Dexmedetomidine inhibits fear memory consolidation via the astrocyte-specific Srebf1-Phgdh pathway in the prelimbic prefrontal cortex

Post-traumatic stress disorder (PTSD) develops following exposure to a traumatic event. However, effective prevention and treatments remain elusive. In this study, we report that sub-anesthetic doses of dexmedetomidine can alleviate fear in mice by inhibiting the consolidation of fear memory. Transcriptomic analysis identifies sterol regulatory element-binding protein 1 (Srebf1) as a key mediator of dexmedetomidine's effects. The potential mechanism of this involves dexmedetomidine reducing the nuclear translocation of Srebf1 specifically in prelimbic prefrontal cortex astrocytes, thereby decreasing the active transcriptional form of Srebf1. This results in the downregulation of its target gene, phosphoglycerate dehydrogenase (Phgdh). Phgdh, as the main synthetase of the N-methyl-D-aspartate receptor co-agonist D-serine, plays a crucial role in regulating synaptic stability and ultimately inhibiting the consolidation of fear memory. This work identifies the mechanism by which dexmedetomidine inhibits fear memory consolidation, providing a rationale for its preventive application and uncovering novel targets for PTSD intervention.