O-GlcNAc transferase in astrocytes modulates depression-related stress susceptibility through glutamatergic synaptic transmission
Jun Fan, … , Tian-Ming Gao, Xiong Cao
Jun Fan, … , Tian-Ming Gao, Xiong Cao
Published February 9, 2023
Citation Information: J Clin Invest. 2023;133(7):e160016. https://doi.org/10.1172/JCI160016.
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Research Article Neuroscience

O-GlcNAc transferase in astrocytes modulates depression-related stress susceptibility through glutamatergic synaptic transmission

Abstract

Major depressive disorder is a common and devastating psychiatric disease, and the prevalence and burden are substantially increasing worldwide. Multiple studies of depression patients have implicated glucose metabolic dysfunction in the pathophysiology of depression. However, the molecular mechanisms by which glucose and related metabolic pathways modulate depressive-like behaviors are largely uncharacterized. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is a glucose metabolite with pivotal functions as a donor molecule for O-GlcNAcylation. O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, catalyzes protein posttranslational modification by O-GlcNAc and acts as a stress sensor. Here, we show that Ogt mRNA was increased in depression patients and that astroglial OGT expression was specifically upregulated in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social-defeat stress. The selective deletion of astrocytic OGT resulted in antidepressant-like effects, and moreover, astrocytic OGT in the mPFC bidirectionally regulated vulnerability to social stress. Furthermore, OGT modulated glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1) in astrocytes. OGT astrocyte–specific knockout preserved the neuronal morphology atrophy and Ca2+ activity deficits caused by chronic stress and resulted in antidepressant effects. Our study reveals that astrocytic OGT in the mPFC regulates depressive-like behaviors through the O-GlcNAcylation of GLT-1 and could be a potential target for antidepressants.

Authors

Jun Fan, Fang Guo, Ran Mo, Liang-Yu Chen, Jia-Wen Mo, Cheng-Lin Lu, Jing Ren, Qiu-Ling Zhong, Xiao-Jing Kuang, You-Lu Wen, Ting-Ting Gu, Jin-Ming Liu, Shu-Ji Li, Ying-Ying Fang, Cunyou Zhao, Tian-Ming Gao, Xiong Cao

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Figure 5

OE of astrocytic OGT in the mPFC increases stress susceptibility.

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OE of astrocytic OGT in the mPFC increases stress susceptibility. (A) Sc...
(A) Schematic of the AAV vectors engineered to specifically OE astrocytic OGT and behavioral test paradigms. (B) Representative images of the injection sites in the mPFC of Fgfr3-iCreERT2 mice. Scale bars: 500 μm (right, magnified view of the left image); 20 μm (left). (C and D) Western blot images (C) and quantification (D) of OGT in the mPFC of Fgfr3-iCreERT2 mice. n = 5 (Ctrl); n = 4 (OE) mice. (E) Immobility time of mice with selective OGT OE in the FST. n = 10 (Ctrl); n = 11 (OE) mice. (F) SI time in the absence or presence of social targets before and after CSDS. n = 14 (Ctrl); n = 12 (OE) mice. (G) Representative heatmaps of selective OGT-OE mice in the presence of social targets before CSDS (left) and after CSDS (right). (H) Schematic of the AAV vectors engineered to specifically OE astrocytic OGT in the mPFC of Res mice following 10 days of CSDS and behavioral test paradigms. (I) SI ratio in the SI test before (SI test 1) and after virus expression (SI test 2). n = 8 (Ctrl); n = 10 (iCre) mice. (J) Representative heatmaps of OE astrocytic OGT in the mPFC of Res mice following CSDS SI test 1 (left) and SI test 2 (right). Data are represented as mean ± SEM. Two-sided unpaired t test (E) or Mann-Whitney U test (D) for 2-group comparisons; 2-way ANOVA with Bonferroni’s multiple-comparisons test (F and I). *P < 0.05; **P < 0.01. See Supplemental Data Set 1 for the statistical details.