Neuron-Glia Interactions in Tuberous Sclerosis Complex Affect the Synaptic Balance in 2D and Organoid Cultures.
Neuron-Glia Interactions in Tuberous Sclerosis Complex Affect the Synaptic Balance in 2D and Organoid Cultures.
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DOI：
10.3390/cells10010134
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发表时间：
2021-01-12
期刊：
影响因子：
6
通讯作者：
Heine VM
中科院分区：
文献类型：
--
作者：
Dooves S;van Velthoven AJH;Suciati LG;Heine VM
结节性硬化症（TSC）是一种影响大脑的遗传性疾病。癫痫和神经发育问题等神经系统症状给患者带来了沉重的负担。神经元和神经胶质细胞都受到TSC突变的影响。先前的研究表明，TSC的兴奋/抑制平衡（E/I平衡）发生了变化。星形胶质细胞在神经元发育中起重要作用，星形胶质细胞功能障碍可引起E/I平衡的改变。我们假设星形胶质细胞影响TSC的突触平衡。TSC患者来源的干细胞分化为星形胶质细胞，与对照星形胶质细胞相比，其增殖能力增强。RNA测序揭示了基因表达的变化，这些基因与表皮生长因子（EGF）信号传导有关，并丰富了编码分泌蛋白或跨膜蛋白的基因。对照神经元在TSC和对照星形胶质细胞的星形细胞条件培养基（ACM）中培养。在TSC ACM中培养后，神经元突触平衡发生改变，VGAT+突触的比例增加。这些发现在类器官中得到证实，呈现出自发的神经元和胶质细胞的三维组织。综上所述，本研究表明TSC星形胶质细胞受到影响并分泌改变突触平衡的因子。由于E/I平衡的改变可能是许多神经性TSC症状的基础，星形胶质细胞可能提供新的治疗靶点。
Tuberous sclerosis complex (TSC) is a genetic disease affecting the brain. Neurological symptoms like epilepsy and neurodevelopmental issues cause a significant burden on patients. Both neurons and glial cells are affected by TSC mutations. Previous studies have shown changes in the excitation/inhibition balance (E/I balance) in TSC. Astrocytes are known to be important for neuronal development, and astrocytic dysfunction can cause changes in the E/I balance. We hypothesized that astrocytes affect the synaptic balance in TSC. TSC patient-derived stem cells were differentiated into astrocytes, which showed increased proliferation compared to control astrocytes. RNA sequencing revealed changes in gene expression, which were related to epidermal growth factor (EGF) signaling and enriched for genes that coded for secreted or transmembrane proteins. Control neurons were cultured in astrocyte-conditioned medium (ACM) of TSC and control astrocytes. After culture in TSC ACM, neurons showed an altered synaptic balance, with an increase in the percentage of VGAT+ synapses. These findings were confirmed in organoids, presenting a spontaneous 3D organization of neurons and glial cells. To conclude, this study shows that TSC astrocytes are affected and secrete factors that alter the synaptic balance. As an altered E/I balance may underlie many of the neurological TSC symptoms, astrocytes may provide new therapeutic targets.
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影响因子：
6
作者：
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通讯作者：
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影响因子：
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