Microglia Function in Central Nervous System Development and Plasticity

Schafer, Dorothy P.; Stevens, Beth

doi:10.1101/cshperspect.a020545

Cited by 300 publications

(278 citation statements)

References 141 publications

(162 reference statements)

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“…Microglia have traditionally been thought of as the immune cells of the brain, but a body of recent research suggests that these cells may also play important roles in nonpathological brain function, specifically the pruning and alteration of synapses (90). Animal live-imaging studies have demonstrated that microglia interact dynamically with synapses undergoing developmental pruning (93,94).…”

Section: Discussionmentioning

confidence: 99%

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Brain aerobic glycolysis and motor adaptation learning

Shannon

Vaishnavi

Vlassenko

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Ten percent to 15% of glucose used by the brain is metabolized nonoxidatively despite adequate tissue oxygenation, a process termed aerobic glycolysis (AG). Because of the known role of glycolysis in biosynthesis, we tested whether learning-induced synaptic plasticity would lead to regionally appropriate, learningdependent changes in AG. Functional MRI (fMRI) before, during, and after performance of a visual-motor adaptation task demonstrated that left Brodmann area 44 (BA44) played a key role in adaptation, with learning-related changes to activity during the task and altered resting-state, functional connectivity after the task. PET scans before and after task performance indicated a sustained increase in AG in left BA 44 accompanied by decreased oxygen consumption. Intersubject variability in behavioral adaptation rate correlated strongly with changes in AG in this region, as well as functional connectivity, which is consistent with a role for AG in synaptic plasticity.T he resting brain's energy needs are supported almost entirely by the metabolism of glucose to carbon dioxide and water (1). The first step of this process, glycolysis, requires no oxygen whereas the second step, oxidative phosphorylation, does. In the normal adult human brain, 10-15% of the glucose never reaches the second step-it is shunted away from oxidative phosphorylation despite the presence of adequate oxygen (2-5). This process is commonly referred to as aerobic glycolysis (AG).Several roles for AG have been identified, including biosynthesis (for recent reviews, see refs. 6-8), the regulation of cellular redox states (9, 10), the regulation of apoptosis (11), the provision of ATP for membrane pumps (12)(13)(14), and the regulation of cell excitability (15, 16). More recently, similar functions of AG have been observed in the posttranscriptional control of T-cell effector function (17, 18), an observation now extended to the microglia (19), where it is associated with an activated state related to inflammation as well as synaptic pruning.In the developing human brain, at a time when synaptic growth rates are highest (approximately age 10), total glucose consumption is twice that of the adult, and 30% of that glucose consumption is AG (a recent summary of this early literature is contained in ref. 20), suggesting an important role in brain development. Another remarkable feature of AG in the adult human brain is that it varies regionally (21): nearly 25% of resting glucose consumption in the medial prefrontal cortex is AG whereas AG constitutes as little as 2% glucose consumption in the cerebellum and medial temporal lobes. Correlation of these regional data with regional gene expression in the adult human brain revealed increased gene expression typical of infancy (i.e., neotony) that is related to synapse formation and growth (20).Further supporting the link between AG and plasticity are findings demonstrating that lactate, released by astrocytes and taken up by neurons, is critical for memory formation. Neuronal uptake of lactate ch...

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Section: Discussionmentioning

confidence: 99%

“…The cellular processes involved in synaptic elimination include localized, mitochondrial-mediated apoptosis in dendritic spines (82)(83)(84) that trigger immune functions mediated by the complement system (85,86), which, in turn, initiate the removal of synaptic detritus by microglia (87)(88)(89)(90)(91) and possibly even astrocytes (92).…”

Section: Discussionmentioning

confidence: 99%

Brain aerobic glycolysis and motor adaptation learning

Shannon

Vaishnavi

Vlassenko

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Microglia engage in constructive pruning to maintain synaptic and functional specialization during critical developmental phases and in neurogenesis (Matcovitch-Natan et al, 2016;Schafer and Stevens, 2015). In contrast, toxic pruning by microglia results from excessive immune activation and aggressive neural signaling (eg, during prenatal infections and severe stress) and appears to move the trajectory toward synaptic destruction or aberrant synaptic construction (Brites and Fernandes, 2015).…”

Section: Alternative Activation and Acquired Deactivation Statesmentioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

389

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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“…Microglia once activated are critically involved in neuronal events at various stages in development and adulthood, including synaptic remodeling to improve neuronal network signaling (Schafer and Stevens, 2015). An increasing body of evidence suggests a link between microglia and the microbiota-gut-brain axis which has implications for many stress-related and neurodegenerative disorders There is a close link between HPA axis activation and the regulation of the peripheral and central immune responses, leading to monocyte priming and trafficking, subsequent alterations in microglia phenotype and, ultimately resulting in neuroinflammation.…”

Section: Microbiota As a Regulator Of Neuroimmune Functionmentioning

confidence: 99%

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

Dinan

Cryan

2016

Neuropsychopharmacol

191

121

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There is now a large volume of evidence to support the view that the immune system is a key communication pathway between the gut and brain, which plays an important role in stress-related psychopathologies and thus provides a potentially fruitful target for psychotropic intervention. The gut microbiota is a complex ecosystem with a diverse range of organisms and a sophisticated genomic structure. Bacteria within the gut are estimated to weigh in excess of 1 kg in the adult human and the microbes within not only produce antimicrobial peptides, short chain fatty acids, and vitamins, but also most of the common neurotransmitters found in the human brain. That the microbial content of the gut plays a key role in immune development is now beyond doubt. Early disruption of the host-microbe interplay can have lifelong consequences, not just in terms of intestinal function but in distal organs including the brain. It is clear that the immune system and nervous system are in continuous communication in order to maintain a state of homeostasis. Significant gaps in knowledge remain about the effect of the gut microbiota in coordinating the immune-nervous systems dialogue. However, studies using germ-free animals, infective models, prebiotics, probiotics, and antibiotics have increased our understanding of the interplay. Early life stress can have a lifelong impact on the microbial content of the intestine and permanently alter immune functioning. That early life stress can also impact adult psychopathology has long been appreciated in psychiatry. The challenge now is to fully decipher the molecular mechanisms that link the gut microbiota, immune, and central nervous systems in a network of communication that impacts behavior patterns and psychopathology, to eventually translate these findings to the human situation both in health and disease. Even at this juncture, there is evidence to pinpoint key sites of communication where gut microbial interventions either with drugs or diet or perhaps fecal microbiota transplantation may positively impact mental health.

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Microglia Function in Central Nervous System Development and Plasticity

Cited by 300 publications

References 141 publications

Brain aerobic glycolysis and motor adaptation learning

Brain aerobic glycolysis and motor adaptation learning

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

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