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

Abstract

Major depressive disorder, characterized by aberrant glutamatergic signaling in the prefrontal cortex (PFC), is a leading cause of disability worldwide. Depression is highly comorbid with metabolic disorders, but a mechanistic link is elusive. In this issue of the JCI , Fan and coauthors report that elevated posttranslational modification with the glucose metabolite N -acetylglucosamine (GlcNAc) by O-GlcNAc transferase (OGT) contributed to stress-induced establishment of depression-like behaviors in mice. This effect was specific to medial PFC (mPFC) astrocytes, with glutamate transporter-1 (GLT-1) identified as an OGT target. Specifically, O-GlcNAcylation of GLT-1 resulted in diminished glutamate clearance from excitatory synapses. Further, astrocytic OGT knockdown restored stress-induced deficits in glutamatergic signaling, promoting resilience. These findings provide a mechanistic link between metabolism and depression and have relevance for antidepressant targets.

How Oxidative Stress Induces Depression?

“…Moreover, the OGT overexpression increased CSDS susceptibility of mice, whereas the OGT knockout reduced the astrocytic GLT-1 GlcNAcylation, and resulted in antidepressant effect ( Fan et al, 2023 ). The results indicate the prominent role of mPFC O-GlcNAcylation in the modulation of depression, however, the detailed underlying mechanisms and the potential differential roles of neurons and astrocytes (e.g., astrocytic GLT-1) require further in-depth investigations for clarification ( Fan et al, 2023 ; Paton & Menard, 2023 ). The above evidence indicates central glutamate excitotoxicity, caused by GLT-1 inhibition disrupted astrocytic reuptake of synaptic glutamate, as an important pathogenesis of depression.…”

“…The mutual influence between mitochondrial impairment and neuroinflammation is critically involved in depression ( Hollis et al, 2022 ; Visentin et al, 2020 ; Figure 1AB ). Impaired mitochondria leads to increased mtROS generation, which promotes pro-inflammatory cytokine gene expression through promoting protein-1 (AP-1) and NF-κB, and increasing histone acetylation ( Adcock et al, 2005 ; Rahman et al, 2004 ), or activating caspase-1 and inflammasome NOD-like receptor thermal protein domain associated protein 3 (NLRP3) ( Visentin et al, 2020 ; Zhou et al, 2011 ), or affecting astrocytic mitochondrial oxidative phosphorylation activity ( Mi et al, 2023 ). In turn, neuroinflammation promotes mtROS generation, for instance, interleukin-1β (IL-1β) and IL-18 promote kynurenine pathway (KP) of tryptophan metabolism, through activating the enzymes of indoleamine 2,3-dioxygenase (IDO), tryptophan-2,3-dioxygenase (TDO) and kynurenine 3-monooxygenase (KMO), and generating tryptophan catabolites (TRYCATs) among which quinolinic acid (QUIN) directly activates N-methyl-D-aspartic acid (NMDA) receptors, increases synaptic glutamate, triggers Ca 2+ influx that depolarizes mitochondrial membrane, which finally increases mtROS generation and reduces antioxidant activity ( de Oliveira et al, 2021 ; Schwarcz et al, 2012 ; Visentin et al, 2020 ).…”