Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis

Abstract

The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2-3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…In addition, recent data suggest that microglia may exhibit dynamic alterations over time as a function of duration of illness. For example, in a recent study in laboratory animals exposed to chronic unpredictable stress, microglia were found to be activated within days following stressor exposure, whereas at the end of 5 weeks of stress, microglial numbers were decreased (Kreisel et al, 2014). Depressive-like behavior was associated with both of these microglial changes, and additional data indicated that inhibiting microglia had therapeutic efficacy early in disease, whereas stimulating microglia had antidepressant effects after prolonged stress (Kreisel et al, 2014).…”

“…There has been increasing interest in the use of various pharmacologic agents that can reduce microglial activation in the CNS. Drugs such as minocycline, a broadspectrum tetracycline antibiotic that effectively crosses the BBB, have been shown to have potent anti-inflammatory and neuroprotective effects in laboratory animal models of neurodegenerative disorders as well as following stress or LPS (Henry et al, 2008;Kreisel et al, 2014). Unfortunately, unlike the biologic agents that target peripheral inflammatory responses (where target engagement can be established in the periphery), microglial activation has proven difficult to assess in humans, even with currently available secondgeneration TSPO ligands, the exception being following administration of endotoxin (see above).…”

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

“…In recent years, there has been growing interest in the potential role of microglia in normal brain development and maturation, especially in those events that relate to synaptic pruning (Bilimoria and Stevens, 2015;Kreisel et al, 2014;Paolicelli et al, 2011;Schafer et al, 2012;Schafer and Stevens, 2013). Microglia are the major immunocompetent cells residing in the brain parenchyma and can adopt different morphological characteristics and functions: In their ramified state, they constantly survey the brain 4 microenvironment to detect and to respond to alterations in brain homeostasis, which in turn can induce the transition of ramified into phagocytic microglia (Gomez--Nicola and Perry, 2015).…”

“…As phagocytes, they can quickly remove cellular debris and dying neurons, thereby preventing possible toxic damage to neighboring cells. The phagocytic capacity of microglia is particularly important during early brain development and subsequent maturation, where they can contribute to the removal of excessive synapses in certain neuronal pathways (Bilimoria and Stevens, 2015;Kreisel et al, 2014;Paolicelli et al, 2011;Schafer et al, 2012). For these reasons, it has been suggested that abnormal microglia functions during critical periods of brain development and maturation may be an important etiopathological mechanism linking neuroinflammation to synaptic deficits (Rao et al, 2012).…”

“…Based on the growing evidence suggesting an important role of microglia in forming and maintaining synaptic integrity (Bilimoria and Stevens, 2015;Kreisel et al, 2014;Paolicelli et al, 2011;Schafer et al, 2012;Schafer and Stevens, 2013), we hypothesized that the prenatal infection--induced synaptic abnormalities would be associated with altered densities and/or activation patterns of microglia. Contrary to this hypothesis, we did not find any evidence for overt microglia abnormalities in offspring exposed to poly(I:C)--induced prenatal immune activation.…”