Neuroscience 300 (2015) 141154
REVIEW
THE ROLE OF INFLAMMATION AND MICROGLIAL ACTIVATION
IN THE PATHOPHYSIOLOGY OF PSYCHIATRIC DISORDERS
G. Z. REUS, a,b* G. R. FRIES, a,c L. STERTZ, a,c
M. BADAWY, a I. C. PASSOS, a,c T. BARICHELLO, a,d
F. KAPCZINSKI a,c AND J. QUEVEDO a,b
a
Center for Translational Psychiatry, Department of Psychiatry
and Behavioral Sciences, The University of Texas Medical School
at Houston, Houston, TX, USA
b
Laboratorio de Neurociencias, Programa de Pos-Graduacao
em Ciencias da Saude, Unidade Academica de Ciencias da
Saude, Universidade do Extremo Sul Catarinense, Criciuma, SC,
Brazil
c mechanisms
Molecular Psychiatry Unit and National Science and
Technology Institute for Translational Medicine (INCT-TM),
Hospital de Clnicas de Porto Alegre (HCPA), Universidade
Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
d
Laboratorio de Microbiologia Experimental, Programa de
Pos-Graduacao em Ciencias da Saude, Unidade Academica
de Ciencias da Saude, Universidade do Extremo Sul
Catarinense, Criciuma, SC, Brazil
AbstractPsychiatric disorders, including major depres-
sive disorder (MDD), bipolar disorder (BD) and schizophre-
nia, aect a signicant percentage of the world population.
These disorders are associated with educational diculties,
decreased productivity and reduced quality of life, but their
underlying pathophysiological mechanisms are not fully
elucidated. Recently, studies have suggested that psychi-
atric disorders could be considered as inammatory disor-
ders, even though the exact mechanisms underlying this
association are not known. An increase in inammatory
response and oxidative stress may lead to inammation,
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-1b (IL-1b) and
*Correspondence to: G. Z. Reus, Center for Experimental Models in
Psychiatry, Department of Psychiatry and Behavioral Sciences, The
University of Texas Medical School at Houston, Houston, TX 77054,
USA. Fax: +1-713-486-2553.
E-mail address: gislaine.z.reus@uth.tmc.edu (G. Z. Reus).
Abbreviations: ADX, adrenalectomized; ASD, autism spectrum
disorders; BD, bipolar disorder; CSF, cerebrospinal uid; DAMPs,
damage-associated molecular patterns; FS, forced swimming; HDACi,
histone deacetylase inhibitor; HSP, heat shock protein; IDO,
indoleamine 2,3 dioxygenase; IFN-c, interferon-c; IL-1b, interleukin-
1b; iNOS, inducible nitric oxide synthase; LH, learned helplessness;
LPS, lipopolysaccharide; MDD, major depressive disorder; NMDA,
N-methyl-D-aspartate; NO, nitric oxide; OB, olfactory bulbectomised;
P2X7R, P2X7purinergic receptor; PET, positron emission tomography;
PTSD, post-traumatic stress disorder; QUIN, quinolinic acid; SSRIs,
selective serotonin reuptake inhibitors; TGF-b, transforming growth
factor-b; Th1, T-helper 1; Th2, T-helper 2; TLRs, toll-like receptors;
TNF-a, tumor necrosis factor-a; TS, tail suspension; VPA, valproate.
http://dx.doi.org/10.1016/j.neuroscience.2015.05.018
0306-4522/ 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
tumor necrosis factor-a (TNF-a). On the contrary, M2 pheno-
type is associated with a release of anti-inammatory cyto-
kines. Thus, it is possible that the inammatory response
from microglial activation can contribute to brain pathology,
as well as inuence treatment responses. This review will
highlight the role of inammation in the pathophysiology
of psychiatric disorders, such as MDD, BD, schizophrenia,
and autism. More specically, the role of microglial activa-
tion and associated molecular cascades will also be dis-
cussed as a means by which these neuroinammatory
take place, when appropriate.
2015 IBRO. Published by Elsevier Ltd. All rights reserved.
Key words: microglia, neuroinammation, major depressive
disorder, bipolar disorder, autism, schizophrenia.
Contents
Introduction 141
The role of microglia in stress and depression 142
The role of microglia in BD 146
Microglial hypothesis of schizophrenia 147
Microglial activation in autism 149
Conclusion 150
Acknowledgments 150
References 150
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 inammatory
mechanisms in the periphery and in the central nervous
system (CNS). The relevance of inammation 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 inammatory 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).
Inammation in the context of the nervous system, termed
141
142 G. Z. Reus et al. / Neuroscience 300 (2015) 141154
neuroinammation, 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
rst to be activated in response to tissue damage or brain
infections (Stertz et al., 2013). These small cells have sev-
eral 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 detrimental functions in the brain in dierent psychiatric
microglia are constantly surveilling the surrounding envi-
ronment 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 dierent mole-
cules, such as the P2X7purinergic receptor (P2X7R), and
endogenous constituents that are normally released from
injured cells, including adenosine 50 -triphosphate (ATP),
S100 molecules, histones and heat shock protein (HSP),
which are known as damage-associated molecular pat-
terns (DAMPs) (Lu et al., 2014; Wiersinga et al., 2014).
Specically, 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 specic 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-
