Elsevier

Neuroscience

Volume 300, 6 August 2015, Pages 141-154
Neuroscience

Review
The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders

https://doi.org/10.1016/j.neuroscience.2015.05.018Get rights and content

Highlights

  • Microglial activation is evident in psychiatric conditions.

  • It is not clear if microglia activation can lead to the onset of psychiatric disorders.

  • Microglia may be a target in the development of new drugs to treat psychiatric disorders.

Abstract

Psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia, affect a significant percentage of the world population. These disorders are associated with educational difficulties, decreased productivity and reduced quality of life, but their underlying pathophysiological mechanisms are not fully elucidated. Recently, studies have suggested that psychiatric disorders could be considered as inflammatory disorders, even though the exact mechanisms underlying this association are not known. An increase in inflammatory response and oxidative stress may lead to inflammation, which in turn can stimulate microglia in the brain. Microglial activation is roused by the M1 phenotype, which is associated with an increase in interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). On the contrary, M2 phenotype is associated with a release of anti-inflammatory cytokines. Thus, it is possible that the inflammatory response from microglial activation can contribute to brain pathology, as well as influence treatment responses. This review will highlight the role of inflammation in the pathophysiology of psychiatric disorders, such as MDD, BD, schizophrenia, and autism. More specifically, the role of microglial activation and associated molecular cascades will also be discussed as a means by which these neuroinflammatory mechanisms take place, when appropriate.

Introduction

A growing body of evidence suggests that many psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, and autism are associated with distinct inflammatory mechanisms in the periphery and in the central nervous system (CNS). The relevance of inflammation in these conditions has been proposed by several studies, linking them with alterations in cytokines and acute-phase reactants. Risk factors for MDD and BD include medical conditions associated with chronic inflammatory and immunological alterations, such as rheumatoid arthritis, obesity and diabetes (Leboyer et al., 2012). Moreover, peripheral immune modulators have been shown to induce psychiatric symptoms in humans and in animal models (Dantzer et al., 2008, Harrison et al., 2009, Eisenberger et al., 2010, Haroon et al., 2012). Inflammation in the context of the nervous system, termed ‘neuroinflammation’, has been reported in patients with psychiatric disorders (Najjar et al., 2013), and is typically associated with microglial activation.

Microglia are CNS-resident cells that are usually the first to be activated in response to tissue damage or brain infections (Stertz et al., 2013). These small cells have several functions described, including (but not limited to): pathogen recognition, phagocytosis, antigen presentation, and synapse remodeling (reviewed in Boche et al., 2013). Non-activated microglia termed “quiescent” or “resting” microglia are constantly surveilling the surrounding environment in non-pathological conditions (Nimmerjahn et al., 2005, Marshall et al., 2013). In response to changes in the environment, microglial cells can be activated by changing their morphology and function (Marshall et al., 2013). Their activators include a range of different molecules, such as the P2X7purinergic receptor (P2X7R), and endogenous constituents that are normally released from injured cells, including adenosine 5′-triphosphate (ATP), S100 molecules, histones and heat shock protein (HSP), which are known as damage-associated molecular patterns (DAMPs) (Lu et al., 2014, Wiersinga et al., 2014). Specifically, P2X7R acts as a “sensor of danger” by responding to the so-called “danger signal” ATP, which is released from injured cells and activates microglia (Weisman et al., 2012, Gubert et al., 2013). The same goes for other DAMPs with their specific receptors.

Microglial activation can be divided into two distinct types: a classical M1 and an alternative M2 activation. In the M1 activation, microglial cells may become hyper-ramified or ameboid/phagocytic (Boche et al., 2013), and may synthesize proinflammatory molecules (interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, among others), superoxide radicals, glutamate (Barger et al., 2007, Takaki et al., 2012), nitric oxide (NO) and ultimately clear infections and repair tissues. Alternatively, M2 activation, which can be triggered by cytokines such as IL-4, IL-13 or IL-25 (Boche et al., 2013, Maiorino et al., 2013), has been associated with a release of anti-inflammatory cytokines such as IL-10, insulin-growth factor-1(IGF-1), transforming growth factor-β (TGF-β), and neurotrophic factors (Ekdahl, 2012, Boche et al., 2013, Hu et al., 2015), which facilitate healing and limit neuronal injury (Najjar et al., 2013). The nature and the magnitude of the injury, along with several other factors, can influence the development of these distinct microglial phenotypes (Marshall et al., 2013). In addition to this dichotomous phenotype classification, a graded level of microglia activation has also been proposed, in which cells can go from a resting stage, to an alert, homing, phagocytic stage and finally to bystander activation, which can be differentiated by morphological features and the levels of cytokines and growth factors secreted (Raivich et al., 1999). Most importantly, identifying activated microglia in a pathological condition, although being a marker of inflammation, does not allow for an understanding of the inflammatory process. Thus, only by determining the phenotype of microglia can one identify its role in cytotoxicity and/or neuroprotection (Colton and Wilcock, 2010, Graeber et al., 2011, Marshall et al., 2013).

