Zhou Chunyi, Feng Zhihua, Ko Chien-Ping
Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-2520.
Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-2520
J Neurosci. 2016 Feb 24;36(8):2543-53. doi: 10.1523/JNEUROSCI.3534-15.2016.
Spinal muscular atrophy (SMA) is a motoneuron disease caused by loss or mutation in Survival of Motor Neuron 1 (SMN1) gene. Recent studies have shown that selective restoration of SMN protein in astrocytes partially alleviates pathology in an SMA mouse model, suggesting important roles for astrocytes in SMA. Addressing these underlying mechanisms may provide new therapeutic avenues to fight SMA. Using primary cultures of pure motoneurons or astrocytes from SMNΔ7 (SMA) and wild-type (WT) mice, as well as their mixed and matched cocultures, we characterized the contributions of motoneurons, astrocytes, and their interactions to synapse loss in SMA. In pure motoneuron cultures, SMA motoneurons exhibited normal survival but intrinsic defects in synapse formation and synaptic transmission. In pure astrocyte cultures, SMA astrocytes exhibited defects in calcium homeostasis. In motoneuron-astrocyte contact cocultures, synapse formation and synaptic transmission were significantly reduced when either motoneurons, astrocytes or both were from SMA mice compared with those in WT motoneurons cocultured with WT astrocytes. The reduced synaptic activity is unlikely due to changes in motoneuron excitability. This disruption in synapse formation and synaptic transmission by SMN deficiency was not detected in motoneuron-astrocyte noncontact cocultures. Additionally, we observed a downregulation of Ephrin B2 in SMA astrocytes. These findings suggest that there are both cell autonomous and non-cell-autonomous defects in SMA motoneurons and astrocytes. Defects in contact interactions between SMA motoneurons and astrocytes impair synaptogenesis seen in SMA pathology, possibly due to the disruption of the Ephrin B2 pathway.
脊髓性肌萎缩症（SMA）是一种由运动神经元存活蛋白1（SMN1）基因缺失或突变引起的运动神经元疾病。最近的研究表明，在星形胶质细胞中选择性恢复SMN蛋白可部分缓解SMA小鼠模型中的病理状况，这表明星形胶质细胞在SMA中发挥着重要作用。阐明这些潜在机制可能为对抗SMA提供新的治疗途径。我们使用来自SMNΔ7（SMA）和野生型（WT）小鼠的纯运动神经元或星形胶质细胞的原代培养物，以及它们混合和匹配的共培养物，来确定运动神经元、星形胶质细胞及其相互作用对SMA中突触丧失的影响。在纯运动神经元培养物中，SMA运动神经元表现出正常存活，但在突触形成和突触传递方面存在内在缺陷。在纯星形胶质细胞培养物中，SMA星形胶质细胞在钙稳态方面存在缺陷。在运动神经元-星形胶质细胞接触共培养物中，与野生型运动神经元与野生型星形胶质细胞共培养相比，当运动神经元、星形胶质细胞或两者均来自SMA小鼠时，突触形成和突触传递显著减少。突触活动的降低不太可能是由于运动神经元兴奋性的变化。在运动神经元-星形胶质细胞非接触共培养物中未检测到SMN缺乏导致的突触形成和突触传递的这种破坏。此外，我们观察到SMA星形胶质细胞中Ephrin B2的下调。这些发现表明，SMA运动神经元和星形胶质细胞中存在细胞自主和非细胞自主缺陷。SMA运动神经元和星形胶质细胞之间接触相互作用的缺陷损害了SMA病理中所见的突触形成，这可能是由于Ephrin B2通路的破坏所致。