ramied or ameboid/phagocytic (Boche et al., 2013),
and may synthesize proinammatory molecules
(interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a),
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-inammatory cytokines such as IL-10,
insulin-growth factor-1(IGF-1), transforming growth
factor-b (TGF-b), 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 inuence the development of these dis-
tinct microglial phenotypes (Marshall et al., 2013). In addi-
tion to this dichotomous phenotype classication, a
graded level of microglia activation has also been pro-
posed, in which cells can go from a resting stage, to an
alert, homing, phagocytic stage and nally to bystander
activation, which can be dierentiated by morphological
features and the levels of cytokines and growth factors
secreted (Raivich et al., 1999). Most importantly, identify-
ing activated microglia in a pathological condition,
although being a marker of inammation, does not allow
for an understanding of the inammatory 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; Muller 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 benecial or
disorders remains to be elucidated (Dheen et al., 2007).
Specically, given that microglia can be activated in either
a cytotoxic or a neuroprotective way, characteristics of the
microglial activation assessed in a specic condition need
to be taken into account. This review article aims to sum-
marize evidence of inammation and in major psychiatric
disorders, such as major depression, BD, schizophrenia,
and autism, including the role it plays in their progression
and therapeutics. More specically, the role of microglial
activation and polarization, as well as associated molecu-
lar cascades, will also be discussed as a means by which
these neuroinammatory mechanisms take place, when
appropriate.
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
aected 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 intracellular sig-
naling cascades would be directly or indirectly responsible
for the mood dysregulation, as well as to the mechanism
of action of antidepressant drugs (Reus et al., 2013a,
2014; Abelaira et al., 2014a,b; Hoyo-Becerra et al.,
2014; Ignacio et al., 2014).
Since patients with autoimmune and inammatory
disorders, such as diabetes and bromyalgia, present
with depressive symptoms, it has been proposed that
depression may be linked to inammation (Ceretta
et al., 2012; Abelaira et al., 2014a,b; Hoyo-Becerra
et al., 2014; Iseme et al., 2014; McInnis et al., 2014). In
fact, patients with depression have been shown to pre-
sent an increase in serum levels of proinammatory
cytokines, such as IL-1, IL-6, IL-8, IL-12, interferon-c
(IFN-c) and TNF-a (Schiepers et al., 2005; OBrien
et al., 2007). In addition, elevated plasma levels of IL-
1b, IL-1 receptor antagonist, IL-5, IL-6, IL-7, IL-8, IL-10,
granulocyte colony-stimulating factor (G-CSF), and IFN-
c have been reported in patients during ongoing depres-
sion. Of note, cytokines were reduced to normal levels
after 12 weeks of treatment with antidepressants (Dahl
et al., 2014). On this same vein, Song et al. (2009)
showed an increase in serum IL-1b and a decrease in
IL-10 levels (proinammatory cytokine) in depressed
patients. In addition, T-helper 1 (Th1) and T-helper 2
 G. Z. Reus et al. / Neuroscience 300 (2015) 141154
(Th2), which are responsible for pathogens elimination
and antibody regulation, respectively, were also found to
be altered in untreated depressed patients (Song et al.,
2009). Nevertheless, acupuncture and uoxetine treat-
ments reduced IL-1b levels in responders, whereas
acupuncture was also able to restore the balance
between Th1 and Th2 systems by attenuating TNF-a con-
centration and INF-gamma/IL-4 ratio toward the control
level (Song et al., 2009). Furthermore, injecting the bacte-
rial endotoxin lipopolysaccharide (LPS) was shown to
induce inammation and to cause subsequent
depressive-like behavior in rodents (OConnor et al.,
2009; Ohgi et al., 2013). Even though the underlying
mechanisms associated with the onset of inammation
and its relation to the development of depression are
not well known, one theory suggests that the inamma-
tory process in depression emerges from alterations of
immune regulators in the CNS. A recent review suggests
that psychological stress can activate the immune
response in the CNS (Xanthos and Sandkuhler, 2014)
through enhanced neuronal activity. This would happen
through direct interactions between the neurons and the
glial cells. Neurons and microglia interact bidirectionally
and communicate through fractalkine, a transmembrane
chemokine that is expressed by neurons and acts through
a receptor (CX3CR1) that is exclusively present on micro-
glia (Xanthos and Sandkuhler, 2014; Cardona et al.,
2006).
Central immune response is modulated by microglia
and astrocytes. Microglia exerts an inammatory role
against danger signals from both the central and
peripheral nervous system (McNally et al., 2008;
Ransoho and Perry, 2009; Serrats et al., 2010).
Interestingly, an increase in microglial activation and
macrophage recruitment was found in postmortem dorsal
anterior cingulate matter from individuals suering from
MDD (Torres-Platas et al., 2014). Microglial activation
