Insulin regulates astrocyte gliotransmission and modulates behavior
Insulin regulates astrocyte gliotransmission and modulates behavior
复制标题
DOI：
10.1172/jci99366
复制
发表时间：
2018-07-02
影响因子：
15.9
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
--
作者：
Cai, Weikang;Xue, Chang;Kahn, C. Ronald
糖尿病的并发症会影响全身组织，包括中枢神经系统。流行病学研究表明，糖尿病患者患抑郁症、焦虑症、与年龄相关的认知功能减退和阿尔茨海默病的风险增加。大脑或下丘脑神经元缺乏胰岛素受体(IR)的小鼠表现出一系列代谢异常；然而，胰岛素对星形胶质细胞和神经行为的作用仍未得到很好的研究。在这里，我们证明星形胶质细胞是大脑中的直接胰岛素靶点，敲除星形胶质细胞上的IR会导致小鼠焦虑和抑郁样行为的增加。这可以通过删除伏隔核星形胶质细胞上的IR来部分复制。在分子水平上，星形胶质细胞中胰岛素信号的缺失会损害Muncl8c的酪氨酸磷酸化。这导致星形胶质细胞对ATP的胞吐减少，导致多巴胺能神经元上的嘌呤能信号减少。这些减少导致脑片释放的多巴胺减少。中枢给予ATP类似物可逆转星形胶质细胞IR基因敲除小鼠的抑郁样行为。因此，星形细胞胰岛素信号在多巴胺能信号中起着重要作用，提供了星形细胞胰岛素作用可能导致糖尿病、肥胖和其他胰岛素抵抗状态患者抑郁发生率增加的潜在机制。
Complications of diabetes affect tissues throughout the body, including the central nervous system. Epidemiological studies show that diabetic patients have an increased risk of depression, anxiety, age-related cognitive decline, and Alzheimer's disease. Mice lacking insulin receptor (IR) in the brain or on hypothalamic neurons display an array of metabolic abnormalities; however, the role of insulin action on astrocytes and neurobehaviors remains less well studied. Here, we demonstrate that astrocytes are a direct insulin target in the brain and that knockout of IR on astrocytes causes increased anxiety-and depressive-like behaviors in mice. This can be reproduced in part by deletion of IR on astrocytes in the nucleus accumbens. At a molecular level, loss of insulin signaling in astrocytes impaired tyrosine phosphorylation of Muncl8c. This led to decreased exocytosis of ATP from astrocytes, resulting in decreased purinergic signaling on dopaminergic neurons. These reductions contributed to decreased dopamine release from brain slices. Central administration of ATP analogs could reverse depressive-like behaviors in mice with astrocyte IR knockout. Thus, astrocytic insulin signaling plays an important role in dopaminergic signaling, providing a potential mechanism by which astrocytic insulin action may contribute to increased rates of depression in people with diabetes, obesity, and other insulin-resistant states.