Several studies in the past year speculated that alterations in the number and/or morphology of microglial cells are involved in cognitive and behavioral changes observed in psychiatry disorders (Di Benedetto and Rupprecht, 2013, Müller et al., 2015, Nakagawa and Chiba, 2014, Watkins et al., 2014, Zeidan-Chulia et al., 2014, Najjar and Pearlman, 2015). However, although activation of microglia is a typical hallmark of brain pathology, the extent to which it has beneficial or detrimental functions in the brain in different psychiatric disorders remains to be elucidated (Dheen et al., 2007). Specifically, given that microglia can be activated in either a cytotoxic or a neuroprotective way, characteristics of the microglial activation assessed in a specific condition need to be taken into account. This review article aims to summarize evidence of inflammation and in major psychiatric disorders, such as major depression, BD, schizophrenia, and autism, including the role it plays in their progression and therapeutics. More specifically, the role of microglial activation and polarization, as well as associated molecular cascades, will also be discussed as a means by which these neuroinflammatory mechanisms take place, when appropriate.

Section snippets

The role of microglia in stress and depression

MDD is considered a critical public health problem, and it is estimated that approximately 350 million individuals are affected worldwide (WHO, 2012). In addition, almost 1 million lives are lost yearly due to suicide, which translates to 3000 suicide deaths every day (WHO, 2012). Until recently, the monoaminergic hypothesis appeared to be the most widely accepted theory for depression. However, a series of new studies have shown that other pathways involved with neuroplasticity or

The role of microglia in BD

BD is a severe mood disorder characterized by recurrent episodes of mania followed by depression. Although the clinical characteristic for the diagnosis of BD is the presence of manic symptoms, depression represents the predominant mood state in patients with BD type I and BD type II. The pathophysiology of BD has been attributed to deficits in monoamine neurotransmitters, such as dopamine. However, the neurobiology of BD, as well as the mechanism of action of mood stabilizers used to treat BD,

Microglial hypothesis of schizophrenia

Schizophrenia is a chronic and debilitating disorder that affects 0.5–1% of the world population (Tandon et al., 2008). Patients with this disorder present positive and negative symptoms. Positive symptoms are characterized by extra feelings or behaviors, such as hallucinations and delusions. On the other hand, negative symptoms are associated with lack of behaviors, for example, apathy and loss of interest in everyday activities. Evidence suggests that the dopamine dysfunction hypothesis,

Microglial activation in autism

The autism spectrum disorders (ASD) are neurodevelopmental disorders, which are characterized by language and intelligence deficits, as well as impairment in social interactions (Abrahams and Geschwind, 2008, Theoharides et al., 2013). Recent studies have demonstrated a relationship between autism and inflammation dysregulation/alteration (Young et al., 2011, Theoharides et al., 2013). Microglial activation has also been reported in patients with ASD. For instance, Tetreault et al. (2012)

Conclusion

Microglial activation and neuroinflammation are evident in psychiatric conditions and have been reported by preclinical and clinical studies. However, the pathological mechanisms involved in the microglial dysfunction are still not fully elucidated. Of note, it remains unclear whether microglia activation can lead to the onset of psychiatric disorders and consequently to a neuroinflammatory process. More specifically, even though microglial activation can present two opposite phenotypes, the

Acknowledgments

Laboratory of Neurosciences (Brazil) is a center within the National Institute for Translational Medicine (INCT-TM) and a member of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq (J.Q., T.B., F.K. and G.Z.R.), FAPESC (J.Q. and T.B.), Instituto Cérebro e Mente, UNESC (J.Q.), and ĹOréal/UNESCO/ABC Brazil Fellowship for Women in Science 2011 (G.Z.R.). J.Q., T.B. and F.K. are CNPq Research Fellows. Center for

References (168)

  • Y.C. Chung et al.

    Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation

    Neuropharmacology

    (2011)
  • F. Correa et al.

    Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: restoring effects of inhibitors of HDACs, p38 MAPK and GSK3beta

    Neurobiol Dis

    (2011)
  • Y. Couch et al.

    Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia

    Brain Behav Immun

    (2013)
  • J. Dahl et al.

    The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery

    Psychoneuroendocrinology

    (2014)
  • Y. Diz-Chaves et al.

    Prenatal stress increases the expression of proinflammatory cytokines and exacerbates the inflammatory response to LPS in the hippocampal formation of adult male mice

    Brain Behav Immun

    (2013)
  • N.I. Eisenberger et al.

    Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward

    Biol Psychiatry

    (2010)
  • M.G. Frank et al.

    Chronic exposure to exogenous glucocorticoids primes microglia to pro-inflammatory stimuli and induces NLRP3 mRNA in the hippocampus

    Psychoneuroendocrinology

    (2014)
  • M.G. Frank et al.

    Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses

    Brain Behav Immun

    (2012)
  • L.S. Garcia et al.

    Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus

    Prog Neuropsychopharmacol Biol Psychiatry

    (2008)
  • L.S. Garcia et al.

    Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats

    Prog Neuropsychopharmacol Biol Psychiatry

    (2009)
  • R.R. Girgis et al.

    The cytokine model of schizophrenia: emerging therapeutic strategies

    Biol Psychiatry

    (2014)
  • M.B. Graeber et al.

    Role of microglia in CNS inflammation

    FEBS Lett

    (2011)
  • B.C. Haarman et al.

    Neuroinflammation in bipolar disorder – A [(11)C]-(R)-PK11195 positron emission tomography study

    Brain Behav Immun

    (2014)
  • M. Hamidi et al.

    Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes

    Biol Psychiatry

    (2004)
  • N.A. Harrison et al.

    Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity

    Biol Psychiatry

    (2009)
  • C. Hoyo-Becerra et al.

    Insights from interferon-alpha-related depression for the pathogenesis of depression associated with inflammation

    Brain Behav Immun

    (2014)
  • X. Hu et al.

    Neurobiology of microglial action in CNS injuries: receptor-mediated signaling mechanisms and functional roles

    Progr Neurobiol

    (2014)
  • Z.M. Ignacio et al.

    Epigenetic and epistatic interactions between serotonin transporter and brain-derived neurotrophic factor genetic polymorphism: insights in depression

    Neuroscience

    (2014)
  • Y. Imai et al.

    A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage

    Biochem Biophys Res Commun

    (1996)
  • R.A. Iseme et al.

    Autoantibodies and depression: evidence for a causal link?

    Neurosci Biobehav Rev

    (2014)
  • J.J. Kim et al.

    Identification of antibodies to heat shock proteins 90 kDa and 70 kDa in patients with schizophrenia

    Schizophr Res

    (2001)
  • J.J. Kim et al.

    Association analysis of heat shock protein 70 gene polymorphisms in schizophrenia

    Eur Archiv Psychiatry Clin Neurosci

    (2008)
  • J.E. Le Belle et al.

    Maternal inflammation contributes to brain overgrowth and autism-associated behaviors through altered redox signaling in stem and progenitor cells

    Stem Cell Rep

    (2014)
  • M. Leboyer et al.

    Can bipolar disorder be viewed as a multi-system inflammatory disease?

    J Affec Dis

    (2012)
  • S.A. Marshall et al.

    Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: the importance of microglia phenotype

    Neurobiol Dis

    (2013)
  • U. Meyer

    Developmental neuroinflammation and schizophrenia

    Progr Neuropsychopharmacol Biol Psychiatry

    (2013)
  • A.H. Miller et al.

    Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression

    Biol Psychiatry

    (2009)
  • B.J. Miller et al.

    Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects

    Biol Psychiatry

    (2011)
  • S. Missault et al.

    The risk for behavioural deficits is determined by the maternal immune response to prenatal immune challenge in a neurodevelopmental model

    Brain Behav Immun

    (2014)
  • H. Mitani et al.

    Correlation between plasma levels of glutamate, alanine and serine with severity of depression

    Progr Neuropsychopharmacol Biol Psychiatry

    (2006)
  • J.T. Morgan et al.

    Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism

    Brain Res

    (2012)
  • P.B. Mortensen et al.

    Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth

    Biol Psychiatry

    (2007)
  • S. Najjar et al.

    Neuroinflammation and white matter pathology in schizophrenia: systematic review

    Schizophrenia Res

    (2015)
  • S.M. O’Brien et al.

    Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy

    J Psychiatr Res

    (2007)
  • Y. Ohgi et al.

    Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration

    Pharmacol Biochem Behav

    (2013)
  • G.S. Peng et al.

    Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia

    Brain Res Mol Brain Res

    (2005)
  • H.M. Abelaira et al.

    Animal models as tools to study the pathophysiology of depression

    Rev Bras Psiquiatr

    (2013)
  • H.M. Abelaira et al.

    Animal models as tools to study the pathophysiology of depression

    Rev Bras Psiquiatr

    (2014)
  • B.S. Abrahams et al.

    Advances in autism genetics: on the threshold of a new neurobiology

    Nat Rev Genet

    (2008)
  • S.A. Acosta et al.

    Influence of post-traumatic stress disorder on neuroinflammation and cell proliferation in a rat model of traumatic brain injury

    PLoS One

    (2013)
  • Cited by (0)

    View full text