was also greater in the ventral prefrontal white matter in
individuals who committed suicide (Schnieder et al.,
2014). In the same matter, a correlation between suicide
and microglial activation in the dorsolateral prefrontal cor-
tex, anterior cingulate cortex, hippocampus and
mediodorsal thalamus from schizophrenic and depressive
patients (Steiner et al., 2008) was observed. Altogether,
these studies suggest that microglial activation may be
considered as an important marker in suicide. Of note,
Steiner et al. (2008) did not nd any evidence of microglial
activation in the same brain areas from patients who were
suering from depression, but did nd in patients who had
committed suicide, suggesting that microglial activation
might be a consequence of presuicidal stress.
Stress has been known to contribute to the
development of clinical depression, and evidence from
preclinical studies has suggested a role of microglia in
depression and stress. Moreover, morphological
activation of residential microglia was induced by
exposures to acute stress (Sugama et al., 2007).
SpragueDawley rats exposed to restraint stress showed
an increase in microglial activation in the prefrontal cortex,
while minocycline, a tetracycline antibiotic, which
presents with anti-inammatory and antidepressant
143
properties (Soczynska et al., 2012; Reus et al., 2014b),
was able to reduce the impact of stress on neural and
microglial activation (Hinwood et al., 2012). These nd-
ings support the theory that microglia plays a pivotal role
in modulating the impact of stress. In addition, pro-
inammatory prole and intensied microglial activation
were associated with the development of stress-induced
anhedonia in susceptible mice (Couch et al., 2013).
When changes in neural plasticity occur, the brain
becomes susceptible to stress by disrupting glial interac-
tions at the level of the synapse. Indeed, chronic stress
promotes microglial hyper-ramication and astroglial atro-
phy in the prefrontal cortex of rodents (Tynan et al., 2013).
In addition, mice exposed to acute stress presented mor-
phological activation of microglia in the thalamus,
hypothalamus, hippocampus, substantia nigra and central
gray (Sugama et al., 2007). Knockout mouse to IL-18
(/), which is a pro-inammatory cytokine, showed
reduced stress-induced morphological microglial activa-
tion, indicating a role of IL-18 in restraint stress response
(Sugama et al., 2007). It is important to note that animal
models of stress are used as a tool to investigate neuro-
biology of depression and also anxiety. In fact, stress
has been linked to the development of both depression
and anxiety (Phillips et al., 2015). However, animal mod-
els of stress do not always have criteria to validate an ani-
mal model, such as face, construct and predictive
validities (Abelaira et al., 2013). In the face validity,
behavioral changes should be similar to symptoms
observed in depressive patients; in the construct validity
the pathophysiological changes found in patients should
be present in animals; and in the predictive validity behav-
ioral changes should be reversed by eective treatment,
such as antidepressants (Abelaira et al., 2013). Thus,
studies which showed microglial activation in response
to stress could be related to an acute response to stress.
In addition, these changes could be related not only to the
development of depression, but also anxiety. Long-term
changes need to be better investigated in animal models
that show criteria for validity. Table 1 presents dierent
animal models of stress and depression and their criteria
validity. In addition, microglial alterations induced by
stress and the animal models of depression are also
summarized.
Prenatal restraint stress in mice was able to induce an
increase in IL-1b mRNA levels and in the total number of
ionized calcium binding adaptor molecule-1 (Iba1)-
immunoreactive microglial cells in the hippocampus.
Moreover, when prenatally restraint stressed mice
received LPS injections, they presented with an
increase in mRNA levels such as IL-6, TNF-a and IP10
(Diz-Chaves et al., 2012). In the same study, the authors
showed a higher proportion of Iba1-immunoreactive cells
in the hippocampus with morphological characteristics of
activated microglia compared to non-stressed mice (Diz-
Chaves et al., 2012). Furthermore, prenatally restraint
stressed mice presented an increase in TNF-a immunore-
activity in the CA1 region, as well as an increase in the
number of Iba-1 immunoreactive microglia and GFAP-
immunoreactive astrocytes in the dentate gyrus after
LPS administration (Diz-Chaves et al., 2013), thus
144 G. Z. Reus et al. / Neuroscience 300 (2015) 141154
Table 1. Eects of animal model of stress or depression on microglial activation and its criteria of validity
Animal model Criteria Microglial activation
Face Construct Predictive
Restraint stress   + +
Acute stress    +
Prenatal restraint stress    +
PTSD    +
Maternal sleep deprivation  +  +
Adrenalectomy  + + +
Stress footshock  + + +
LPS  + + +
OB  + + +
suggesting that the hippocampus plays an important role
in the inammatory response induced by stress.
Accordingly, the hippocampus is a region with a high den-
sity of microglial cells, especially in the CA1 region (Imai
et al., 1996). It has been suggested that microglial density
