Eva Simoncicova

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The goal of this activity is to learn about the impact of microglial reactivity on mental health and detect it in patients.

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1. Delineate at least 8 physiological functions of microglia.

2. Discuss methodology to analyze microglia in psychiatric conditions.

3. Outline the current understanding of how microglia are altered in various psychiatric conditions.

This continuing medical education (CME) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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A complex relationship exists between inflammation and neuropsychiatric disorders, particularly those related to psychological stress exposure, such as anxiety disorders and major depressive disorder. For example, patients with chronic inflammatory conditions (eg, asthma or arthritis) show a high degree of comorbidity for these and 

 There is, perhaps, an evolutionary explanation for this relationship: with sickness, there are a sequelae of behaviors intended to allocate energy resources to deal with the illness, such as drowsiness, anorexia, fatigue, anxiety, altered cognition, anhedonia, along with reduced locomotor activity, social interaction, and exploration. These sequalae appear in 

 This behavioral shift is mediated by changes in brain activity among specific regions, including the insula (cortical representation of interoceptive pathways), ventral striatum (reduced reward processing and appetitive motivations), substantia nigra (psychomotor slowing), and dorsolateral prefrontal cortex (cognitive impairment),

 among others. The neural basis of these and other changes in 

 and behavior may arise from the diverse activities of microglia, which act as the brain’s resident immune cells.

Posing as the orchestrators of the defense system in the brain, microglia comprise approximately 10% of its cellular population.

 Unlike the other brain glial cells, astrocytes and oligodendrocytes, microglia originate from the embryonic yolk sac.

 They migrate to the brain early in development (embryonic day 9.0 in mice, corresponding to 4 to 5 weeks of human gestation) and 

 Microglia are crucial for the formation and wiring of neuronal circuits during brain development, and for synaptic plasticity as well as learning and memory processes throughout adolescence, adulthood, and aging.

 Microglia are highly dynamic, and typically exhibit a ramified morphology with processes that constantly survey the brain parenchyma.

 Their secretion of growth factors supports the maturation of neurons, oligodendrocytes, and astrocytes, as well as axonal growth, myelination, and synapse formation.

 Microglia-mediated phagocytosis eliminates cellular debris, apoptotic cells, and even synapses in processes such as synaptic pruning.

 Furthermore, region-, age-, and sex-dependent differences in microglial distribution, morphology, and function in the homeostatic brain have been 

Microglia act as the brain’s primary responders to homeostatic alterations, including stress-induced changes in neuronal activity and synaptic plasticity. Microglia also respond to more global and systemic disturbances associated with altered sleep, inflammation in the central and peripheral nervous system, and dietary imbalance.

 Exposure to immunological (eg, viral and bacterial infection), physiological (eg, trauma, hypoxia-ischemia, disease, or malnutrition), or psychosocial (eg, low socio-economic status or substance abuse) stressors is associated with altered microglial function and an increased risk of developing a wide range of psychiatric conditions.

 The vulnerability to these environmental stressors is exacerbated during prenatal, perinatal, and early postnatal development, which are the periods of life associated with the onset of neurodevelopmental disorders.

 Stress in adolescence or adulthood can contribute to anxiety or depression and potentiate the onset of age-related cognitive decline and neurodegenerative diseases, all of which have an affective component and involve microglial dysfunction.

Microglia appear to play a contributing role in the onset and progression of various neuropsychiatric disorders throughout life through abnormal homeostasis maintenance leading to neurodegeneration and synaptic loss.

 These are outwardly reflected as cognitive impairments or behavioral alterations, 2 common symptoms of psychological disorders.

