Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
J Neurosci. 2010 Sep 15;30(37):12432-45. doi: 10.1523/JNEUROSCI.0895-10.2010.
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 Ig-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 NMDA receptor-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 extracellular signal-regulated kinase 1/2 (ERK1/2), signaling intermediates known to regulate neuronal growth and synaptic function. In primary cortical 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.
在成年哺乳动物中枢神经系统中，生长抑制剂少突胶质细胞-髓鞘糖蛋白 (OMgp) 和网蛋白 RTN4 (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 (NgR1) 和配对免疫球蛋白样受体-B (PirB) 复合物，调节神经元形态。在健康的中枢神经系统中，NgR1 调节树突棘形状，并减弱 Schaffer 侧枝-CA1 突触的活动驱动的突触可塑性。在这里，我们研究了 Nogo 和 OMgp 是否影响功能突触可塑性，即突触传递发生的效率。在成年小鼠的急性海马切片中，局部应用于 Schaffer 侧枝-CA1 突触时，Nogo-66 和 OMgp 抑制 NMDA 受体依赖性长时程增强 (LTP)。Nogo-66 和 OMgp 均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形式。PirB(-/-) 和 NgR1(-/-) 单突变体和 NgR1(-/-);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，NgR1(-/-) 切片中的 LTD 缺失，但 PirB(-/-) 切片中缺失。机制研究表明，Nogo-66 和 OMgp 以 NgR1 依赖性方式抑制 LTP。OMgp 通过 PirB 抑制 LTP，但独立于 p75。这表明 NgR1 和 PirB 参与配体依赖性抑制突触可塑性。NgR1 的缺失导致细胞外信号调节激酶 1/2 (ERK1/2) 的磷酸化增加，ERK1/2 是已知调节神经元生长和突触功能的信号转导中间物。在原代皮质神经元中，BDNF 诱发的 AKT 和 p70S6 激酶的磷酸化在髓鞘抑制剂存在时减弱。总之，我们提供的证据表明，神经元生长抑制和突触强度抑制的机制是相关的。因此，髓鞘抑制剂及其受体可能协调中枢神经系统健康和疾病中结构和功能的神经元可塑性。