is involved in site-specic vulnerability of the hippocam-
pus, and the heterogeneous distribution of microglia might
have a role in modulating hippocampal neuronal activity
(Jinno et al., 2007; Choi and Won, 2011). Of note, the
eects of stress on hippocampal microglial activation
have been shown in several studies (Diz-Chaves et al.,
2012; Walker et al., 2013a,b; Weber et al., 2015), and it
is likely that they might not only be relevant in the patho-
physiology of MDD, but also in other psychiatric and
stress-related disorders, such as post-traumatic stress
disorder (PTSD). PTSD diers from prenatal stress by
exacerbating activated microglial cells along with dysfunc-
tional cell proliferation in the hippocampus (Acosta et al.,
2013). Nevertheless, Wistar rats exposed to cold stress
presented morphological microglial activation and an
increase of IL-1b in the hippocampus and the hypothala-
mus. Additionally, IL-1b was predominantly expressed in
the astroglia, rather than microglia, suggesting that expo-
sure to the cold stress may be involved in the communica-
tion between the neuron, microglia, and astroglia
(Sugama et al., 2011).
Maternal sleep deprivation, an animal model of
depression, inhibited neurogenesis through inammatory
cytokines (IL-1b, IL-6 and TNF-a) released from
activated microglia in young ospring rats; these eects
were associated with memory impairment and
anhedonic behavior (Zhao et al., 2014). Prenatal stress
induced by the forced swimming (FS) test was able to
reduce the number of immature microglia and accelerate
microglial dierentiation in the neonate Wistar rats, and
these eects were associated with an increase in plasma
corticosterone in the pregnant rat (Gomez-Gonzalez and
Escobar, 2010), thus suggesting that the eects on micro-
glial development and dierentiation are mediated by
microglial corticosterone receptors. Moreover, corticos-
teroid receptors are expressed in neurons and also in
microglial cells (Tanaka et al., 1997), and it is well known
that corticosteroids and their receptors play a pivotal role
in stress and depression (Garcia et al., 2009; Reus et al.,
2012; Ventura-Junca et al., 2014). Additionally, Frank
et al. (2014) demonstrated that chronic corticosterone
increased gene expression of inammasome NLRP3,
Iba-1, MHCII, and NF-kBIA, and also potentiated the
Reference
Hinwood et al. (2012)
Sugama et al. (2007)
Diz-Chaves et al. (2012, 2013)
Acosta et al. (2013)
Gomez-Gonzalez and Escobar (2010), Zhao et al. (2014)
Sugama et al. (2012), Burke et al. (2014)
Catanzaro et al. (2014), Frank et al. (2012)
Walker et al. (2013a,b)
Burke et al. (2014)
microglial pro-inammatory response (TNF-a, IL-1b, IL-6
and NLRP3) to LPS in adrenalectomized (ADX) rodents
compared to sham. Thus, it is possible that cortisol signal-
ing in microglia may play an important role in the inam-
matory process related to depression (Fig. 1); these
eects were dependent on the corticosterone dose,
though. In fact, corticosterone administration in low dose
was able to reverse microglial activation induced by stress
and adrenalectomy (Sugama et al., 2012). Interestingly,
treatment with RU486, an antagonist of glucocorticoid
receptor, or ADX blocked the sensitization of the micro-
glial pro-inammatory response induced by stress foot-
shock (Frank et al., 2012). Moreover, glucocorticoid
receptors appear to regulate microglial properties during
the inammatory process in the brain (Carrillo-de
Sauvage et al., 2013). (See Table 2).
Studies have shown that glutamate, an important
neurotransmitter in the CNS that plays a key role in the
pathophysiology of depression, is also involved in
microglial neurotoxicity (Piani et al., 1992; Barger and
Basile, 2001). Inammatory cytokines are able to
decrease the expression of the glutamate transporter
and increase glutamate release from astrocytes (Miller,
2013). Activation of microglia by inammatory cytokines,
in turn, can induce a release of glutamate that contributes
to neuronal damage during neuroinammation (Barger
et al., 2007). Furthermore, cytokines also rouse vesicular
release of glutamate from astrocytes, thereby activating
presynaptic N-methyl-D-aspartate (NMDA) receptors
(Santello and Volterra, 2012) and stimulating indoleamine
2,3 dioxygenase (IDO), which is a potent NMDA agonist
and stimulator of glutamate release (Miller et al., 2009).
Moreover, glutamate accumulation causes an increase
of intracellular Ca2+, which in turn may lead to the pro-
duction of reactive oxygen species (ROS) due to mito-
chondrial dysfunction and reduction of antioxidant
capacity (Schinder et al., 1996; Stanciu et al., 2000).
Thus, mitochondrial dysfunction and oxidative stress con-
tribute to glutamate excitotoxicity and consequently
increase proinammatory genes (Fig. 1). Glutamate and
their receptors play an important role in the pathophysiol-
ogy of depression. Indeed, patients with depression pre-
sented a signicant increase of serum glutamate levels
when compared with healthy controls (Kim et al., 1982;
Mitani et al., 2006). In addition, several preclinical and
clinical studies have demonstrated that NMDA antago-
nists, such as ketamine, memantine, amantadine and
others present antidepressant eects (Berman et al.,
 G. Z. Reus et al. / Neuroscience 300 (2015) 141154 145

