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Published on: July 9, 2016
Relationships between gene expression and behavior in mice in response to systemic modulation of the O-GlcNAcylation
Margaret B Bell1, Xiaosen Ouyang1, Abigail K Shelton1
1Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Abstract:
Enhancing protein O-GlcNAcylation by pharmacological inhibition of the enzyme O-GlcNAcase (OGA), which removes the O-GlcNAc modification from proteins, has been explored in mouse models of amyloid-beta and tau pathology. However, the O-GlcNAcylation-dependent link between gene expression and neurological behavior remains to be explored. Using chronic administration of Thiamet G (TG, an OGA inhibitor) in vivo, we used a protocol designed to relate behavior with the transcriptome and selected biochemical parameters from the cortex of individual animals. TG-treated mice showed improved working memory as measured using a Y-maze test. RNA sequencing analysis revealed 151 top differentially expressed genes with a Log2fold change >0.33 and adjusted p-value <0.05. Top TG-dependent upregulated genes were related to learning, cognition and behavior, while top downregulated genes were related to IL-17 signaling, inflammatory response and chemotaxis. Additional pathway analysis uncovered 3 pathways, involving gene expression including 14 cytochrome c oxidase subunits/regulatory components, chaperones or assembly factors, and 5 mTOR (mechanistic target of rapamycin) signaling factors. Multivariate Kendall correlation analyses of behavioral tests and the top TG-dependent differentially expressed genes revealed 91 statistically significant correlations in saline-treated mice and 70 statistically significant correlations in TG-treated mice. These analyses provide a network regulation landscape that is important in relating the transcriptome to behavior and the potential impact of the O-GlcNAC pathway.
Insights
Inhibiting O-GlcNAcase (OGA) with Thiamet G improved mouse working memory. This enhancement correlated with significant changes in gene expression related to learning and inflammation.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Protein O-GlcNAcylation is a post-translational modification implicated in various cellular processes.
- Pharmacological inhibition of O-GlcNAcase (OGA) enhances O-GlcNAcylation, showing promise in models of neurodegenerative diseases.
- The direct link between O-GlcNAcylation, gene expression, and neurological behavior requires further investigation.
Purpose of the Study:
- To investigate the relationship between O-GlcNAcylation, gene expression, and neurological behavior.
- To explore the effects of chronic OGA inhibition using Thiamet G (TG) on working memory and the transcriptome.
- To identify specific genes and pathways influenced by OGA inhibition and their correlation with behavioral outcomes.
Main Methods:
- Chronic in vivo administration of Thiamet G (TG), an OGA inhibitor, in a mouse model.
- Behavioral assessment using the Y-maze test to measure working memory.
- RNA sequencing analysis to identify differentially expressed genes in the cortex.
- Pathway analysis and multivariate Kendall correlation to link gene expression with behavior.
Main Results:
- TG-treated mice exhibited improved working memory compared to controls.
- RNA sequencing identified 151 differentially expressed genes, with upregulated genes linked to learning and cognition, and downregulated genes associated with IL-17 signaling and inflammation.
- Pathway analysis revealed significant alterations in cytochrome c oxidase and mTOR signaling pathways.
- Multivariate analysis identified numerous correlations between gene expression and behavioral performance, differing between TG-treated and control mice.
Conclusions:
- Pharmacological enhancement of O-GlcNAcylation via OGA inhibition positively impacts working memory.
- OGA inhibition modulates gene expression networks involved in learning, cognition, and inflammatory responses.
- These findings highlight the O-GlcNAc pathway as a potential therapeutic target for neurological disorders and provide insights into the transcriptome-behavior relationship.
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