Early-Life Stress Alters Synaptic Plasticity and mTOR Signaling: Correlation With Anxiety-Like and Cognition-Related Behavior.

Anfeng Wang,Xiaojuan Zou,Xiaojuan Li,Jiaxu Chen,Naijun Yuan,Fengmin Ding,Jiajia Wu,Qingyu Ma

doi:10.3389/fgene.2020.590068

Abstract

Early-life stress (ELS) predisposes individuals to psychiatric disorders, including anxiety and depression, and cognitive impairments later in life. However, the underlying molecular mechanisms are not completely understood. Developmental deficits in hippocampal synaptic plasticity are among the primary detrimental alterations in brain function induced by ELS. Impaired synaptic plasticity is usually accompanied by decreased synaptic proteins, such as postsynaptic density 95 (PSD95) and synaptophysin, which are important for synaptic function. The mTOR signaling pathway plays a vital role in regulating protein translation, and mTOR activation is functionally associated with synaptic protein synthesis. In the present study, we observed whether ELS impacts synaptic protein synthesis and mTOR signaling, which is involved in synaptic plasticity. Herein, we established a maternal separation (MS) and chronic restraint stress (CRS) model and evaluated anxiety-like behavior and cognitive function (e.g., learning and memory) in adulthood through behavioral examination and analyzed hippocampal expression levels of PSD95 and synaptophysin. To explore whether the mTOR signaling pathway was associated with ELS, we also examined the activity of mTOR and s6. The behavior tests indicated that maternally separated mice showed increased anxiety-like behavior and cognitive impairments. PSD95 and synaptophysin mRNA and protein expression levels were decreased in the hippocampus, and phosphorylated mTOR and phosphorylated s6 were significantly decreased in maternally separated mice vs. those not exposed to MS. Our data demonstrate that MS impairs synaptic plasticity and inhibits mTOR signaling, specifically via s6. Therefore, we speculate that ELS decreased synaptic plasticity via the inhibition of the mTOR pathway in the hippocampus, which may underlie vulnerability to stress and mental disorders in adulthood.

Highlights

Early-life stress (ELS), such as experiencing emotional neglect, physical abuse or traumatic events, can lead to long-lasting changes in neuronal physiology (Fumagalli et al, 2007)
The results showed that the levels of phospho-Mammalian target of rapamycin (mTOR) and phospho-s6 were significantly lower in the Maternal separation (MS) + chronic restraint stress (CRS) group than in the CRS group (P < 0.05) (Figure 7)
Our results showed that the levels of phosphorylated mTOR and s6 were significantly decreased in the hippocampus of MS + CRS mice compared to CRS and control mice

Summary

Introduction

Early-life stress (ELS), such as experiencing emotional neglect, physical abuse or traumatic events, can lead to long-lasting changes in neuronal physiology (Fumagalli et al, 2007). Clinical and epidemiological studies have suggested that individuals exposed to early adverse experiences have an increased risk of mental disorders, including anxiety and depression, and cognitive deficits (Harkness et al, 2006; Carr et al, 2013; Ménard et al, 2016). Several studies have reported that MS negatively impacts brain function, resulting in increased anxietyand depressive-like behaviors and impaired cognitive function (Boccia et al, 2007; Desbonnet et al, 2010; Nishi et al, 2014). It has been suggested that adverse experiences in early life may induce vulnerability to the effects of stress later in life. The mechanisms by which this occurs are still not completely understood

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