Relationships between gene expression and behavior in mice in response to systemic modulation of the O‐GlcNAcylation pathway

Abstract

AbstractEnhancing 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.image