 In both health and disease, microglia exert their effector functions through a variety of mechanisms (

 As microglia cross the blood-brain barrier, they shape neuronal circuits and maintain brain integrity over the course of life via the a) promotion of oligodendrocyte precursor cell maturation and oligodendrocyte-mediated myelination; b) dynamic scanning of their microenvironment for potential threats or insults using their extensive processes of arborization; c) production of trophic factors to support neuronal maturation and survival, axonal growth and formation of new synapses; d) production of inflammatory cytokines in steady state and increased release with aging or in response to stress/pathological insult; e) and f) active phagocytosis of cellular debris, apoptotic or excessive immature cells and precursors; as well as g) and h) the regulation of synaptic plasticity by active elimination/modification of synapses using synaptic stripping (physical separation of synaptic elements) or synaptic pruning (complement-mediated phagocytosis of synaptic elements/whole synapses).

-, stress- or disease-associated alterations of microglia may cause impairment of these beneficial physiological processes and result in neuroinflammation, neurodegeneration, synaptic loss, behavioral changes and/or increased susceptibility to mental diseases in later life stages.

In response to homeostatic challenges, microglia can alter their phenotype and function, thereby adopting a reactive state.

 Reactive microglia may change their morphology to a hyperramified or amoeboid shape, upregulate danger associated molecular pattern receptors on their surface and release increased amounts of cytokines and/or other inflammatory factors.

 Homeostatic challenges are able to prime microglia to intensify phagocytosis and respond more robustly to a subsequent alteration.

 It was previously thought that reactive microglia exist in 2 states: M1, which resembles a proinflammatory, pathological, and classical reactive phenotype; and M2, which represents an anti-inflammatory, restorative/reparative phenotype.

 M1-like cells are stimulated by interferon-g and lipopolysaccharide (LPS) or tumor necrosis factor alpha and express mRNA for inducible nitric oxide synthase and CD86 (a costimulatory molecule).

 These cells have upregulated phagocytic activity, secrete pro-inflammatory cytokines (eg, interleukin [IL]-1b, IL-12), and generate reactive oxygen species (ROS).

 M1-like cell functions, which include increased motility, ROS and other proinflammatory mediator production, and membrane turnover, require the following metabolic activities: glycolysis, pentose phosphate pathway activity, nicotinamide adenine dinucleotide phosphate production, and fatty acid synthesis.

 M2-like cells, on the other hand, are stimulated by IL-4 or IL-13 and express mRNA for arginase and CD206.

 These cells secrete anti-inflammatory cytokines (eg, IL-10) and growth factors as well as stimulate stem cell production and differentiation.

 M2-like cells need continual activation to increase the transcription of repair genes as well as produce growth factors, which requires energy production utilizing oxidative phosphorylation (and amino acid/fatty acid oxidation).

 It is important to note, however, that these classifications, which arose from in vitro cell culture studies, often failed to translate to in vivo conditions.

 Instead, microglia are now known to adopt various phenotypes, in which they can perform specialized functions, highlighting an important need for more nuanced tools to investigate microglial function.

 Microglia are heterogeneous: they comprise different subtypes that can be differentially recruited with each adopting different phenotypes depending on the context of health or disease.

To assess the role of microglia in humans, brain imaging techniques have been developed (

. For example, positron emission tomography (PET) can use radioligands that bind to translocator protein (TSPO).

 TSPO is a nonspecific indicator of a proinflammatory phenotype expressed by microglia as well as astrocytes and endothelial cells.

 Another method relies on the use of magnetic resonance spectroscopy (MRS) to quantify levels of the metabolite myo-inositol that functions as an osmolyte.

 Myo-inositol localizes to microglia, but also to astrocytes, and therefore is considered more of a marker of overall neuroinflammation than microglial reactivity.

 Analysis of microglia in postmortem brain samples (rodent or human) typically utilizes immunostaining for ionized calcium binding adaptor molecule 1 (IBA1) to assess changes in density and morphology, in combination with immunostaining for cell surface receptors (eg, CX3CR1, TREM2, CD11b, TMEM119) and/or phagolysosomal proteins (eg, CD68) to provide functional insight (

 of immunostaining can be performed using various techniques, including fluorescence and electron microscopy, providing ultrastructural insights into changes in microglial function (eg, phagocytosis), cellular stress, aging, dysfunction, or degeneration, as well as intercellular relationships (eg, microglia-synapse interactions), at nanoscale resolution.

