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, 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. 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 of susceptible mice after chronic social defeat stress. The selective deletion of astrocytic OGT resulted in antidepressant-like behaviors, 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 Ca 2+ activity deficits caused by chronic stress and resulted in antidepressant effects. Altogether, 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.

Glutamate shall not pass: a mechanistic role for astrocytic O-GlcNAc transferase in stress and depression

“…The report of Fan et al ( 25 ) links what were previously considered distinct systems to gain mechanistic insights and shed light on glial regulation of stress-related neurobiology and MDD. However, many unknowns still remain.…”

“…In this issue of the JCI , Fan et al ( 25 ) describe a mechanistic link between altered OGT-mediated O-GlcNAcylation and abnormal glutamate neurotransmission in a mouse model of depression ( Figure 1 ). Initially, the authors discovered that OGT mRNA was upregulated in the blood as well as in the mPFC of men with MDD.…”

“…It was found that cultured astrocytes, but not neurons, upregulated OGT in response to damage. The authors followed with a clever combination of in vivo functional and pharmacological experiments using transgenic mice, viral vectors, and OGT inhibitors to bidirectionally manipulate expression and activity of OGT in astrocytes and neurons, demonstrating a causal relationship between increased astrocytic OGT and the development of depressive behaviors ( 25 ).…”

“…Based on these findings, Fan et al ( 25 ) generated astrocytic OGT conditional knockout transgenic mice to further explore the contribution of OGT to stress resilience. With this approach, the glutamate transporter GLT-1 was identified as a target of OGT, with elevated O-GlcNAcylation observed after stress exposure only in wild-type mice.…”

“…The Fan et al study ( 25 ) elegantly bridges two distinct concepts of neurobiological research on depression, namely dysregulation of OGT and O-GlcNAcylation in the brain ( 11 – 13 ) and GLT-1 inhibition resulting in loss of astrocytic control over synapses ( 4 , 20 , 23 ), deepening our understanding of the cellular mechanisms underlying stress-related cognitive deficits and possibly MDD. It establishes a molecular pathway connecting stress-induced metabolic disruption, elevated O-GlcNAcylation, and loss of astrocytic control over excitatory glutamate transmission leading to behavioral deficits.…”