Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress

Milior, Giampaolo; Lecours, Cynthia; Samson, Louis; Bisht, Kanchan; Poggini, S.; Pagani, Francesca; Deflorio, Cristina; Lauro, Clotilde; Alboni, Silvia; Limatola, Cristina; Branchi, Igor; Tremblay, Marie‐Ève; Maggi, Laura

doi:10.1016/j.bbi.2015.07.024

Cited by 202 publications

(191 citation statements)

References 90 publications

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“…It is worth noting that, in order to assess the effects of treatment in individuals showing a depression-like phenotype, we administered fluoxetine to mice previously exposed to chronic stress. Such pre-exposure activates the hypothalamic-pituitary-adrenal axis, increasing corticosterone levels (Alboni et al, 2016;Milior et al, 2015), and likely affects the interaction among the drug, the brain and immune system, making the results not applicable to different circumstances. However, this procedure has been chosen because it reproduces the clinical condition of patients who, before receiving the treatment, already show depressive symptoms and have high levels of cortisol (Juruena et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

“…Fractalkine signaling was recently found to play also a prominent role in mediating the influence of environment on brain function, regulating key brain processes such as microglial phagocytosis of synaptic elements and short-and long-term neuronal plasticity (Maggi et al, 2011;Milior et al, 2015). We found that, though CX3CR1 receptor levels were not affected, hippocampal fractalkine expression was reduced in fluoxetine-treated mice compared to vehicle in the stressful condition (t= -3.519; p= 0.0038), suggesting an "activation" or phenotypic transformation of microglia induced by the drug when administered in mice exposed to stress (Fig.…”

Section: Microglial Modulation By Fluoxetine Upon Environmental Stimumentioning

confidence: 99%

“…Only cells whose cell body and proximal processes were perfectly in focus were included in the analysis. Every IBA1-immunopositive microglia in a particular picture was analyzed before moving on to the next picture as to not introduce selection bias (Tremblay et al, 2012;Milior et al, 2015). For each microglia, the soma area was determined by drawing a line around the cell body by using the freehand selection tool.…”

Section: Light Microscopy Imaging and Analysismentioning

confidence: 99%

“…Total cell number was divided by the total area to determine cellular density on a per animal basis. A spacing index was calculated as the square of the average nearest neighbor distance multiplied by microglial density on a per animal basis (Tremblay et al, 2012;Milior et al, 2015).…”

Section: Light Microscopy Imaging and Analysismentioning

confidence: 99%

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Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

Alboni

Poggini

Garofalo

et al. 2016

Brain, Behavior, and Immunity

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It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti-or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti-and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions. AbstractIt has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these drugs act either as anti-or proinflammatory. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21 days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti-and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that...

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Section: Resultsmentioning

confidence: 99%

Section: Microglial Modulation By Fluoxetine Upon Environmental Stimumentioning

confidence: 99%

Section: Light Microscopy Imaging and Analysismentioning

confidence: 99%

Section: Light Microscopy Imaging and Analysismentioning

confidence: 99%

See 2 more Smart Citations

Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

Alboni

Poggini

Garofalo

et al. 2016

Brain, Behavior, and Immunity

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“…In the adult brain, the microglia is an important player in the regulation of synaptic plasticity [121,123,124] and in clearing newborn adult hippocampal progenitors [125]. Thus, there is evidence of the involvement of microglia in the control of long-term potentiation [126][127][128] long-term depression [129], synaptogenesis [130,131], and in sensing and eliminating defunct synapses [119].…”

Section: Refining Control Of Neuroinflammation In Alsmentioning

confidence: 99%

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

Rodrı́guez¹,

Mahy²

2016

CMC

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Dark microglia: A new phenotype predominantly associated with pathological states

Bisht¹,

Sharma²,

Lecours³

et al. 2016

Glia

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338

435

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The past decade has witnessed a revolution in our understanding of microglia. These immune cells were shown to actively remodel neuronal circuits, leading to propose new pathogenic mechanisms. To study microglial implication in the loss of synapses, the best pathological correlate of cognitive decline across chronic stress, aging, and diseases, we recently conducted ultrastructural analyses. Our work uncovered the existence of a new microglial phenotype that is rarely present under steady state conditions, in hippocampus, cerebral cortex, amygdala, and hypothalamus, but becomes abundant during chronic stress, aging, fractalkine signaling deficiency (CX3CR1 knockout mice), and Alzheimer's disease pathology (APP‐PS1 mice). Even though these cells display ultrastructural features of microglia, they are strikingly distinct from the other phenotypes described so far at the ultrastructural level. They exhibit several signs of oxidative stress, including a condensed, electron‐dense cytoplasm and nucleoplasm making them as “dark” as mitochondria, accompanied by a pronounced remodeling of their nuclear chromatin. Dark microglia appear to be much more active than the normal microglia, reaching for synaptic clefts, while extensively encircling axon terminals and dendritic spines with their highly ramified and thin processes. They stain for the myeloid cell markers IBA1 and GFP (in CX3CR1‐GFP mice), and strongly express CD11b and microglia‐specific 4D4 in their processes encircling synaptic elements, and TREM2 when they associate with amyloid plaques. Overall, these findings suggest that dark microglia, a new phenotype that we identified based on their unique properties, could play a significant role in the pathological remodeling of neuronal circuits, especially at synapses. GLIA 2016;64:826–839

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Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress

Cited by 202 publications

References 90 publications

Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

Dark microglia: A new phenotype predominantly associated with pathological states

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