Resilience Dysregulation in Major Depressive Disorder: Focus on Glutamatergic Imbalance and Microglial Activation

Abstract

Background: Many studies have been shown an important role of glutamatergic system as well microglial activa-tion in the pathophysiology of major depressive disorder (MDD). In humans most resistant to the development of psychiat-ric disorders, including MDD, are observed a greater degree of resilience resulting from stress. Less resilience is associated with neuroendocrine and neuroinflammatory markers, as well as with glutamatergic system dysregulation. Thus, this review we highlighted findings from literature identifying the function of glutamatergic system, microglial activation and inflamma-tion in resilience.Methods: We conducted a review of computerized databases from 1970 to 2017.Results: There is an association between microglial activation and glutamatergic system activation with stress vulnerability and resilience.Conclusions: Glutamate neurotransmission, including neurotransmitter synthesis, signalling, and glutamate receptor func-tions and expression all seem to be involved with both stress vulnerability and resilience. Moreover, inflammation and mi-croglial activation mediate individual differences in resilience and the risk of stress-induced MDD.

JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress

“…Many groups have reported similar peripheral and CNS inflammatory alteration in the CSDS model, including microglia activation, monocyte trafficking, and increased pro-inflammatory cytokine levels [43,62,64]. Based on the idea that aberrant glutamate signaling and neuroinflammation may converge to affect synaptic function and behavioral abnormalities relevant to depression [5,6,22], Haroon et al proposed that stress-induced inflammation may exaggerate release and inhibit clearance of glutamate from microglia and astrocytes, resulting in an increase of extracellular glutamate that ultimately leads to synaptic dysfunction underlying depressive phenotypes [22]. In agreement with this hypothesis, our results showed that CSDS simultaneously induces an increase of proinflammatory cytokines IL-1β and TNF-α and augment glutaminase activity in CD11b + cells, effects which are suppressed by JHU-083.…”

“…Growing evidence suggests that altered glutamate signaling system is implicated in MDD pathophysiology [4][5][6]. Several studies have reported increased levels of glutamate in the serum and plasma of MDD patients as well as high concentrations of glutamine, the major synthetic precursor for glutamate production in the brain [7][8][9][10].…”

“…Complimentary findings from preclinical studies highlight the importance of glial cells in the control of extracellular glutamate and the regulation of glutamatergic neurotransmission [5,6,20,21]. Microglia and astrocytes play critical roles in the glutamate/glutamine metabolic cycle and are key regulators of glutamate release and clearance especially under conditions of neuroinflammation (Miller et al [22]).…”

Inflammation associated with chronic heart failure leads to enhanced susceptibility to depression

“…Inflammatory cytokines have been shown to be expressed principally by glial cells in the central nervous system (CNS) . Given the strong induction of inflammatory cytokines in the hippocampus and PFC of Sus mice, we examined whether it was associated with alterations in the glial population.…”

The Contribution of Rat Studies to Current Knowledge of Major Depressive Disorder: Results From Citation Analysis

“…Among those, the majority of the studies indicate dopamine, norepinephrine, and serotonin as the most implicated in MDD etiology (Belujon and Grace, 2017). Others stress the involvement of glutamate (Réus et al, 2018). Nonetheless, some studies find no differences in neurotransmitters between MDD patients and healthy controls (for a review, see Beijers et al, 2019).…”