Abnormalities in social interactions and communication, repetitive behavioral patterns, or sensor and emotional processing impairments—core symptoms of ASD—were repeatedly associated with dysfunctions in the neuroimmune crosstalk.

 People with ASD reportedly exhibit alterations of synaptic density and excitatory versus inhibitory tone, accompanied by a decrease in the expression of synaptic plasticity-related genes and an increase of TSPO signals across multiple brain regions, most notably the cerebral cortex, cerebellum, hippocampus, and amygdala.

 Results from preclinical studies provided further information on the synaptic changes, their association with impaired neuronal migration, and circuitry formation; and pointed to the role of mutations in microglial genes in ASD pathology.

 Among these is the gene coding for fractalkine receptor (CX3CR1), which mediates neuronal communication with microglia and is important for their response to stress.

 According to the 2-hit hypothesis of neurodevelopmental disorders, developmental activation of the immune system may act as a first hit, causing microglial priming, which in vulnerable individuals may result in increased sensitivity as well as inflammatory and phagocytic response to latter stimuli.

 Altered pruning activities of primed microglia could result in inappropriate brain circuit wiring, giving rise to ASD or other neurodevelopmental disorders.

 As an animal model of prenatal infection, maternal immune activation (MIA) is frequently used to study the relationship of inflammation with disorders of a developmental origin.

Few studies have focused on the microglia/inflammatory aspect of TS. Alterations of cortico-striato-thalamic pathways leading to aberrant inhibitory control of these circuits were proposed to underlie symptoms of motor disorders, including TS.

 These changes may result from inadequate neuronal support or uncontrolled microglial pruning activities.

 Clinical studies using TSPO neuroimaging or transcriptomics have supported the link between up-regulated microglial activity, expression of inflammatory markers and neuroinflammation in TS.

 These changes were observed in key brain areas such as the basal ganglia, particularly the striatum, of patients across different ages.

 Moreover, a new animal model of TS (knock-out [KO] of the histidine decarboxylase [Hdc] gene—a key enzyme in the histamine pathway) revealed striatal and hippocampal differences in microglial responses.

 Specifically, microglia of Hdc-KO mice basally displayed a reactive profile associated with reduced ramification and decreased expression of insulin-like growth factor, which is involved in neuronal support and survival.

On the contrary, LPS challenge resulted in exaggerated microglial inflammatory response in this model.

OBSESSIVE COMPULSIVE DISORDER (OCD) AND RELATED DISORDERS.

 OCD and related disorders are presumed to result from abnormal wiring in pathways similar to those of TS. Therefore, they share a high degree of comorbidity.

 Review of available data indicates peripheral inflammation and neuroinflammation in patients with OCD, of whom approximately 40% to 50% also suffer from an autoimmune disease of metabolic or cardiovascular character.

 Heightened TSPO binding in orbitofrontal cortex implies increased microglial/inflammatory activity in patients with OCD compared with healthy controls.

 A preclinical model in which there is a selective ablation of a microglial subpopulation from the homeobox protein 8 lineage produced an OCD-like behavioral phenotype.

ANXIETY, DEPRESSIVE, AND TRAUMA-RELATED DISORDERS.

 There is a large degree of overlap in the preclinical models for aspects of these disorders. Many researchers use chronic stress paradigms (social stressors such as intruder, social defeat, or subpar housing), fear learning, threat appraisal paradigms, or reward learning and processing to study precipitating factors or symptoms common across multiple disorders.

There are numerous reports in animal models of increased microglial density and activity following exposure to chronic stressors. The reports noted morphological changes; increased phagocytosis, notably involved in neuronal circuit remodeling; and secretion of primarily proinflammatory factors.

 These effects, along with associated pathological events (eg, monocyte trafficking across the blood brain barrier), are necessary for driving chronic-stress induced anxiety-like behavior, anhedonia, or learned helplessness.

