Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance

Abstract

Major depressive disorder (MDD) is associated with repeated exposure to environmental stress. Autophagy is activated under various stress conditions that are associated with several diseases in the brain. This study was aimed at elucidating the autophagy signaling changes in the prefrontal cortex (PFC) under repeated social defeat (RSD) to investigate the involvement of microglial autophagy in RSD-induced behavioral changes. We found that RSD stress, an animal model of MDD, significantly induced initial autophagic signals followed by increased transcription of autophagy-related genes (Atg6, Atg7, and Atg12) in the PFC. Similarly, significantly increased transcripts of ATGs (Atg6, Atg7, Atg12, and Atg5) were confirmed in the postmortem PFC of patients with MDD. The protein levels of the prefrontal cortical LC3B were significantly increased, whereas p62 was significantly decreased in the resilient but not in susceptible mice and patients with MDD. This indicates that enhanced autophagic flux may alleviate stress-induced depression. Furthermore, we identified that FKBP5, an early-stage autophagy regulator, was significantly increased in the PFC of resilient mice at the transcript and protein levels. In addition, the resilient mice exhibited enhanced autophagic flux in the prefrontal cortical microglia, and the autophagic deficiency in microglia aggravated RSD-induced social avoidance, indicating that microglial autophagy involves stress-induced behavioral changes.

N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-α Signaling

“…The SPT was performed as previously described [ 20 ]. It employed a two-bottle, free-choice sucrose consumption paradigm.…”

“…Immunohistochemistry was performed using a standard protocol [ 20 , 21 ]. In brief, mice were anesthetized with an i.p.…”

“…Microglia are primary immune cells in the brain that contribute to CNS development and homeostasis by removing apoptotic newborn neurons and pruning developing axons and synapses [ 20 ]. Lipopolysaccharide (LPS) induces microglia activation by releasing pro-inflammatory cytokines and NO [ 21 , 22 ], which promote ROS to trigger apoptosis [ 23 , 24 , 25 ].…”

Neurobiological mechanisms of mood disorders: Stress vulnerability and resilience

“…Based on the understanding of the existence of plasticity, stressful events can evoke adaptive coping mechanisms that occur both in the central nervous system (CNS) and in the peripheral nervous system and are able to generate resilience ( Russo et al, 2012 ; Pfau and Russo, 2015 ). Recently, a research group demonstrated that synaptic plasticity-related molecules in the hippocampus are associated with susceptibility to social defeat stress in mice ( Lee et al, 2021 ) and another group revealed the involvement of autophagy signaling proteins; however, these proteins are increased in microglia cells of the prefrontal cortex of susceptible and resilient male mice ( Sakai et al, 2022 ). In the hippocampus, autophagy also was reported to be associated with chronic unpredictable mild stress ( Xiao et al, 2018 ).…”

The role of microglial autophagy in Parkinson’s disease

“…Li showed that a miR-223 inhibitor induced autophagosome and autolysosome production in microglial BV2 cells via the ATG16L1-LC3 pathway in response to LPS stimulation (Li et al, 2019). Sakai found that defective autophagy in microglia of the prefrontal cortex exacerbated repeated social defeat (RSD)-induced social avoidance (Sakai et al, 2022). Unlike canonical autophagy, noncanonical pathways do not require the hierarchical contribution of all ATG proteins.…”