Integrative Transcriptomic Analysis Reveals Impaired Oligodendrocyte Maturation and Myelination Signature in the Hippocampus of a Murine Model of Neuropsychiatric Lupus

Abstract

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe manifestation of lupus marked by cognitive and mood disorders, yet the molecular mechanisms underlying hippocampal dysfunction remain poorly understood. To address this, we performed bulk RNA sequencing on hippocampal tissue from 17-week-old female MRL/Lpr mice and MRL+/+ controls, followed by an integrative multi-layered analytical workflow. Differential gene expression analysis identified 223 significant differentially expressed genes, with a predominant downregulation of myelin-related transcripts. Gene set enrichment analysis confirmed coordinated suppression of oligodendrocyte differentiation, neuron ensheathment, and Wnt signaling programs. Weighted gene co-expression network analysis identified a disease-associated module enriched in myelination and glial developmental pathways, with hub genes spanning structural, transcriptional, and adhesion-related functions. Cell-type deconvolution revealed a selective reduction in mature oligodendrocytes, while oligodendrocyte precursor cells remained largely unaffected, consistent with impaired lineage maturation rather than global loss. RT-qPCR and Western blot validated the repression of key myelin-related genes and MBP protein in MRL/Lpr hippocampi. Collectively, these findings challenge an inflammation-centric interpretation of NPSLE hippocampal pathology, highlighting instead an additional contribution of impaired oligodendrocyte maturation. This transcriptomic resource establishes a molecular foundation for future mechanistic and histological investigations.