A P2RY12 Deficiency Results in Sex-specific Cellular Perturbations and Sexually Dimorphic Behavioral Anomalies

TL;DR

This study shows that a gene called P2RY12 has sex-specific effects on brain cells and behavior in mice.

Contribution

The study reveals that P2RY12 deficiency causes sex-specific cellular and behavioral changes in mice.

Findings

Adult female microglia express P2RY12 more than males.

P2RY12 deletion causes greater cellular changes in females than males.

Female mice without P2RY12 show unique behavioral anomalies.

Abstract

Microglia are sexually dimorphic, yet, this critical aspect is often overlooked in neuroscientific studies. Decades of research have revealed the dynamic nature of microglial-neuronal interactions, but seldom consider how this dynamism varies with microglial sex differences, leaving a significant gap in our knowledge. This study focuses on P2RY12, a highly expressed microglial signature gene that mediates microglial-neuronal interactions, we show that adult females have a significantly higher expression of the receptor than adult male microglia. We further demonstrate that a genetic deletion of P2RY12 induces sex-specific cellular perturbations with microglia and neurons in females more significantly affected. Correspondingly, female mice lacking P2RY12 exhibit unique behavioral anomalies not observed in male counterparts. These findings underscore the critical, sex-specific roles of P2RY12 in microglial-neuronal interactions, offering new insights into basal interactions and potential implications for CNS disease mechanisms.

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