Prenatal stress is a vulnerability factor for altered morphology and biological activity of microglia cells.

Joanna Ślusarczyk,Władysław Lasoń,Katarzyna Popiołek-Barczyk,Krzysztof Wędzony,Joanna Mika,Marta Kubera,Katarzyna Głombik,Ewa Trojan,Bogusława Budziszewska,Agnieszka Basta-Kaim

doi:10.3389/fncel.2015.00082

Joanna Ślusarczyk, Władysław Lasoń + Show 8 more

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https://doi.org/10.3389/fncel.2015.00082

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Abstract

Several lines of evidence suggest that the dysregulation of the immune system is an important factor in the development of depression. Microglia are the resident macrophages of the central nervous system and a key player in innate immunity of the brain. We hypothesized that prenatal stress (an animal model of depression) as a priming factor could affect microglial cells and might lead to depressive-like disturbances in adult male rat offspring. We investigated the behavioral changes (sucrose preference test, Porsolt test), the expression of C1q and CD40 mRNA and the level of microglia (Iba1 positive) in 3-month-old control and prenatally stressed male offspring rats. In addition, we characterized the morphological and biochemical parameters of potentially harmful (NO, iNOS, IL-1β, IL-18, IL-6, TNF-α, CCL2, CXCL12, CCR2, CXCR4) and beneficial (insulin-like growth factor-1 (IGF-1), brain derived neurotrophic factor (BDNF)) phenotypes in cultures of microglia obtained from the cortices of 1–2 days old control and prenatally stressed pups. The adult prenatally stressed rats showed behavioral (anhedonic- and depression-like) disturbances, enhanced expression of microglial activation markers and an increased number of Iba1-immunopositive cells in the hippocampus and frontal cortex. The morphology of glia was altered in cultures from prenatally stressed rats, as demonstrated by immunofluorescence microscopy. Moreover, in these cultures, we observed enhanced expression of CD40 and MHC II and release of pro-inflammatory cytokines, including IL-1β, IL-18, TNF-α and IL-6. Prenatal stress significantly up-regulated levels of the chemokines CCL2, CXCL12 and altered expression of their receptors, CCR2 and CXCR4 while IGF-1 production was suppressed in cultures of microglia from prenatally stressed rats. Our results suggest that prenatal stress may lead to excessive microglia activation and contribute to the behavioral changes observed in depression in adulthood.

Highlights

A growing number of studies indicate that adverse early life experiences may be an important factor in the pathogenesis of depression, due to effects on neurodevelopment (Teicher et al, 2003; de Kloet et al, 2005; Weber et al, 2008)
To study the mechanisms underlying the impact of prenatal stress on the biological activity of cells, we evaluated the following: the expression of mRNA for CD40 and MHC II; synthesis and release of nitric oxide (NO); the expression of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 and IL-18; chemokines, including CCL2 (MCP-1; monocyte chemoattractant protein-1), CXCL12 (SDF-1; stromal cell-derived factor 1) and their receptors (CCR2, CXCR4)
This study clearly demonstrates that stress during the critical late period of pregnancy in rats leads to disturbances in the morphology and biological activity of microglial cells

Summary

Introduction

A growing number of studies indicate that adverse early life experiences may be an important factor in the pathogenesis of depression, due to effects on neurodevelopment (Teicher et al, 2003; de Kloet et al, 2005; Weber et al, 2008). Recent data has shown that changes in the intrauterine environment during the prenatal period, which is critical for growth and neuronal development, might have lifelong effects (Kohman et al, 2008; Diz-Chaves et al, 2013). Among these risk factors stress has been a focus of attention in recent years. According to evidence from epidemiological studies in humans, prenatal stress may rise to behavioral changes including hyperactivity, anxiety, aggression, attention-deficit disorders and cognitive alterations in adolescence and adulthood (Gutteling et al, 2005; O’Connor et al, 2005; Talge et al, 2007). Maternal stress in humans leads to neuro-immuno-endocrine disturbances that enhance susceptibility to some immune-related diseases (e.g., asthma, allergy or diabetes) in adult life (Barker, 2004; Knackstedt et al, 2005)

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