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

Abstract

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.