Stress Depression
SSRI

Antagonist
GR
Chronic
CORT
GR Microglial
activation
IL-1 , IL-6,
TNF-, Iba1
Acute CORT

Minocycline

Glu uptake Astrocyte

atrophy IL-1

Glu NMDA 2+
Ca GR
ROS
Cytokine Pro-
inflammatory
genes

Antagonist
GR

Postsynaptic
Presynaptic Ketamine neuron
neuron

Fig. 1. The role of neuron-glia, glutamatergic signaling and immune system interactions in the pathophysiology of depression. Stress, higher CORT
or cytokines from the periphery may lead to microglial activation and increase proinammatory mediators in the CNS, such as IL-1b and TNF-a.
Microglial activation may induce atrophy in astrocytes, which in turn may tempt IL-1b elevation and decrease the Glu uptake, increasing Glu levels in
the synaptic cleft and consequently intraneuronal Ca2+ levels via NMDA receptors. This leads to ROS, cytokine production, and proinammatory
genes activation, thus leading to a vicious cycle with elevation of proinammatory cytokine levels, which is observed in patients with depression. On
the other hand, anti-inammatory modulators, such as GR antagonist, low dose CORT, NMDA antagonist and classical antidepressants act to
reduce the microglial activation and pro-inammatory cytokine production. CORT = corticosterone; GR = glucocorticoid receptor;
Glu = glutamate; NMDA = N-methyl-D-aspartate; ROS = reactive oxygen species; SSRI = selective serotonin reuptake inhibitors.

