Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures

Bohlen, Christopher J.; Bennett, F. Chris; Tucker, Andrew F.; Collins, Hannah Y.; Mulinyawe, Sara B.; Barres, Ben A.

doi:10.1016/j.neuron.2017.04.043

Cited by 497 publications

(600 citation statements)

References 79 publications

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“…Because TREM2 has been shown to be required for phagocytosis of a variety of substrates, including apoptotic cells (Hsieh et al, ; Yeh, Wang, Tom, Gonzalez, & Sheng, ) this could have been due to intrinsic differences in the ability of Trem2 −/− microglia to take up or degrade synapses. However, Trem2 +/+ and Trem2 −/− microglia displayed no differences in synaptic uptake or degradation in vitro, although because microglia undergo extensive transcriptional changes when removed from the brain microenvironment (Bohlen et al, ), we cannot exclude that in vivo these cells have a different capacity for synaptic uptake or degradation. Alternatively, we thought that synapses themselves may be different in Trem2 −/− mice in some way that made them a better substrate for engulfment.…”

Section: Discussionmentioning

confidence: 85%

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Jay

Saucken

Muñoz

et al. 2019

Glia

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Variants in the microglial receptor TREM2 confer risk for multiple neurodegenerative diseases. However, it remains unknown how this receptor functions on microglia to modulate these diverse neuropathologies. To understand the role of TREM2 on microglia more generally, we investigated changes in microglial function in Trem2−/− mice. We found that loss of TREM2 impairs normal neurodevelopment, resulting in reduced synapse number across the cortex and hippocampus in 1‐month‐old mice. This reduction in synapse number was not due directly to alterations in interactions between microglia and synapses. Rather, TREM2 was required for microglia to limit synaptic engulfment by astrocytes during development. While these changes were largely normalized later in adulthood, high fat diet administration was sufficient to reinitiate TREM2‐dependent modulation of synapse loss. Together, this identifies a novel role for microglia in instructing synaptic pruning by astrocytes to broadly regulate appropriate synaptic refinement, and suggests novel candidate mechanisms for how TREM2 and microglia could influence synaptic loss in brain injury and disease.

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Section: Discussionmentioning

confidence: 85%

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Jay

Saucken

Muñoz

et al. 2019

Glia

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“…We used an immunopanning purification method for rat microglia based on a published protocol that minimized microglia activation (Bohlen et al, ; Bohlen, Bennett, & Bennett, ). Briefly, we first anesthetized postnatal Day 6 rat pups with ketamine and xylazine.…”

Section: Methodsmentioning

confidence: 99%

Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

Khankan

Caneda

et al. 2019

Glia

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Astrocytes are critical for the development and function of the central nervous system. In developing brains, immature astrocytes undergo morphological, molecular, cellular, and functional changes as they mature. Although the mechanisms that regulate the maturation of other major cell types in the central nervous system such as neurons and oligodendrocytes have been extensively studied, little is known about the cellular and molecular mechanisms that control astrocyte maturation. Here, we identified molecular markers of astrocyte maturation and established an in vitro assay for studying the mechanisms of astrocyte maturation. Maturing astrocytes in vitro exhibit similar molecular changes and represent multiple molecular subtypes of astrocytes found in vivo. Using this system, we found that astrocyte‐to‐astrocyte contact strongly promotes astrocyte maturation. In addition, secreted signals from microglia, oligodendrocyte precursor cells, or endothelial cells affect a small subset of astrocyte genes but do not consistently change astrocyte maturation. To identify molecular mechanisms underlying astrocyte maturation, we treated maturing astrocytes with molecules that affect the function of tumor‐associated genes. We found that a positive feedback loop of heparin‐binding epidermal growth factor‐like growth factor (HBEGF) and epidermal growth factor receptor (EGFR) signaling regulates astrocytes maturation. Furthermore, HBEGF, EGFR, and tumor protein 53 (TP53) affect the expression of genes important for cilium development, the circadian clock, and synapse function. These results revealed cellular and molecular mechanisms underlying astrocytes maturation with implications for the understanding of glioblastoma.

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“…The presence of cytokines like interleukin (IL)-1β and tumor growth factor (TGF)-β allows the differentiation of premacrophages in early microglia at E14.5, which then generate mature microglia at P14. In fact, TGF-β seems to be crucial for microglial specification in the CNS [51,52].…”

Section: The Intimate Relationship Between the Central Nervous Systemmentioning

confidence: 99%

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Deckmann

Schwingel

Fontes-Dutra

et al. 2018

Neuroimmunomodulation

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Autism spectrum disorder (ASD) is a highly prevalent developmental disorder characterized by deficits in communication and social interaction and in stereotyped or repetitive behaviors. Besides the classical behavioral dyad, several comorbidities are frequently present in patients with ASD, such as anxiety, epilepsy, sleep disturbances, and gastrointestinal tract dysfunction. Although the etiology of ASD remains unclear, there is supporting evidence for the involvement of both genetic and environmental factors. Valproic acid (VPA) is an anticonvulsant and mood stabilizer that, when used during the gestational period, increases the risk of ASD in the offspring. The animal model of autism induced by prenatal exposure to VPA demonstrates important structural and behavioral features that can be observed in individuals with autism; it is thus an excellent tool for testing new drug targets and developing novel behavioral and drug therapies. In addition, immunological alterations during pregnancy could affect the developing embryo because immune molecules can pass through the placental barrier. In fact, exposure to pathogens during the pregnancy is a known risk factor for ASD, and maternal immune activation can lead to autistic-like features in animals. Interestingly, neuroimmune alterations are common in both autistic individuals and in animal models of ASD. We summarize here the important alterations in inflammatory markers, such as cytokines and chemokines, in patients with ASD and in the VPA animal model.

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Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures

Cited by 497 publications

References 79 publications

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

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