Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation

Jafari, Mehrnoosh; Schumacher, Adrian-Minh; Snaidero, Nicolas; Gavilanes, Emily M. Ullrich; Neziraj, Tradite; Kocsis-Jutka, Virág; Engels, Daniel; Jürgens, Tanja; Wagner, Ingrid; Weidinger, Juan Daniel Flórez; Schmidt, Stephanie S.; Beltrán, Eduardo; Hagan, Nellwyn; Woodworth, Lisa; Ofengeim, Dimitry; Gans, Joseph H.; Wolf, Fred; Kreutzfeldt, Mario; Portugues, Rubén; Merkler, Doron; Misgeld, Thomas; Kerschensteiner, Martin

doi:10.1038/s41593-020-00780-7

Cited by 68 publications

(44 citation statements)

References 60 publications

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“…In a mouse model of cortical multiple sclerosis in vivo imaging demonstrated that cortical inflammation disrupts circuit activity, which coincides with a widespread, but reversible, loss of dendritic spines. Under these circumstances, spines displaying local calcium accumulations are eliminated by invading macrophages or resident activated microglia [ 85 ].…”

Section: Glutamate Receptor-mediated Neurotoxicitymentioning

confidence: 99%

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

Kasatkina

Rittchen

Sturm

2021

IJMS

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Endocannabinoids (eCBs) are lipid-based retrograde messengers with a relatively short half-life that are produced endogenously and, upon binding to the primary cannabinoid receptors CB1/2, mediate multiple mechanisms of intercellular communication within the body. Endocannabinoid signaling is implicated in brain development, memory formation, learning, mood, anxiety, depression, feeding behavior, analgesia, and drug addiction. It is now recognized that the endocannabinoid system mediates not only neuronal communications but also governs the crosstalk between neurons, glia, and immune cells, and thus represents an important player within the neuroimmune interface. Generation of primary endocannabinoids is accompanied by the production of their congeners, the N-acylethanolamines (NAEs), which together with N-acylneurotransmitters, lipoamino acids and primary fatty acid amides comprise expanded endocannabinoid/endovanilloid signaling systems. Most of these compounds do not bind CB1/2, but signal via several other pathways involving the transient receptor potential cation channel subfamily V member 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)-α and non-cannabinoid G-protein coupled receptors (GPRs) to mediate anti-inflammatory, immunomodulatory and neuroprotective activities. In vivo generation of the cannabinoid compounds is triggered by physiological and pathological stimuli and, specifically in the brain, mediates fine regulation of synaptic strength, neuroprotection, and resolution of neuroinflammation. Here, we review the role of the endocannabinoid system in intrinsic neuroprotective mechanisms and its therapeutic potential for the treatment of neuroinflammation and associated synaptopathy.

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Section: Glutamate Receptor-mediated Neurotoxicitymentioning

confidence: 99%

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

Kasatkina

Rittchen

Sturm

2021

IJMS

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“…65 During cortical inflammatory demyelination, microglial phagocytosis of synaptic structures is preceded by localized Ca 2+ accumulation in dendritic shafts and spines, suggestive of synaptic dysfunction. 70 Microglial elimination of compromised synapses may also protect surrounding surviving synapses from the leakage of toxic amounts of glutamate and from the spread of oxidative stress. 71 The engulfment of apoptotic synaptic material may also transform microglia to an anti-inflammatory phenotype, as has been reported for macrophages in vitro, potentially dampening inflammation and aiding regeneration.…”

Section: Microglia Protect Synaptic Healthmentioning

confidence: 99%

“…In acute EAE, synaptic sites express apoptotic signals prior to neuronal loss and preceding their microglial removal 65 . During cortical inflammatory demyelination, microglial phagocytosis of synaptic structures is preceded by localized Ca 2+ accumulation in dendritic shafts and spines, suggestive of synaptic dysfunction 70 . Microglial elimination of compromised synapses may also protect surrounding surviving synapses from the leakage of toxic amounts of glutamate and from the spread of oxidative stress 71 .…”

Section: Microglia Are Involved In All Aspects Of Gray Matter Pathology In Msmentioning

confidence: 99%

Multifaceted Involvement of Microglia in Gray Matter Pathology in Multiple Sclerosis

Tsouki

Williams

2021

Stem Cells

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In the inflammatory demyelinating neurodegenerative disease multiple sclerosis (MS), there is increasing interest in gray matter pathology, as neuronal loss and cortical atrophy correlate with disability and disease progression, and MS therapeutics fail to significantly slow or stop neurodegeneration. Microglia, the central nervous system (CNS)-resident macrophages, are extensively involved in white matter MS pathology, but are also implicated in gray matter pathology, similar to other neurodegenerative diseases, for which there is synaptic, axonal, and neuronal degeneration. Microglia display regional heterogeneity within the CNS, which reflects their highly plastic nature and their ability to deliver context-dependent responses tailored to the demands of their microenvironment. Therefore, microglial roles in the MS gray matter in part reflect and in part diverge from those in the white matter. The present review summarizes current knowledge of microglial involvement in gray matter changes in MS, in demyelination, synaptic damage, and neurodegeneration, with evidence implicating microglia in pathology, neuroprotection, and repair. As our understanding of microglial physiology and pathophysiology increases, we describe how we are moving toward potential therapeutic applications in MS, harnessing microglia to protect and regenerate the CNS.

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“…One limitation has been, that, due to the disseminated nature of inflammatory infiltration, which results in variable neuronal tracking systems being affected in different mice, inter-individual differences in the pattern of locomotor changes are to be expected. For this purpose, targeted EAE models have been developed that allow inflammatory lesions to be directed to a predetermined anatomical location in the brain or spinal cord [44][45][46] . However, the stereotactic injection procedure required for the induction of such models limits their application, e.g., for studying disease initiation.…”

Section: Discussionmentioning

confidence: 99%

A deep-learning-based toolbox for Automated Limb Motion Analysis (ALMA) in murine models of neurological disorders

Aljović

Zhao

Chahin

et al. 2021

Preprint

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In neuroscience research, the refined analysis of rodent locomotion is complex and cumbersome, and access to the technique is limited because of the necessity for expensive equipment. In this study, we implemented a new deep-learning-based toolbox for Automated Limb Motion Analysis (ALMA) that requires only basic behavioral equipment and an inexpensive camera. The ALMA toolbox enables the unbiased and comprehensive analyses of locomotor kinematics and paw placement and can be applied to neurological conditions affecting the brain and spinal cord. We demonstrated that the ALMA toolbox can (1) robustly track the evolution of locomotor deficits after spinal cord injury, (2) sensitively detect locomotor abnormalities after traumatic brain injury, and (3) correctly predict disease onset in a multiple sclerosis model. We, therefore, established a broadly applicable automated and standardized approach that requires minimal financial and time commitments to facilitate the comprehensive analysis of locomotion in rodent disease models.

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Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation

Cited by 68 publications

References 60 publications

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

Multifaceted Involvement of Microglia in Gray Matter Pathology in Multiple Sclerosis

A deep-learning-based toolbox for Automated Limb Motion Analysis (ALMA) in murine models of neurological disorders

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