Plcg2 Deficiency Leads to Sex‐Associated Divergent Effects on Glial Transcriptomes

Plcg2 encodes an intracellular phospholipase C signaling enzyme expressed predominately in microglia in the brain. Genome-wide association studies implicate PLCG2 in Alzheimer's disease (AD) risk and loss of Plcg2 alters amyloid pathology in mouse models. However, the physiological impact of Plcg2 loss remains unclear. To address this gap, we performed single-cell RNA sequencing (scRNA-seq) of wild-type, heterozygous, and homozygous Plcg2-deficient mouse brains in the absence of amyloid or tau pathology. Our analyses generated a comprehensive, publicly available atlas of glial transcriptomic states across genotypes and sexes. Genotype-associated changes in microglia and astrocytes were enriched in neurodegenerative disease-related pathways, as well as oxidative phosphorylation and proteostasis pathways. Genotype-by-sex interaction and sex-stratified analyses revealed divergent regulation of many of these pathways in males and females, while co-expression and cell-cell communication analyses identified additional sex-associated differences in glial signaling networks. Overall, these data provide a framework for understanding how variation in PLCG2 function may shape glial biology and modify pathways relevant to neurodegenerative disease in a sex-associated manner.