Impaired microglia fractalkine signaling affects stress reaction and coping style in mice

Winkler, Zsuzsanna; Kuti, Dániel; Ferenczi, Szilamér; Gulyás, Krisztina; Polyák, Alexandra; Kovács, Krisztina

doi:10.1016/j.bbr.2017.07.023

Cited by 44 publications

(29 citation statements)

References 44 publications

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“…Cx3cr1 knockout mice also failed to develop anhedonia, which is a measure of depressive-like behavior ( Milior et al, 2016 ). Similar findings of an increased resistance to stress in the Cx3cr1 knockout mice were reported by other groups using different stress paradigms ( Hellwig et al, 2016 ; Rimmerman et al, 2017 ; Winkler et al, 2017 ). In addition, microglial depletion, using systemic administration of a colony stimulating factor 1 receptor antagonist, in mice exposed to repeated social defeat stress, prevented anxiety ( McKim et al, 2017 ).…”

Section: Chronic Stress As An Environmental Risk Factorsupporting

confidence: 90%

“…Similarly, chronic stress was shown to ‘prime’ or sensitize microglia to generate heightened, exaggerated responses to a second stimulus occurring later in life ( Santos et al, 2016 ). Studies by our group and others have detailed the effects of chronic stress on microglia using a number of paradigms in rodents, including maternal separation, physical restraint, tail suspension, forced swim or water immersion, social defeat or isolation, and unpredictable modifications of the housing conditions ( Calcia et al, 2016 ; Lehmann et al, 2016 ; Roque et al, 2016 ; Sugama et al, 2011 , 2007 ; Wang et al, 2017 ; Winkler et al, 2017 ; Wohleb et al, 2018 ). Overall, these studies revealed that microglia are integral partners in mediating the response of the brain and behavior to stress.…”

Section: Chronic Stress As An Environmental Risk Factormentioning

confidence: 99%

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Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress

Bisht

Sharma

Tremblay

2018

Neurobiology of Stress

290

155

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Microglia are the predominant immune cells of the central nervous system (CNS) that exert key physiological roles required for maintaining CNS homeostasis, notably in response to chronic stress, as well as mediating synaptic plasticity, learning and memory. The repeated exposure to stress confers a higher risk of developing neurodegenerative diseases including sporadic Alzheimer's disease (AD). While microglia have been causally linked to amyloid beta (Aβ) accumulation, tau pathology, neurodegeneration, and synaptic loss in AD, they were also attributed beneficial roles, notably in the phagocytic elimination of Aβ. In this review, we discuss the interactions between chronic stress and AD pathology, overview the roles played by microglia in AD, especially focusing on chronic stress as an environmental risk factor modulating their function, and present recently-described microglial phenotypes associated with neuroprotection in AD. These microglial phenotypes observed under both chronic stress and AD pathology may provide novel opportunities for the development of better-targeted therapeutic interventions.

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Section: Chronic Stress As An Environmental Risk Factorsupporting

confidence: 90%

Section: Chronic Stress As An Environmental Risk Factormentioning

confidence: 99%

Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress

Bisht

Sharma

Tremblay

2018

Neurobiology of Stress

290

155

View full text Add to dashboard Cite

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“…Finally, it has to be considered that discrepancies in the literature could also arise from the age, sex or environmental conditions, including health/housing status of the animals used. Microglia react to stress stimuli (Bollinger, Bergeon Burns, & Wellman, 2016;Tian et al, 2017) and may undergo genotype-specific changes following different types of environmental challenges (Hellwig et al, 2016;Maggi et al, 2011;Milior et al, 2016;Reshef et al, 2014;Winkler et al, 2017). Collectively, the described heterogeneities could explain some area-and context-dependent microglia properties.…”

Section: Discussionmentioning

confidence: 99%

Microglia shape presynaptic properties at developing glutamatergic synapses

Basilico

Pagani

Grimaldi

et al. 2018

Glia

114

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Deficient neuron–microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron‐to‐microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission. We characterized the functional properties of CA3–CA1 synapses in hippocampal slices from these mice and found that they display altered glutamatergic release probability, maintaining immature properties also at late developmental stages. In particular, CA1 synapses of Cx3cr1 KO show (i) immature AMPA/NMDA ratio across developmental time, displaying a normal NMDA component and a defective AMPA component of EPSC; (ii) defective functional connectivity, as demonstrated by reduced current amplitudes in the input/output curve; and (iii) greater facilitation in the paired pulse ratio (PPR), suggesting decreased release probability. In addition, minimal stimulation experiments revealed that excitatory synapses have normal potency, but an increased number of failures, confirming a deficit in presynaptic release. Consistently, KO mice were characterized by higher number of silent synapses in comparison to WT. The presynaptic deficits were corrected by performing experiments in conditions of high release probability (Ca2+/Mg2+ratio 8), where excitatory synapses showed normal synaptic multiplicity, AMPA/NMDA ratio, and proportion of silent synapses. These results establish that neuron–microglia interactions profoundly influence the functional maturation of excitatory presynaptic function.

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“…The study by Milior et al [ 244 ] provided evidence that disorders in neuron – microglia signalling occurred via the CX3CL1-CX3CR1 pathway in response to chronic unpredictable stress. Winkler et al [ 245 ] showed that Cx3cr1 -deficient mice were resilient to chronic stress-induced depression, as demonstrated by a lack of anhedonia. In another study, Cx3cr1 knockout mice were completely unaffected by the exposure to chronic unpredictable stress in terms of emotional, cognitive, neurogenic and microglial responses to the insult, while their wild-type counterparts displayed these depressive-like characteristics [ 246 ].…”

Section: The Roles Of Cx3cl1-cx3cr1 and Cd200-cd200r Axes Malfunctionmentioning

confidence: 99%

The Potential Role of Dysfunctions in Neuron-Microglia Communication in the Pathogenesis of Brain Disorders

Chamera

Trojan

Szuster-Głuszczak

et al. 2020

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: The bidirectional communication between neurons and microglia is fundamental for the proper functioning of the central nervous system (CNS). Chemokines and clusters of differentiation (CD) along with their receptors represent ligand-receptor signalling that is uniquely important for neuron – microglia communication. Among these molecules, CX3CL1 (fractalkine) and CD200 (OX-2 membrane glycoprotein) come to the fore because of their cell-type-specific localization. They are principally expressed by neurons when their receptors, CX3CR1 and CD200R, respectively, are predominantly present on the microglia, resulting in the specific axis which maintains the CNS homeostasis. Disruptions to this balance are suggested as contributors or even the basis for many neurological diseases. : In this review, we discuss the roles of CX3CL1, CD200 and their receptors in both physiological and pathological processes within the CNS. We want to underline the critical involvement of these molecules in controlling neuron – microglia communication, noting that dysfunctions in their interactions constitute a key factor in severe neurological diseases, such as schizophrenia, depression and neurodegeneration-based conditions.

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Impaired microglia fractalkine signaling affects stress reaction and coping style in mice

Cited by 44 publications

References 44 publications

Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress

Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress

Microglia shape presynaptic properties at developing glutamatergic synapses

The Potential Role of Dysfunctions in Neuron-Microglia Communication in the Pathogenesis of Brain Disorders

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