Early Life Stress and High FKBP5 Interact to Increase Anxiety-Like Symptoms through Altered AKT Signaling in the Dorsal Hippocampus.

Marangelie Criado-Marrero,Roy J Blackburn,Sojeong Kim,Taylor M Smith,Lauren A Gould,Chad A Dickey,Niat T Gebru,Laura J Blair

doi:10.3390/ijms20112738

Abstract

Clinical studies show a significant association of childhood adversities and FK506-binding protein 5 (FKBP5) polymorphisms on increasing the susceptibility for neuropsychiatric disorders. However, the mechanisms by which early life stress (ELS) influences FKBP5 actions have not been fully elucidated. We hypothesized that interactions between ELS and high FKBP5 induce phenotypic changes that correspond to underlying molecular changes in the brain. To test this, we exposed newborn mice overexpressing human FKBP5 in the forebrain, rTgFKBP5, to ELS using a maternal separation. Two months after ELS, we observed that ELS increased anxiety levels, specifically in mice overexpressing FKBP5, an effect that was more pronounced in females. Biochemically, Protein kinase B (AKT) phosphorylation was reduced in the dorsal hippocampus in rTgFKBP5 mice, which demonstrates that significant molecular changes occur as a result of ELS when FKBP5 levels are altered. Taken together, our results have a significant impact on our understanding mechanisms underlying the gene x environment interaction showing that anxiety and AKT signaling in the hippocampus were affected by the combination of ELS and FKBP5. An increased knowledge of the molecular mechanisms underlying these interactions may help determine if FKBP5 could be an effective target for the treatment of anxiety and other mood-related illnesses.

Highlights

Mental health disorders are very common, affecting around 1.1 billion people worldwide and 44.7 million adults in the United States [1]
Life Stress Selectively Increases Anxiety-Like Behavior in rTgFKBP5 Mice
To examine the outcomes of the interaction between an adverse environment during early ages with high FK506-binding protein 5 (FKBP5), we evaluated phenotypic and biochemical changes in mice following maternal separation as the early life stress (ELS) (Figure 1A)

Summary

Introduction

Mental health disorders are very common, affecting around 1.1 billion people worldwide and 44.7 million adults in the United States [1]. Clinical studies have highlighted several factors like age, genetics, and environment [4,5], which can increase susceptibility to neuropsychiatric diseases, including anxiety, depression, and posttraumatic stress disorder (PTSD) [6,7]. These factors are not entirely separate but can influence each other. Some of the most commonly affected genes in neurotransmission and stress response include the serotonin transporter, brain-derived neurotrophic factor, nerve growth factor, and glucocorticoid receptor [8] These genes encode for proteins involved in crucial developmental, synaptic, and stress response processes

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