Table 2. Summary of microglial abnormalities observed in psychiatry disorders

Abnormalities Depression and Bipolar disorder Schizophrenia Autism Reference

stress

Astrocyte ; ; ; Steiner et al. (2009), Correa et al. (2011), Diz-Chaves

density et al. (2012)
Microglial " " " " Tetreault et al. (2012), Morgan et al. (2012), Suzuki et al.
activation (2013), Haarman et al. (2014), Torres-Platas et al. (2014)
Inammatory " IL-6, IL-8, IL-12, " IL-1b and IL-1 " IL-1b, IL-6, " IL-1b Young et al. (2011), Miller et al. (2011), Schiepers et al.
mediators IFN-c, IL-1b and receptor and TGF-b (2005), OBrien et al. (2007), Rao et al. (2010), Reus
TNF-a et al. (2013b)
Microglial " Iba1 " [11C]-(R)- " iNOS and Ribeiro et al. (2013), Haarman et al. (2014), Rao et al.
stimulators PK11195, iNOS DAMPs (2010), Diz-Chaves et al. (2012)
and c-fos

2000; Zarate et al., 2006; Ferguson and Shingleton, 2007;
Garcia et al., 2008a,b, 2009; Roman et al., 2009; Reus
et al., 2010). Moreover, ketamine has been shown to
have anti-inammatory properties by inhibiting TNF-a
and IL-6 gene expression in LPS-activated macrophages
(Wu et al., 2008), ultimately abrogating LPS-induced
depressive-like behavior (Walker et al., 2013a,b).
Additionally, studies from our group revealed that keta-
mine reverses the increase of proinammatory cytokines
induced by maternal deprivation (Reus et al., 2015a). In
conclusion, it is possible that modulators of the gluta-
matergic system may play an important role in reducing
microglial activation.
Several studies have emerged showing the role of
inammatory modulators in response to stress or
microglial activation. In fact, A-804598, an antagonist of
P2X7R, has been shown to play an important role in the
synthesis and conversion of IL-1b by partially
146 G. Z. Reus et al. / Neuroscience 300 (2015) 141154
attenuating the increased levels of IL-1b and CD14 mRNA
in the paraventricular nucleus of rats exposed to stress by
footshock (Catanzaro et al., 2014). CD14 acts as a co-
receptor (along with the Toll-like receptors TLR 4 and
MD-2) for the detection of LPS.
The upregulation of inammatory cytokines, such as
IL-1b and TNF-a, may be suggestive of microglial
activation; however, in the case of footshock exposure,
these eects do not appear to be mediated totally by
P2X7R. Nevertheless, Brilliant Blue G (BBG), another
potent P2X7R antagonist, revealed anti-inammatory
properties by decreasing TNF-a levels and
antidepressant behavior in the tail suspension (TS) and
FS tests (Ma et al., 2014) in rodents after LPS injection.
FS and TS are classical tests to investigate new antide-
pressant drugs (Abelaira et al., 2013).
Minocycline, which is a suppressor of activated
microglia, when chronically administrated, reduces the
expression of microglial activation maker CD11b and the
M1 pro-inammatory cytokine IL-1b in the prefrontal
cortex of control rats which were not subjected to
olfactory bulbectomised (OB), an animal model of
depression (Burke et al., 2014). Moreover, minocycline
increased the expression of the M2 microglial marker
MRC2 and of the associated anti-inammatory cytokines
IL-10 and IL-6 in the prefrontal cortex of OB rats, indicat-
ing that the eects of minocycline on microglial markers
are dependent on the presence or absence of a depres-
sive phenotype (Burke et al., 2014). Additionally, minocy-
cline potentiated the eects of quercetin, a bioavonoid
with antidepressant properties, in reducing the oxidative
stress and microglial activation induced by OB in rodents
(Rinwa and Kumar, 2013). Also, minocycline adminis-
trated into the cerebral ventricle of rats subjected to
learned helplessness (LH) (an animal model of depres-
sion) showed antidepressant eects and increased dopa-
mine and its metabolites in the amygdala when compared
to untreated rats, but did not alter the LH-induced eects
in serotonin turnover and in the BDNF levels in the hip-
pocampus (Arakawa et al., 2012). We also previously
demonstrated that minocycline protected against oxida-
tive damage in the brain of rats subjected to chronic mild
stress (Reus et al., 2015b). Thus, minocycline might be
promising as a therapeutic target to treat depression by
reducing microglial activation, oxidative stress and
inammation.
Antidepressant drugs used to treat depression also
act in microglial regulation. In fact, selective serotonin
reuptake inhibitors (SSRIs) potently inhibit microglial
TNF-a and NO production induced by LPS
administration, and cAMP signaling was involved in
regulating this anti-inammatory response (Tynan et al.,
2012). Fluoxetine, an SSRI, also reduced the microglial
activation in dopaminergic neurons induced by an animal
model of Parkinson (Chung et al., 2011), and also pre-
