Enhanced contextual fear memory in peroxiredoxin 6 knockout mice is associated with hyperactivation of MAPK signaling pathway

Sarayut Phasuk,Sutisa Nudmamud-Thanoi,Pavithra Suresh,Shun-Ping Huang,Chien-Chang Chen,Chee-Hing Yang,Supin Chompoopong,Ingrid Y Liu,Tanita Pairojana,Narawut Pakaprot,Sittiruk Roytrakul

doi:10.1186/s13041-021-00754-1

Abstract

Fear dysregulation is one of the symptoms found in post-traumatic stress disorder (PTSD) patients. The functional abnormality of the hippocampus is known to be implicated in the development of such pathology. Peroxiredoxin 6 (PRDX6) belongs to the peroxiredoxin family. This antioxidant enzyme is expressed throughout the brain, including the hippocampus. Recent evidence reveals that PRDX6 plays an important role in redox regulation and the modulation of several signaling molecules involved in fear regulation. Thus, we hypothesized that PRDX6 plays a role in the regulation of fear memory. We subjected a systemic Prdx6 knockout (Prdx6−/−) mice to trace fear conditioning and observed enhanced fear response after training. Intraventricular injection of lentivirus-carried mouse Prdx6 into the 3rd ventricle reduced the enhanced fear response in these knockout mice. Proteomic analysis followed by validation of western blot analysis revealed that several proteins in the MAPK pathway, such as NTRK2, AKT, and phospho-ERK1/2, cPLA2 were significantly upregulated in the hippocampus of Prdx6−/− mice during the retrieval stage of contextual fear memory. The distribution of PRDX6 found in the astrocytes was also observed throughout the hippocampus. This study identifies PRDX6 as a participant in the regulation of fear response. It suggests that PRDX6 and related molecules may have important implications for understanding fear-dysregulation associated disorders like PTSD.

Highlights

Fear acquisition and expression to threatening stimuli are innate responses to avoid dangers or predators to ensure safety and survival [1, 2]
The present study reports that the loss of the Prdx6 gene in the brain led to enhanced trace fear memory to context
(MAPK) signaling pathways were highly activated in the hippocampi of Prdx6−/− mice during the expression of contextual fear memory

Summary

Introduction

Fear acquisition and expression to threatening stimuli are innate responses to avoid dangers or predators to ensure safety and survival [1, 2]. Several pieces of evidence suggest that brain regions, including the amygdala, medial prefrontal cortex, and hippocampus, are required for an appropriate level of fear response [3,4,5]. PRDX6 is expressed in various brain regions associated with fear regulation, including the hippocampus [11, 12] and expressed in all cell types with high expression level in the astrocytes [11, 13, 14], its function regarding cognition, fear memory regulation has not yet been identified. Previous findings confirmed the association between enhanced fear memory and decreased overall enzymatic activity of GPx in the hippocampus, suggesting that GPx-PRDX6 may be involved in the regulation of fear response [15]. All the evidence mentioned above led us to hypothesize that PRDX6 may play an important role in regulating fear memory

Methods

Results

Conclusion