Center for Translational Neuromedicine, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen N 2200, Denmark.
Department of Computer Science, University of Copenhagen, Faculty of Science, Copenhagen N 2200, Denmark.
Proc Natl Acad Sci U S A. 2023 Jun 13;120(24):e2210719120. doi: 10.1073/pnas.2210719120. Epub 2023 Jun 6.
Astroglial dysfunction contributes to the pathogenesis of Huntington's disease (HD), and glial replacement can ameliorate the disease course. To establish the topographic relationship of diseased astrocytes to medium spiny neuron (MSN) synapses in HD, we used 2-photon imaging to map the relationship of turboRFP-tagged striatal astrocytes and rabies-traced, EGFP-tagged coupled neuronal pairs in R6/2 HD and wild-type (WT) mice. The tagged, prospectively identified corticostriatal synapses were then studied by correlated light electron microscopy followed by serial block-face scanning EM, allowing nanometer-scale assessment of synaptic structure in 3D. By this means, we compared the astrocytic engagement of single striatal synapses in HD and WT brains. R6/2 HD astrocytes exhibited constricted domains, with significantly less coverage of mature dendritic spines than WT astrocytes, despite enhanced engagement of immature, thin spines. These data suggest that disease-dependent changes in the astroglial engagement and sequestration of MSN synapses enable the high synaptic and extrasynaptic levels of glutamate and K that underlie striatal hyperexcitability in HD. As such, these data suggest that astrocytic structural pathology may causally contribute to the synaptic dysfunction and disease phenotype of those neurodegenerative disorders characterized by network overexcitation.
星形胶质细胞功能障碍导致亨廷顿病（HD）的发病机制，而胶质细胞替代可以改善疾病进程。为了确定 HD 中病变星形胶质细胞与中脑皮质投射神经元（MSN）突触的拓扑关系，我们使用双光子成像来绘制 turboRFP 标记的纹状体星形胶质细胞与 R6/2 HD 和野生型（WT）小鼠中狂犬病追踪的、EGFP 标记的偶联神经元对之间的关系。然后，通过相关光电子显微镜和连续块面扫描 EM 对标记的、前瞻性鉴定的皮质纹状体突触进行研究，允许在 3D 中对突触结构进行纳米级评估。通过这种方法，我们比较了 HD 和 WT 大脑中单个纹状体突触的星形胶质细胞参与情况。与 WT 星形胶质细胞相比，R6/2 HD 星形胶质细胞表现出收缩域，成熟树突棘的覆盖范围明显减少，尽管不成熟的、细的棘突参与度增强。这些数据表明，MSN 突触的星形胶质细胞参与和隔离的疾病相关变化使谷氨酸和 K 的突触和 extrasynaptic 水平升高，这是 HD 纹状体过度兴奋的基础。因此，这些数据表明，星形胶质细胞的结构病理学可能是导致以网络过度兴奋为特征的神经退行性疾病的突触功能障碍和疾病表型的原因。
