CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-α

Garré, Juan Mauricio; Silva, Hernandez Moura; Lafaille, Juan J.; Yang, Guang

doi:10.1038/nm.4340

Cited by 110 publications

(104 citation statements)

References 64 publications

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“…This dichotomy also rules out a general impact of irradiation on cognitive tasks when assessed more than 8 weeks post reconstitution. Of note, other publications in the field have employed this approach to dissect the impact of radioresistant versus radiosensitive immune cells on learning (22,52).…”

Section: Discussionmentioning

confidence: 99%

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

et al. 2019

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The notion of "immune privilege" of the brain has been revised to accommodate its infiltration, at steady state, by immune cells that participate in normal neurophysiology. However, the immune mechanisms that regulate learning and memory remain poorly understood. Here we show that noninflammatory IL-17 derived from a previously unknown foetal-derived meningeal-resident γδ T cell subset promotes cognition. When tested in classical spatial learning paradigms, mice lacking γδ T cells or IL-17 displayed deficient short-term memory, while retaining long-term memory.

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Section: Discussionmentioning

confidence: 99%

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

et al. 2019

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“…The specific role of microglia can be investigated using microglial depletion models [22][23][24][25][26][27][28][29][30][31][32]. Most studies on microglial depletion employ pharmacological strategies involving the colony-stimulating factor 1 receptor (CSF1R), including PLX33397 or PLX5622 [33].…”

Section: Introductionmentioning

confidence: 99%

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice

Tsuji

Martino

Mukai

et al. 2020

J Neuroinflammation

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Background: Neuroinflammation plays an important role in neonatal hypoxic-ischemic encephalopathy (HIE). Although microglia are largely responsible for injury-induced inflammatory response, they play beneficial roles in both normal and disease states. However, the effects of microglial depletion on neonatal HIE remain unclear. Methods: Tamoxifen was administered to Cx3cr1 CreER/+ Rosa26 DTA/+ (microglia-depleted model) and Cx3cr1 CreER/+ Rosa26 DTA/− (control) mice at P8 and P9 to assess the effect of microglial depletion. The density of microglia was quantified using Iba-1 staining. Moreover, the proportion of resident microglia after the HI insult was analyzed using flow cytometric analysis. At P10, the HI insult was conducted using the Rice-Vannucci procedure at P10. The infarct size and apoptotic cells were analyzed at P13. Cytokine analyses were performed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at P13.Results: At P10, tamoxifen administration induced > 99% microglial depletion in DTA + mice. Following HI insult, there was persisted microglial depletion over 97% at P13. Compared to male DTA − mice, male DTA + mice exhibited significantly larger infarct volumes; however, there were no significant differences among females. Moreover, compared to male DTA − mice, male DTA + mice had a significantly higher density of TUNEL + cells in the caudoputamen, cerebral cortex, and thalamus. Moreover, compared to female DTA − mice, female DTA + mice showed a significantly greater number of TUNEL + cells in the hippocampus and thalamus. Compared to DTA − mice, ELISA revealed significantly lower IL-10 and TGF-β levels in both male and female DTA + mice under both normal conditions and after HI (more pronounced). Conclusion: We established a microglial depletion model that aggravated neuronal damage and apoptosis after the HI insult, which was predominantly observed in males.

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“…cortex, one of the brain regions involved in social behavior 39,40 , using transcranial two-photon microscopy 41 . We found that Mecp2 308/Y mice with neurological dysfunction and social behavioral deficits exhibited increased dendritic spine elimination ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…P2X7R-mediated IL-1β release may potentiate other inflammatory pathways. For example, peripherally generated TNFα has been shown to be involved in cortical synaptic remodeling 41,62 and is released upon activation of P2X7Rs 63 . Meningeal inflammation may prime IFNγmediated immune responses which have been associated with interneuron dysfunction and social deficits 64 .…”

Section: Discussionmentioning

confidence: 99%

“…Littermate mice were group-housed in temperature-controlled rooms on a 12-h light-dark cycle and were randomly assigned to different treatment groups. The group size was determined based on previous studies using the same methodologies 41 . All mice were generated and maintained at the New York University Skirball Institute or Columbia University specific pathogen-free animal facility.…”

Section: Methodsmentioning

confidence: 99%

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P2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice

et al. 2020

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Dysregulated immunity has been implicated in the pathogenesis of neurodevelopmental disorders but its contribution to synaptic and behavioral deficits in Rett syndrome (RTT) remains unknown. P2X7 receptors (P2X7Rs) are unique purinergic receptors with proinflammatory functions. Here, we report in a MECP2-deficient mouse model of RTT that the border of the cerebral cortex exhibits increased number of inflammatory myeloid cells expressing cell-surface P2X7Rs. Total knockout of P2X7Rs in MECP2 deficient mice decreases the number of inflammatory myeloid cells, restores cortical dendritic spine dynamics, and improves the animals' neurological function and social behavior. Furthermore, either genetic depletion of P2X7Rs in bone-marrow derived leukocytes or pharmacological block of P2X7Rs primarily outside of the central nervous system parenchyma, recapitulates the beneficial effects of total P2X7R depletion on the social behavior. Together, our results highlight the pathophysiological roles of P2X7Rs in a mouse model of RTT.

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CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-α

Cited by 110 publications

References 64 publications

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice

P2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice

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