Although there is a paucity of postmortem studies in humans, there is evidence of IBA1+ cells as well as an upregulation of human leukocyte antigen-D related (HLA-DR; a marker associated with antigen presentation during autoimmunity and infection) in the anterior cingulate cortex of patients with severe mood disorders (including major depressive disorder and bipolar disorder), particularly those who died by suicide.

 In vivo analysis shows mixed evidence regarding TSPO binding in patients with mood disorders, depending on the study and radiotracer.

 Although investigators observed no difference in TSPO binding in patients with mild to moderate depression, using a different TSPO tracer in a sample of patients with severe depression showed increased TSPO binding in the striatum, hippocampus, and prefrontal cortex,

 on the role of microglia in anxiety disorders is quite scarce, particularly in humans.

 However, a large degree of clinical overlap exists in populations of individuals with depressive and anxiety disorders.

 There is evidence of increased peripheral inflammation in anxiety disorders, notably associated with increased circulating levels of pro-inflammatory cytokines. These mediators are thought to signal to endothelial cells, but also to parenchymal microglia and astrocytes, resulting in 

 in their activity that increase cytokine release, which leads to neuroinflammation (ie, brain correlate of peripheral inflammation).

 may alter neuronal structure and function, which contributes to driving changes in behavior associated with these disorders.

 However, there are reports of low correlation between brain TSPO binding and peripheral indices of inflammation in humans,

Both neuroimaging and postmortem studies highlight alterations of microglia in schizophrenia.

 Postmortem human samples showed increased numbers of IBA1+ cells, especially with an ameboid morphology throughout the brain. They also showed an elevation of pro-inflammatory parameters.

 TSPO binding was increased in grey matter across the frontal and temporal lobes of patients with schizophrenia, as well as of those at high risk of developing the disorder.

 This increase in number and pro-inflammatory activity may be driving an increase in synaptic pruning, which is observed in this disorder.

Results from studies in humans showed upregulation of certain cytokines during 

 or early postnatal life stages to be involved in the pathogenesis of the disease.

 Although modeling some of the positive aspects of schizophrenia is difficult in rodents, MIA can be utilized and is associated with elevated brain cytokines, which may potentially alter synaptic formation, refinement, and oligodendrocyte maturation.

 A more defined link has been demonstrated between microglia and the complement system in schizophrenia. The complement component 4 (C4) promotes synapse elimination, while mice lacking C4 show reduced synaptic pruning.

 Furthermore, variations in the gene encoding for C4 (resulting in its abnormally increased expression and promoting synapse elimination) are associated with increased risk for schizophrenia.

 As schizophrenia is associated with over-pruning during adolescence, it is possible that this is due to increased C4-mediated microglial activity. Recent in vitro work, however, found that genetic variations of C4 locus may not be the only contributing factor to this excessive microglial synaptic elimination in patients with schizophrenia.

 Evidence that microglia are altered in bipolar disorder comes from PET imaging and post-mortem studies. PET imaging studies showed an increase in TSPO binding in the right hippocampus.

 However, results of postmortem studies are mixed. A recent systematic review

 highlighted very few changes. However, there were few studies with decreased levels of HLA-DR, CD68, CD11b, and quinolinic acid (a N-methyl-D-aspartate receptor agonist, which can induce neurotoxicity) in IBA1+ cells throughout the brain, including the dorsal raphe nucleus, frontal cortex, anterior cingulate cortex, and hippocampus.

 Other evidence shows microglial reactivity in patients with bipolar disorder who died by suicide, but this may be broadly true across diagnoses.

 Thus, there is currently no consensus as to the role that microglia play in bipolar disorder. It may be that the reduction in reactivity indicates an impairment of synaptic pruning and refinement, as there is no good evidence that bipolar disorder results in a loss of neuropil. Adequate animal models for the mania-associated symptoms of bipolar disorder are lacking, as ae models for depressive symptoms, as previously discussed.

 highlighted neuroimmune changes in response to tobacco, alcohol, cannabis, cocaine, methamphetamine and 3,4-methlyenedioxymethamphetamine (

), and opioid use. Preclinical work and studies using myo-inositol and TSPO reveal accentuated levels and binding.

