Elevated O-GlcNAcylation induces an antidepressant-like phenotype and decreased inhibitory transmission in medial prefrontal cortex

Abstract

Depression is a devastating mental disorder affected by multiple factors that can have genetic, environmental, or metabolic causes. Although previous studies have reported an association of dysregulated glucose metabolism with depression, its underlying mechanism remains elusive at the molecular level. A small percentage of glucose is converted into uridine diphosphate-Nacetylglucosamine (UDP-GlcNAc) via the hexosamine biosynthetic pathway, which serves as an immediate donor for protein O-GlcNAc modification. O-GlcNAcylation is a particularly common posttranslational modification (PTM) in the brain, and the functional significance of O-GlcNAcylation in neurodegenerative diseases has been extensively reported. However, whether the degree of O-GlcNAc modification is associated with depressive disorder has not been examined. In this study, we show that increased o-GlcnAcylation levels reduce inhibitory synaptic transmission in the medial prefrontal cortex (mPFC), and that Oga +/− mice with chronically elevated o-GlcnAcylation levels exhibit an antidepressant-like phenotype. Moreover, we found that virus-mediated expression of OGA in the mPFC restored both antidepressant-like behavior and inhibitory synaptic transmission. Therefore, our results suggest that O-GlcNAc modification in the mPFC plays a significant role in regulating antidepressant-like behavior, highlighting that the modulation of O-GlcNAcylation levels in the brain may serve as a novel therapeutic candidate for antidepressants. Depressive disorder is a devastating mental disorder characterized by symptoms such as loss of interest, low mood, fatigue, and diminished cognitive functions 1-3. A deficit in monoamine metabolism including serotonin, dopamine, and norepinephrine is known to contribute to its etiology 4-6 , and the regulation of synaptic function through monoamine neurotransmitters serves as the primary approach to treat patients with depressive disorder 7,8. In addition, malfunctions of neuronal networks, such as an impaired balance between excitatory and inhibitory inputs, modulate emotional states, and previous studies suggest that glutamatergic and GABAergic systems are impaired in patients with depression 2,9,10. Furthermore, altered GABAergic inhibitory function induced by a change in the expression levels of GABAergic receptors also disrupts emotional processes in animal models of depressive disorders 9-14. Although the monoamine theory plays a major role in understanding the pathogenesis of depression, how the monoamine-independent changes in molecular and synaptic functions of neural networks contribute to depressive disorders remains largely elusive. The medial prefrontal cortex (mPFC) underlies the executive control of animal behavior 15,16 , and structural and functional changes in the mPFC, such as synaptic transmission and altered protein expression levels, are implicated in depression-related behaviors in animal models 15-18. For example, the deletion of the N-methyl-D-aspartic

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Isoflurane anesthesia disrupts the cortical metabolome

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Modulatory Effects of Autophagy on APP Processing as a Potential Treatment Target for Alzheimer’s Disease

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