Role of MAPK and PI3K-Akt signaling pathways in cuprizone-induced demyelination and cognitive impairment in mice

• Published in: Behavioural brain research Vol. 458; p. 114755
• Main Authors: Xu, Zhizhong, Wen, Chunyan, Wang, Wenqiang
• Format: Journal Article
• Language: English
• Published: Netherlands 26.02.2024
• Subjects: Animals; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - metabolism; Cuprizone - toxicity; Demyelinating Diseases - chemically induced; Demyelinating Diseases - metabolism; Disease Models, Animal; Mice; Mice, Inbred C57BL; Myelin Sheath; Oligodendroglia; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Schizophrenia; Differentially expressed genes; Cuprizone; Demyelination; Insulin-like growth factor 1; Glial fibrillary acidic protein
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2023.114755

This study aimed to find the genes and signaling pathways underlying cuprizone-induced demyelination and cognitive impairments in mice. We used the cuprizone-exposed mice as an animal model of schizophrenia and assessed cognitive function in mice. Total RNA was extracted from mouse brain tissues for RNA sequencing. The DESeq2 R package was utilized to analyze the differentially expressed genes (DEGs). Functional and pathway enrichment analyses were performed simultaneously. We also constructed a protein-protein interaction (PPI) network to screen potential hub genes, and quantitative real-time polymerase chain reaction (qRT-PCR) was employed to validate the screened genes. After 6 weeks of cuprizone treatment, the cognitive function of mice was impaired. Compared to the controls, the cuprizone-exposed mice contained 351 DEGs, including 167 upregulated and 184 downregulated genes. Enrichment analysis showed that the DEGs were enriched in some biological processes involved in demyelination, including the MAPK pathway. Functional pathway analysis revealed that the DEGs were significantly enriched in the PI3K-Akt signaling pathway, which may be associated with cognitive impairments. MBP, IGF1, GFAP, PTPRC, CD14, CD68, ITGB2, LYN, TLR2, TLR4, VAV1, and PLEK were considered as potential hub genes. Except for MBP, all genes were upregulated in the cuprizone models, as verified by qRT-PCR. We suggest that the MAPK and PI3K-Akt signaling pathways may be associated with demyelination and cognitive impairments, respectively. GFAP and IGF-1 expression levels increased in cuprizone-exposed mice, suggesting that astrocytes may play a role in protecting the myelin sheath following treatment with cuprizone.