Dysfunctional Calcium and Glutamate Signaling in Striatal Astrocytes from Huntington's Disease Model Mice
Dysfunctional Calcium and Glutamate Signaling in Striatal Astrocytes from Huntington's Disease Model Mice
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DOI：
10.1523/jneurosci.3693-15.2016
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发表时间：
2016-03-23
影响因子：
5.3
通讯作者：
Khakh, Baljit S.
中科院分区：
文献类型：
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作者：
Jiang, Ruotian;Diaz-Castro, Blanca;Khakh, Baljit S.
星形胶质细胞覆盖整个中枢神经系统，但它们在健康和疾病的神经回路中的功能仍不完全清楚。我们使用基因编码的 Ca2+ 和谷氨酸指示剂来探索星形胶质细胞参与成年野生型 (WT) 和亨廷顿病 (HD) 模型小鼠皮质纹状体回路的规则，这些小鼠在不伴有明显星形胶质细胞增生的年龄（大约出生后 70-80 天）。 WT纹状体星形胶质细胞显示出广泛的自发Ca2+信号，但对皮质刺激没有反应，这意味着星形胶质细胞很大程度上脱离了健康组织中的皮质输入。相比之下，在HD模型小鼠中，自发Ca2+信号的频率、持续时间和幅度显着降低，但星形胶质细胞对诱发Ca2+信号的皮质刺激反应强烈。这些动作电位依赖性星形胶质细胞 Ca2+ 信号是由皮质刺激期间神经元谷氨酸释放介导的，伴随着星形胶质细胞附近细胞外谷氨酸水平的延长，并受到 Glt1 谷氨酸转运蛋白的严格门控。此外，在 HD 模型小鼠中观察到的功能失调的 Ca2+ 和谷氨酸信号传导在很大程度上（但不是完全）通过 Kir4.1 的星形胶质细胞特异性恢复而得以恢复，这强调了已知在 HD 模型小鼠中减少的 K+ 稳态机制的重要贡献。总的来说，我们的数据表明星形胶质细胞在皮质纹状体回路中的参与在 HD 中显着改变。这种前驱星形胶质细胞功能障碍可能代表 HD 和其他脑部疾病的新治疗靶点。
Astrocytes tile the entire CNS, but their functions within neural circuits in health and disease remain incompletely understood. We used genetically encoded Ca2+ and glutamate indicators to explore the rules for astrocyte engagement in the corticostriatal circuit of adult wild-type (WT) and Huntington's disease (HD) model mice at ages not accompanied by overt astrogliosis (at approximately postnatal days 70-80). WT striatal astrocytes displayed extensive spontaneous Ca2+ signals, but did not respond to cortical stimulation, implying that astrocytes were largely disengaged from cortical input in healthy tissue. In contrast, in HD model mice, spontaneous Ca2+ signals were significantly reduced in frequency, duration, and amplitude, but astrocytes responded robustly to cortical stimulation with evoked Ca2+ signals. These action-potential-dependent astrocyte Ca2+ signals were mediated by neuronal glutamate release during cortical stimulation, accompanied by prolonged extracellular glutamate levels near astrocytes and tightly gated by Glt1 glutamate transporters. Moreover, dysfunctional Ca2+ and glutamate signaling that was observed in HD model mice was largely, but not completely, rescued by astrocyte specific restoration of Kir4.1, emphasizing the important contributions of K+ homeostatic mechanisms that are known to be reduced in HD model mice. Overall, our data show that astrocyte engagement in the corticostriatal circuit is markedly altered in HD. Such prodromal astrocyte dysfunctions may represent novel therapeutic targets in HD and other brain disorders.