元中广泛表达。Nogo和OMgp与神经元细胞表面受体Nogo受体-1（NgR 1）和配对免疫球蛋白样受体-B（PirB）复合以调节神经元形态。在健康的中枢神经系统中，NgR 1调节树突棘的形状，并减弱Schaffer侧支-CA 1突触的活性驱动的突触可塑性。在这里，我们研究是否Nogo和OMgp影响功能性突触可塑性，突触传递发生的功效。在成年小鼠的急性海马切片中，当局部应用于Schaffer侧支-CA 1突触时，Nogo-66和OMgp抑制NMDAR依赖性长时程增强（LTP）。Nogo-66和OMgp都不影响基础突触传递或成对脉冲易化，这是一种短期突触可塑性。PirB−/−和NgR 1 −/−单突变体和NgR 1 −/−;PirB−/−双突变体显示正常的LTP，与野生型对照无区别。在幼年小鼠中，NgR 1 −/−切片中不存在LTD，但PirB−/−切片中不存在LTD。机制研究表明，Nogo-66和OMgp以NgR 1依赖的方式抑制LTP。OMgp部分通过PirB抑制LTP，但不依赖于p75。这表明NgR 1和PirB参与突触可塑性的配体依赖性抑制。NgR 1的缺失导致erk 1/2的磷酸化增加，erk 1/2是已知调节神经元生长和突触功能的信号中间体。在原代海马神经元中，BDNF引起的AKT和p70 S6-激酶磷酸化在髓鞘抑制剂存在下减弱。总的来说，我们提供的证据表明，神经元生长抑制和抑制突触强度的机制是相关的。因此，髓鞘抑制剂和它们的受体可以协调CNS健康和疾病中的结构和功能神经元可塑性。
In the adult mammalian CNS, the growth inhibitors oligodendrocyte-myelin glycoprotein (OMgp) and the reticulon RTN4 (Nogo) are broadly expressed in oligodendrocytes and neurons. Nogo and OMgp complex with the neuronal cell surface receptors Nogo receptor-1 (NgR1) and paired immunoglobulin-like receptor-B (PirB) to regulate neuronal morphology. In the healthy CNS, NgR1 regulates dendritic spine shape and attenuates activity-driven synaptic plasticity at Schaffer collateral-CA1 synapses. Here we examine whether Nogo and OMgp influence functional synaptic plasticity, the efficacy by which synaptic transmission occurs. In acute hippocampal slices of adult mice, Nogo-66 and OMgp suppress NMDAR-dependent long-term potentiation (LTP) when locally applied to Schaffer collateral-CA1 synapses. Neither Nogo-66 nor OMgp influences basal synaptic transmission or paired-pulse facilitation, a form of short-term synaptic plasticity. PirB−/− and NgR1−/− single mutants and NgR1−/−;PirB−/− double mutants show normal LTP, indistinguishable from wild-type controls. In juvenile mice, LTD in NgR1−/− but not PirB−/− slices is absent. Mechanistic studies revealed that Nogo-66 and OMgp suppress LTP in an NgR1–dependent manner. OMgp inhibits LTP in part through PirB but independently of p75. This suggests that NgR1 and PirB participate in ligand-dependent inhibition of synaptic plasticity. Loss of NgR1 leads to increased phosphorylation of erk1/2, signaling intermediates known to regulate neuronal growth and synaptic function. In primary hippocampal neurons, BDNF elicited phosphorylation of AKT and p70S6-kinase is attenuated in the presence of myelin inhibitors. Collectively, we provide evidence that mechanisms of neuronal growth inhibition and inhibition of synaptic strength are related. Thus, myelin inhibitors and their receptors may coordinate structural and functional neuronal plasticity in CNS health and disease.