美国斯坦福大学Michelle Monje，Yuan Pan和美国华盛顿大学医学院团队共同合作，近期取得重要工作进展。他们研究提出，Nf1基因突变会破坏小鼠活动依赖性少突胶质细胞可塑性和运动学习能力。相关研究成果2024年5月30日在线发表于《自然—神经科学》杂志上。

据介绍，神经遗传性疾病，如1型神经纤维瘤病（NF1），可导致认知和运动障碍，传统上归因于固有的神经元缺陷，如突触功能的破坏。活性调节的少突胶质细胞可塑性也通过调节神经回路动力学来促进认知和运动功能。然而，少突胶质细胞可塑性与NF1神经功能障碍的相关性尚不清楚。

研究人员探讨了少突胶质细胞祖细胞（OPC）对小鼠NF1综合征病理特征的贡献。同窝的雄性和雌性（4–24 周龄）在本研究中同样使用。研究人员证明，具有全局或OPC特异性Nf1杂合性的小鼠在活性依赖性少突胶质发生方面表现出缺陷，并具有局灶性OPC高密度，稳态OPC区域边界被破坏。由于不同的PI3K/AKT激活，这些OPC高密度以细胞固有的Nf1突变特异性方式发展。OPC特异性Nf1缺失会损害少突胶质细胞的分化，并消除少突胶质对神经元活动的正常反应，导致运动学习表现受损。

总之，这些发现表明，Nf1突变延迟了少突胶质细胞的发育，并破坏了小鼠正常运动学习所必需的活性依赖性OPC功能。

附：英文原文

Title: Nf1 mutation disrupts activity-dependent oligodendroglial plasticity and motor learning in mice

Author: Pan, Yuan, Hysinger, Jared D., Yaln, Belgin, Lennon, James J., Byun, Youkyeong Gloria, Raghavan, Preethi, Schindler, Nicole F., Anastasaki, Corina, Chatterjee, Jit, Ni, Lijun, Xu, Haojun, Malacon, Karen, Jahan, Samin M., Ivec, Alexis E., Aghoghovwia, Benjamin E., Mount, Christopher W., Nagaraja, Surya, Scheaffer, Suzanne, Attardi, Laura D., Gutmann, David H., Monje, Michelle

Issue&Volume: 2024-05-30

Abstract: Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4–24weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects in activity-dependent oligodendrogenesis and harbor focal OPC hyperdensities with disrupted homeostatic OPC territorial boundaries. These OPC hyperdensities develop in a cell-intrinsic Nf1 mutation-specific manner due to differential PI3K/AKT activation. OPC-specific Nf1 loss impairs oligodendroglial differentiation and abrogates the normal oligodendroglial response to neuronal activity, leading to impaired motor learning performance. Collectively, these findings show that Nf1 mutation delays oligodendroglial development and disrupts activity-dependent OPC function essential for normal motor learning in mice.

DOI: 10.1038/s41593-024-01654-y

Source: https://www.nature.com/articles/s41593-024-01654-y