Functional, synaptoproteomic and structural adaptations underlying sex-dependent traumatic stress susceptibility/resilience in the hippocampus

Although post-traumatic stress disorder (PTSD) occurs more in women than in men, how sex influences trauma susceptibility remains largely unknown. We developed the arousal-based individual screening (AIS) model, which identifies mice as susceptible/resilient to PTSD-like phenotypes, based on changes in startle reactivity induced by 24-hour-restraint. To test the hypothesis that sex drives trauma susceptibility/resilience, we applied a multidisciplinary approach involving electrophysiological, structural, and synaptoproteomic analyses of the hippocampus in susceptible and resilient mice of both sexes. Female mice were more susceptible to the trauma than male mice and exhibited long-lasting PTSD-like phenotypes. Long-term potentiation (LTP) was impaired in hippocampal slices of both male and female susceptible mice, whereas short-term presynaptic forms of plasticity and vesicle recycling remained unchanged. Increased apical dendritic length and augmented basal dendritic spine density of pyramidal neurons were found in CA1 of male susceptible mice, while decreased dendritic length of granule neurons was uncovered in the dentate gyrus of female resilient mice. Although minor synaptoproteomic changes were observed, bioinformatic analysis suggested sex- and susceptibility/resilience-dependent profiles. Notably, several pathways involving RHO Family GTPases were found to be upregulated exclusively in susceptible male mice. Accordingly, the Rac1/Rac3 GTPases inhibitor EHop-016 rescued the hippocampal LTP impairment in susceptible male mice but not in susceptible female mice. Our findings suggest that the AIS model mirrors sex differences in PTSD susceptibility/resilience highlighting associated functional, molecular and structural alterations. This model may represent a critical first step for studying sex-dependent pathophysiological mechanisms subserving PTSD susceptibility and for sex-tailored drug development.