Hippocampal transcriptome analysis in ClockΔ19 mice identifies pathways associated with glial cell differentiation and myelination

Background: ClockΔ19 mice demonstrate behavioral characteristics and neurobiological changes that closely resemble those observed in bipolar disorder (BD). Notably, abnormalities in the hippocampus have been observed in patients with BD, yet direct molecular investigation of human hippocampal tissue remains challenging due to its limited accessibility.

Methods: To model BD, ClockΔ19 mice were employed. Weighted gene co-expression network analysis (WGCNA) was utilized to identify mutation-related modules, and changes in cell populations were determined using the computational deconvolution CIBERSORTx. Furthermore, GeneMANIA and protein-protein interactions (PPIs) were leveraged to construct a comprehensive interaction network.

Results: 174 differentially expressed genes (DEGs) were identified, revealing abnormalities in rhythmic processes, mitochondrial metabolism, and various cell functions including morphology, differentiation, and receptor activity. Analysis identified 5 modules correlated with the mutation, with functional enrichment highlighting disturbances in rhythmic processes and neural cell differentiation due to the mutation. Furthermore, a decrease in neural stem cells (NSC), and an increase in astrocyte-restricted precursors (ARP), ependymocytes (EPC), and hemoglobin-expressing vascular cells (Hb-VC) in the mutant mice were observed. A network comprising 12 genes that link rhythmic processes to neural cell differentiation in the hippocampus was also identified.

Limitations: This study focused on the hippocampus of mice, hence the applicability of these findings to human patients warrants further exploration.

Conclusion: The ClockΔ19 mutation may disrupt circadian rhythm, myelination, and the differentiation of neural stem cells (NSCs) into glial cells. These abnormalities are linked to altered expression of key genes, including DPB, CIART, NR1D1, GFAP, SLC20A2, and KL. Furthermore, interactions between SLC20A2 and KL might provide a connection between circadian rhythm regulation and cell type transitions.