vented LPS-induced degeneration of nigral dopaminergic
neurons by inhibiting microglia-mediated oxidative stress
(Chung et al., 2010).
In conclusion, there are consistent data to indicate
that immune system dysregulation and microglial
activation may be key elements in mood dysregulation.
Moreover, the antidepressant eects of classic and new
modulators could be mediated, at least in part, by its
eects on regulating the immune system. However, how
such eects may occur is not yet well understood.
Therefore, future studies focusing on the association
between immune activation and stress could help in the
development of new therapeutic targets for depression.
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 decits 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, is not yet fully elucidated. Thus, it is
possible that other pathways besides the
monoaminergic system could be involved. Recently,
mood disorders are increasingly being recognized as
inamed moods (Rosenblat et al., 2014). One theory sug-
gests that in BD the immune system is chronically acti-
vated by microglia, which in turn produces cytokines
that render the brain to a vulnerable and unstable state,
precipitating mood disturbances (Schroeter et al., 2011).
In fact, higher levels of IL-1b were associated with dys-
function and increased suicide risk in patients with BD
(Monfrim et al., 2014). Changes in sleep pattern were also
observed in patients with BD, with an increase of IL-6 in
peripheral monocytes (Ritter et al., 2013). Furthermore,
Barbosa et al. (2013) demonstrated an increase in proin-
ammatory cytokines levels in BD. In euthymic patients
with BD, an increase in blood kynurenine concentrations
and in the kynurenine to tryptophan ratio was also
observed (Reininghaus et al., 2014). The kynurenine
pathway plays an important role in psychiatric diseases;
this pathway is an alternate route of tryptophan metabo-
lism that decreases serotonin neurotransmission
(Watkins et al., 2014). Moreover, stimulated microglia
may promote expression of cytokines, such as IFN-c, a
potent activator of Kynurenine pathway (KP). IFN-c
increases the activity of indoleamine 2,3-dioxygenase
(IDO), consequently increasing quinolinic acid (QUIN)
(Watkins et al., 2014), which causes excitotoxicity medi-
ated by the NMDA receptor. In the CNS, activated micro-
glia and inltrating macrophages are considered the main
producers of QUIN (Heyes et al., 1996).
Due to the complexity of BD, most studies using
animal models focus on the eects that mood stabilizers
and antipsychotics have in the microglial cells. Valproate
(VPA), a histone deacetylase inhibitor (HDACi), seems
to play an important role in managing activated
microglial cells. Cells pretreated with VPA showed
decreased levels of proinammatory factors, which were
concentration- and time-dependent (Peng et al., 2005).
The anti-inammatory eects of VPA appear to be based
on its ability to induce apoptosis in activated microglia.
VPA is capable of inducing cell apoptosis in brain
 G. Z. Reus et al. / Neuroscience 300 (2015) 141154
microglia as well as in the microglial cell line BV-2.
Moreover, the apoptosis is possibly mediated by p38
mitogen-activated protein kinase (MAPK) and mitochon-
drial apoptosis pathway (Xie et al., 2010). Additionally,
pre-treatment with HDACi sodium butyrate (SB) and
trichostatin A (TA) reduced LPS-induced dopaminergic
(DA) neurotoxicity in mesencephalic neuron-glia cultures
(Chen et al., 2006, 2007). It is proposed that this eect
in LPS-induced activated microglia may cause an
increased deacetylation of astroglial histone proteins.
Therefore, HDACi would be able to restore the down-
regulation of antioxidant capacity induced by inammation
in astrocytes, as well as reduce cell death following
oxidative stress (Correa et al., 2011). Lithium, a mood sta-
bilizer, was also able to signicantly inhibit LPS-induced
microglial activation and pro-inammatory cytokine
production in vitro. Lithium pretreatment was able to
suppress LPS-induced toll-like receptor 4 (TLR4)
expressions via the PI3K/Akt/FoxO1 pathway (Dong
et al., 2014). Altogether, these results point to an interest-
ing relationship between the mechanism of action of these
classic mood stabilizers (Lithium and VPA) and microglial
cells.
Despite the pharmacological results, there is lack of
research characterizing the microglial population
(number and level of activation) in BD patients, even
though there is an increase in the number of studies
suggesting its involvement in this pathology (Beumer
et al., 2012; Rege and Hodgkinson, 2013; Stertz et al.,
2013). Most of the current studies focus mainly on other
