Insulin regulates astrocyte gliotransmission and modulates behavior
Weikang Cai, … , Emmanuel N. Pothos, C. Ronald Kahn
Weikang Cai, … , Emmanuel N. Pothos, C. Ronald Kahn
Published April 17, 2018
Citation Information: J Clin Invest. 2018;128(7):2914-2926. https://doi.org/10.1172/JCI99366.
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Insulin regulates astrocyte gliotransmission and modulates behavior

Abstract

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 Munc18c. 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.

Authors

Weikang Cai, Chang Xue, Masaji Sakaguchi, Masahiro Konishi, Alireza Shirazian, Heather A. Ferris, Mengyao E. Li, Ruichao Yu, Andre Kleinridders, Emmanuel N. Pothos, C. Ronald Kahn

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Figure 4

IR in astrocytes regulates ATP exocytosis to modulate dopamine release.

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IR in astrocytes regulates ATP exocytosis to modulate dopamine release. ...
(A) mRNA expression of IR and IGF1R in primary IRfl/fl astrocytes infected with adenovirus encoding Cre or GFP. TBP was used as a housekeeping gene. ***P < 0.001, 2-tailed Student’s t test, n = 6. (B) Immunoblotting of phosphorylation of insulin signaling molecules in CTR and IRKO astrocytes following indicated concentrations of insulin stimulation for 10 minutes. (C) Relative expression of astrocyte-specific markers in CTR and IRKO astrocytes. TBP was used as a housekeeping gene. *P < 0.05, **P < 0.01, ***P < 0.001, 2-tailed Student’s t test, n = 6. (D) ATP release from CTR and IRKO astrocytes in the presence or absence of 100 nM insulin stimulation for 30 minutes. ***P < 0.001, 2-tailed Student’s t test, n = 6. (E) Total ATP content in both CTR and IRKO astrocytes. n = 6. (F) Peak amplitude of electrically evoked dopamine release from NAc before and after infusion of aCSF or ATP-γ-S. **P < 0.01 vs. basal, repeated 2-way ANOVA followed by Sidak’s multiple comparisons, n = 5. (G) Peak amplitude of electrically evoked dopamine release from NAc before and after infusion of aCSF or 2-Me-SATP. ***P < 0.001 vs. basal, repeated 2-way ANOVA followed by Sidak’s multiple comparisons, n = 5. (H) Time of immobility of 4-month-old female IRfl/fl CTR and iGIRKO mice in forced swimming test with i.c.v. infusion of saline or 20 pmol 2-Me-SATP 1 hour before the test. *P < 0.05, **P < 0.01, 2-way ANOVA followed by Sidak’s multiple comparisons, n = 9 for CTR groups, n = 10 for iGIRKO groups. All data are mean ± SEM.