Single-Cell RNA-Seq Uncovers Robust Glial Cell Transcriptional Changes in Methamphetamine-Administered Mice

Methamphetamine is a highly addictive stimulant known to cause neurotoxicity, cognitive deficits, and immune dysregulation in the brain. Despite significant research, the molecular mechanisms driving methamphetamine-induced neurotoxicity and glial cell dysfunction remain poorly understood. This study investigates how methamphetamine disrupts glial cell function and contributes to neurodevelopmental and neurodegenerative processes. Using single-cell RNA sequencing (scRNA-seq), we analyzed the transcriptomes of 4000 glial cell-associated genes from the cortical regions of mice chronically administered methamphetamine. Methamphetamine exposure altered the key pathways in astrocytes, including the circadian rhythm and cAMP signaling; in microglia, affecting autophagy, ubiquitin-mediated proteolysis, and mitophagy; and in oligodendrocytes, disrupting lysosomal function, cytoskeletal regulation, and protein processing. Notably, several transcription factors, such as Zbtb16, Hif3a, Foxo1, and Klf9, were significantly dysregulated in the glial cells. These findings reveal profound methamphetamine-induced changes in the glial transcriptomes, particularly in the cortical regions, highlighting potential molecular pathways and transcription factors as targets for therapeutic intervention. This study provides novel insights into the glial-mediated mechanisms of methamphetamine toxicity, contributing to our understanding of its effects on the central nervous system and laying the groundwork for future strategies to mitigate its neurotoxic consequences.