 For tobacco and alcohol, acute exposure leads to a pro-inflammatory phenotype that is reduced with long-term exposure

 However, cannabis (which has not been shown to increase microglial reactivity acutely), cocaine, and methamphetamine/MDMA, are associated with increased TSPO binding or myo-inositol levels with long-term exposure.

This article briefly outlines the role that microglia play in neuropsychiatric disorders. For example, there was little discussion of the mediators of these effects (eg, cytokines, neuroendocrine signals) or the influence of infiltrating immune cells (some of which closely resemble microglia in terms of morphology, molecular expression, and functions).

Although not discussed herein, how treatments for these disorders may alter microglia deserves discussion. There is some evidence that antidepressants such as selective serotonin reuptake inhibitors reduce microglial reactivity (eg, increased IBA1+ staining) and neuroimmune parameters in rodent models.

 of the effects of brain stimulation on microglia (within and outside of neuropsychiatric diseases).

 An interesting study found that cognitive behavior therapy reduced TSPO binding in patients with depression.

 Moreover, in patients with psychiatric disorders, add-on therapy with anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs or minocycline can have beneficial impact on psychiatric symptoms, likely through decreasing microglial reactivity and neuroinflammation.

 It is clear, however, that more work is needed to understand the role of microglia in current treatment strategies, as well as how they can be leveraged for new treatment pathways.

Another interesting area of growing research is the relationship between the gut-brain axis, microglia, and neuropsychiatric disorders. Particularly at the preclinical level, investigators are looking at the role of the microbiota, the effects of pre- and post-biotics and diet on microglia, and neuropsychiatric disorders.

 Changes to the gut-brain axis and microbiota can alter levels of neurotransmitters, short-chain fatty acids, and inflammatory signals that can affect the brain (including microglia), which can lead to changes in behavior.

 This field is still growing, although there is current interest in using pre- and post-biotics as potential therapeutics in neuropsychiatric disorders.

Although this review was separated into disorder types, there are changes in brain regions or experiences that contribute to similar symptoms across disorders. Thus, using a 

 approach to investigate the role in the pathogenesis of symptoms may provide insight into a wide variety of disorders. This also highlights the importance of live human brain imaging and postmortem studies, as many aspects of these disorders cannot be adequately studied in animal models. However, a recent translational study focusing on microglia-complement signaling in schizophrenia

 indicated an ability to take clinical findings back to the animal to discover new pathways and mechanisms.

Better and more specific tool development for human imaging studies is crucial, so that we are better able to understand brain alterations that may be driving pathogenesis. Recent advances in the field include new radiotracers that might provide functional insight into how microglia are behaving in different psychiatric conditions, for instance targeting the fractalkine or purinergic systems. The upcoming years are sure to yield new exciting research that will hopefully lead to better targeted and more efficient treatments.

is a postdoctoral fellow at the Division of Medical Sciences in the University of Victoria. 

 is a doctoral student at the University of Victoria. 

 is an associate professor, Canada Research Chair (Tier II) of Neurobiology of Aging and Cognition, Division of Medical Sciences in the University of Victoria.

We acknowledge that the University of Victoria stands on the territory of the Lekwungen peoples and that the Songhees, Esquimalt and WSÁNEĆ peoples have relationships to this land; and that Université Laval stands on the unceded land of the Huron-Wendat peoples.

We thank J. Savage, PhD; F. González-Ibáñez, MSc; and MK St-Pierre, MSc for confocal and electron microscopy images.

Dr Tremblay is a Canada Research Chair (Tier II) in Neurobiology of Aging and Cognition. Ms Šimončičová was supported by a National Scholarship Programme of Slovak Republic provided by SAIA. Dr Vecchiarelli was supported by fellowships from the Canadian Institutes of Health Research (CIHR) and the Michael Smith Foundation for Health Research. This work was funded by a CIHR Foundation Grant awarded to Dr Tremblay.

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Articles

This CME article briefly outlines the role that microglia play in neuropsychiatric disorders. 