Early Maternal Deprivation Induces Microglial Activation, Alters Glial Fibrillary Acidic Protein Immunoreactivity and Indoleamine 2,3-Dioxygenase during the Development of Offspring Rats

Abstract

Maternal deprivation (MD) induces behavioral changes and impacts brain circuits that could be associated with the pathophysiology of depression. This study investigated the markers of microglia and astrocyte activation as well as indoleamine 2,3-dioxygenase (IDO) expression in developmental programming after early life MD (on postnatal days (PNDs) 20, 30, 40, and 60). On PND 60, the rats that were subjected to MD displayed depressive-like behavior. On PND 10, it was found that there was a decrease in the level of glial fibrillary acidic protein (GFAP) immunopositive cells, a decrease in the level of IDO expression, and an increase in the level of Iba-1 (microglial marker) in the hippocampus of rats that were subjected to MD. On PND 20, levels of GFAP were also found to have decreased in the hippocampus, and there was an increase in the level of Iba-1 in the hippocampus. AIF-1 (microglial marker) expression was observed in the PFC following MD. On PND 30, the levels of Iba-1 remained elevated. On PND 40, the levels of GFAP were found to have increased in the hippocampus of rats that were subjected to MD. On PND 60, the levels of GFAP and AIF-1 remained elevated following MD. These results suggest that early life stress induces negative developmental programming in rats, as demonstrated by depressive-like behavior in adult life. Moreover, MD increases microglial activation in both early and late developmental phases. The levels of GFAP and IDO decreased in the early stages but were found to be higher in later developmental periods. These findings suggest that MD could differentially affect the expression of the IDO enzyme, astrocytes, and microglial activation depending on the neurodevelopmental period. The onset of an inflammatory state from resident brain cells could be associated with the activation of the kynurenine pathway and the development of depressive behavior in adulthood.

Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure

“…At P9, a significant increase in GFAP immunoreactivity was present following ES exposure specifically in the SLM but not in other hippocampal subregions. Strikingly, the existing literature shows that ES in the form of maternal deprivation or separation leads to an acute reduction in GFAP [36,37,57,58], followed by an increase in GFAP when a longer period (4-30 days) between the stressor and the analysis was applied [38,59,60]. This discrepancy with our current results could possibly be explained by the form of ES exposure.…”

“…Such temporal dynamics of GFAP expression, even though on a shorter timescale, have also been observed previously in rats exposed to daily maternal deprivation from P1 to P10. In these rats, no initial changes were observed at P10, but a reduction in GFAP was observed at P20, followed by increased GFAP at P40 [60]. This direction of GFAP modulation at the different ages is not in line with the changes observed in the present study.…”

The involvement of astrocytes in early‐life adversity induced programming of the brain

“…Interestingly, this was accompanied by an increased number of S100β + cells (Braun et al, ), indicating a differential effect of stress on the expression of different astrocyte markers. In contrast to the reduced GFAP signal measured within 24 hr after the stressor, when GFAP expression was measured a few days or weeks after the end of the deprivation or separation period, an increase in the number of GFAP + cells or GFAP expression was found in the hippocampus (Llorente et al, ; Réus et al, ), cerebellum (Llorente et al, ), and prefrontal cortex (Kwak et al, ). Together these results show that MD/MS leads to an acute reduction in GFAP, followed by an increase of GFAP when a longer period between stress and measurement was applied.…”

“…At this stage, more research is necessary to elucidate the specific order of events. Interestingly, also MD/MS induced alterations on astrocytes were sometimes accompanied by activation of microglia (Réus et al, ; Roque et al, ; Saavedra et al, ). It is striking that despite the similar activation of microglia, different effects were described for GFAP, with lasting upregulation after immune challenges but no persistent changes in GFAP after MD/MS, suggesting alternative mediators and processes involved.…”

Antidepressant Potential of Cinnamic Acids: Mechanisms of Action and Perspectives in Drug Development

“…Recent findings of the presence of inflammatory process and oxidative stress in the pathophysiology of depression provide new pathways and treatment targets for improvement of pharmacological approach in depression [11]. Recently, Réus et al (2019) have reported a microglial activation with formation of intracellular multiprotein complexes, the inflammasomes, which in turn activate interleukin-1β (IL-1β) that leads to a significant increase in the production and expression of tumor necrosis factor-α (TNF-α), IL-1β, reactive species of oxygen (ROS), and nitric oxide (NO) [12]. This finding is in accordance with a previous study performed by Oglodek (2017), in which it was identified that major depressive disorders, associated Reports of antidepressant activity on these compounds indicate that they may be an alternative treatment option for depression [17].…”