Nicotine exacerbates fear and depression-like behaviors by promoting microglial phagocytosis of synaptic protein in a mouse model of foot shock

Neurosci Lett. 2025 Sep 25:138394. doi: 10.1016/j.neulet.2025.138394. Online ahead of print.

ABSTRACT

Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder characterized by a complex interplay of genetic and environmental influences. Substantial evidence has demonstrated an intricate nexus between nicotine, the principal psychoactive constituent of cigarette smoke, and PTSD neuropathology. Nevertheless, the intricate mechanism underlying the relationship between nicotine consumption and PTSD has not yet been fully understood. Following two weeks of intraperitoneal nicotine administration at two doses (5 mg/kg and 1 mg/kg), we initiated behavioral testing. Our findings reveal that nicotine supplementation exacerbates fear and depression-like behaviors while promoting microglial phagocytosis of synaptic proteins. Moreover, we observed synaptic protein loss and microglial activation in both the hippocampus and cortex in the 5 mg/kg group. CX3CR1-Cre driven Cre recombinase (Cre) is a widely used genetic tool for enabling gene manipulation in microglia. Here, we investigated a genetic ablation method of the CX3CR1 using a Cre-responsive adeno-associated virus (AAV) vector expressing diphtheria toxin subunit-A (DTA). Conversely, microglial ablation via rAAV-EF1a-DIO-DTA-WPRE hGH pA injection in the ventral hippocampus CA1 region of CX3CR1-Cre mice appears to mitigate the pathologies and behavioral abnormalities induced by nicotine. Our results underscore the role of nicotine in the progression of PTSD and demonstrate that microglial depletion mitigates nicotine-induced pathologies and behavioral disturbances. Consequently, our findings suggest that nicotine enhances microglial phagocytosis of synaptic proteins in PTSD, thereby exacerbating fear and depressive symptoms.

PMID:41015226 | DOI:10.1016/j.neulet.2025.138394