Downregulation of Programmed Cell Death Factor 4 Attenuated Post-Traumatic Stress Disorder-Like Behaviors in Mice by ERK/CREB Pathway

Post-traumatic stress disorder (PTSD) selectively develops in some individuals exposed to a traumatic event.However, the underlying mechanism of anxiety and depressive disorder in PTSD remains unclear.We found that mice receiving single-prolonged-stress (SPS) exhibited increased anxiety/depressive-like behaviors, memory deficits, and prolonged freezing time.Furthermore, cross-omics analyses of the Gene Expression Omnibus (GEO) database, including single-cell RNA sequencing and single-nucleus RNA sequencing from social defeat models or depressive models revealed the significantly upregulated transcripts of programmed cell death factor 4 (PDCD4) in multiple brain regions including hippocampus and lateral habenula.Here, we found that PDCD4 was significantly upregulated in the hippocampus of SPS mice.Further analyses revealed changes in the expressions of synaptic-associated proteins and BDNF, and in the phosphorylation of ERK/CREB paralleled the variation of PDCD4 levels in hippocampus of mice with PTSD-like behaviors.Finally, knockdown of PDCD4 significantly restored aberrant synaptic structures and alleviated PTSD-like behaviors via the ERK/CREB pathway in a SPS mouse model.Together, these results indicate that PDCD4 was involved in the synaptic plasticity and PTSD-like behaviors via the ERK/CREB pathway.