DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders
DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders
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DOI：
10.1111/jnc.13663
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发表时间：
2016-08
影响因子：
4.7
通讯作者：
Meng Xia;Shanshan Zhu;A. Shevelkin;C. Ross;M. Pletnikov
中科院分区：
文献类型：
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作者：
Meng Xia;Shanshan Zhu;A. Shevelkin;C. Ross;M. Pletnikov
精神分裂症1（DISC 1）是一种遗传风险因素，与涉及神经发育和突触信号中断的主要精神障碍有关。神经胶质细胞如星形胶质细胞可以调节神经元和突触的成熟。虽然星形胶质细胞表达DISC 1，但星形胶质细胞DISC 1在突触调节中的作用仍然未知。我们在星形胶质细胞中表达了DISC 1的致病性显性阴性形式，即突变DISC 1，以使用共培养模型阐明星形胶质细胞DISC 1在树突成熟以及兴奋性和抑制性突触中的作用。我们发现，与对照星形胶质细胞相比，野生型原代神经元在与表达突变DISC 1的星形胶质细胞共培养时表现出较不复杂的树突状分支。与对照星形胶质细胞相比，我们观察到与表达突变DISC 1的星形胶质细胞共培养的野生型原代神经元上兴奋性突触而非抑制性突触的密度显著降低。用D-丝氨酸处理共培养物恢复了树突发育和兴奋性突触的密度。我们的研究结果首次表明，突变DISC 1降低了星形胶质细胞支持共培养神经元中树突和突触成熟的能力，并且D-丝氨酸可以恢复树突和突触异常。这些结果为星形胶质细胞内的遗传风险因素可能导致精神疾病的发病机制提供了新的见解。
Disrupted‐In‐Schizophrenia 1 (DISC1) is a genetic risk factor implicated in major mental disorders that involve disrupted neurodevelopment and synaptic signaling. Glial cells such as astrocytes can regulate neuronal and synaptic maturation. Although astrocytes express DISC1, the role of astrocyte DISC1 in synaptic regulation remains unknown. We expressed a pathogenic, dominant‐negative form of DISC1, mutant DISC1, in astrocytes to elucidate the roles of astrocytic DISC1 in maturation of dendrites and excitatory and inhibitory synapses using a co‐culture model. We found that wild‐type primary neurons exhibited less elaborated dendritic arborization when co‐cultured with astrocytes that express mutant DISC1, compared to control astrocytes. We observed significantly decreased density of excitatory but not inhibitory synapses on wild‐type primary neurons that were co‐cultured with astrocytes that express mutant DISC1, compared to control astrocytes. Treatment of co‐cultures with D‐serine restored dendritic development and density of excitatory synapses. Our findings show for the first time that mutant DISC1 diminished the capacity of astrocytes to support dendritic and synaptic maturation in co‐cultured neurons, and that D‐serine can restore the dendritic and synaptic abnormalities. The results provide a new insight into the mechanisms whereby genetic risk factors within astrocytes could contribute the pathogenesis of psychiatric disorders.