Sahel Aurélia, Ortiz Fernando C, Kerninon Christophe, Maldonado Paloma P, Angulo María Cecilia, Nait-Oumesmar Brahim
INSERM U1127, Institut du Cerveau et de la Moelle Epinière Paris, France ; Université Paris 6, Sorbonne Paris Cité, UMR-S1127 Paris, France ; Centre National de la Recherche Scientifique UMR 7225 Paris, France.
INSERM U1128 Paris, France ; Université Paris Descartes, Sorbonne Paris Cité Paris, France.
Front Cell Neurosci. 2015 Mar 17;9:77. doi: 10.3389/fncel.2015.00077. eCollection 2015.
Oligodendrocyte precursor cells (OPCs) are a major source of remyelinating oligodendrocytes in demyelinating diseases such as Multiple Sclerosis (MS). While OPCs are innervated by unmyelinated axons in the normal brain, the fate of such synaptic contacts after demyelination is still unclear. By combining electrophysiology and immunostainings in different transgenic mice expressing fluorescent reporters, we studied the synaptic innervation of OPCs in the model of lysolecithin (LPC)-induced demyelination of corpus callosum. Synaptic innervation of reactivated OPCs in the lesion was revealed by the presence of AMPA receptor-mediated synaptic currents, VGluT1+ axon-OPC contacts in 3D confocal reconstructions and synaptic junctions observed by electron microscopy. Moreover, 3D confocal reconstructions of VGluT1 and NG2 immunolabeling showed the existence of glutamatergic axon-OPC contacts in post-mortem MS lesions. Interestingly, patch-clamp recordings in LPC-induced lesions demonstrated a drastic decrease in spontaneous synaptic activity of OPCs early after demyelination that was not caused by an impaired conduction of compound action potentials. A reduction in synaptic connectivity was confirmed by the lack of VGluT1+ axon-OPC contacts in virtually all rapidly proliferating OPCs stained with EdU (50-ethynyl-20-deoxyuridine). At the end of the massive proliferation phase in lesions, the proportion of innervated OPCs rapidly recovers, although the frequency of spontaneous synaptic currents did not reach control levels. In conclusion, our results demonstrate that newly-generated OPCs do not receive synaptic inputs during their active proliferation after demyelination, but gain synapses during the remyelination process. Hence, glutamatergic synaptic inputs may contribute to inhibit OPC proliferation and might have a physiopathological relevance in demyelinating disorders.
少突胶质前体细胞（OPCs）是脱髓鞘疾病（如多发性硬化症，MS）中髓鞘再生少突胶质细胞的主要来源。虽然在正常大脑中OPCs由无髓鞘轴突支配，但脱髓鞘后这种突触联系的命运仍不清楚。通过在表达荧光报告基因的不同转基因小鼠中结合电生理学和免疫染色，我们研究了卵磷脂（LPC）诱导的胼胝体脱髓鞘模型中OPCs的突触支配情况。损伤部位重新激活的OPCs的突触支配通过AMPA受体介导的突触电流的存在、三维共聚焦重建中VGluT1 +轴突-OPC接触以及电子显微镜观察到的突触连接来揭示。此外，VGluT1和NG2免疫标记的三维共聚焦重建显示在死后MS损伤中存在谷氨酸能轴突-OPC接触。有趣的是，LPC诱导损伤中的膜片钳记录表明，脱髓鞘后早期OPCs的自发突触活动急剧下降，这不是由复合动作电位传导受损引起的。几乎所有用EdU（5-乙炔基-2'-脱氧尿苷）染色的快速增殖OPCs中缺乏VGluT1 +轴突-OPC接触，证实了突触连接性的降低。在损伤的大量增殖阶段结束时，尽管自发突触电流的频率未达到对照水平，但受支配的OPCs比例迅速恢复。总之，我们的结果表明，新生成的OPCs在脱髓鞘后的活跃增殖过程中不接受突触输入，但在髓鞘再生过程中获得突触。因此，谷氨酸能突触输入可能有助于抑制OPCs增殖，并且可能在脱髓鞘疾病中具有生理病理学意义。