types of glial cells, such as astrocytes and oligodendro-
cytes (Gigante et al., 2011; Savitz et al., 2014). A recent
study showed a signicant increase in [11C]-(R)-
PK11195 binding potential, which is indicative of microglia
activation and neuroinammation. This increase was
found in the right hippocampus of patients with BD type
I compared to healthy controls (Haarman et al., 2014).
Still, other independent studies with this marker are nec-
essary to corroborate this nding.
Regarding postmortem studies, increased markers of
excitotoxicity and neuroinammation in the frontal cortex
of BD patients were demonstrated by Rao and cols. The
authors showed signicantly higher protein and mRNA
levels of IL-1b, IL-1 receptor (IL-1R), myeloid
dierentiation factor 88, nuclear factor-kappa B
subunits, astroglial and microglial markers (glial brillary
acidic protein, inducible nitric oxide synthase (iNOS),
c-fos, and CD11b) in these patients (Rao et al., 2010).
Contrary to these ndings, another study focusing on
the prefrontal white matter found an increased density in
oligodendrocyte, but not in the density of Iba-1-stained
microglia in BD samples. Regarding the qualitative
assessment of microglial morphology, the study found
numerous activated microglial cells in schizophrenia sam-
ples, but not in controls or BD samples (Hercher et al.,
2014). Furthermore, an evaluation of microglial cells in
the amygdala of BD patients using stereological methods
also failed to demonstrate dierences in cell numbers
compared to healthy controls (Hamidi et al., 2004). In con-
clusion, despite a lot of speculation, in order to nally
prove that microglial cells are involved in the pathophysi-
ology of the disorder and/or its progression, new tools to
147
target the microglial activation in the human brain needs
to be developed.
MICROGLIAL HYPOTHESIS OF
SCHIZOPHRENIA
Schizophrenia is a chronic and debilitating disorder that
aects 0.51% 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 sug-
gests that the dopamine dysfunction hypothesis, which
involves hyperstimulation of dopaminergic D2 receptors
in certain parts of the brain, may lead to positive symp-
toms. The glutamatergic hypofunction hypothesis of
schizophrenia could be responsible for the negative
symptoms (Meyer, 2013). Additionally, neuroinammation
has been linked to schizophrenia, as well (Monji et al.,
2009). One theory suggests that maternal immune activa-
tion during pregnancy is a risk factor for the progeny to
develop schizophrenia in adulthood (Brown, 2011). The
ndings from preclinical studies using models of prenatal
infection and maternal immune activation through
polyinosinic-polycytidylic (Poly I:C) or LPS can have a
negative impact on ospring brain development
(Missault et al., 2014; Reisinger et al., 2015; Wischhof
et al., 2015). Van den Eynde et al. (2014) demonstrated
that ospring rats born to Poly I:C had an increase in
microglia accompanied by schizophrenic-like behavior.
Inuenza exposure during the rst gestational trimester
signicantly increased the risk of schizophrenia in adult-
hood (Brown et al., 2004). Other studies showed an asso-
ciation between Toxoplasma gondii and early-onset
schizophrenia (Mortensen et al., 2007), and maternal
genital/reproductive infections during periconception
increased the risk of schizophrenia in ospring (Babulas
et al., 2006). On this vein, several models have attempted
to explain how prenatal infection can increase the risk of
schizophrenia. A theory suggests that the host immune
response through cytokines could mediate the eects of
infection (Girgis et al., 2014). During infection the innate
immune cells are also activated by endogenous con-
stituents that are normally released from injured cells,
including ATP, S100 molecules, histones and HSPs,
which are known as DAMPs (Lu et al., 2014; Wiersinga
et al., 2014). Thus, microglia can be stimulated by numer-
ous components including DAMPs or pro-inammatory
mediators to produce cytokines, chemokine, and induce
oxidative stress (Fig. 2). This prolonged and excessive
microglial response may lead to deleterious eects on
neuronal plasticity and apoptosis, leading to behavioral
and cognitive decits through exogenous as well as
endogenous components (Barichello et al., 2013; Hu
et al., 2014).
Microglial activation and an increase in microglial cells
in the brain of schizophrenic patients have been reported
in post-mortem studies (Bayer et al., 1999; Radewicz
et al., 2000). An increase in microglial cells was also
148 G. Z. Reus et al. / Neuroscience 300 (2015) 141154

Astrocyte
S100B
atrophy
iNOS
M1 IL-1, IL-6,
TNF-, ROS RAGE
DAMPS

Cytokines Antipsychotic

Iba-1 Neuronal
M2
apoptosis

IL-10,
HSP70s
TGF-

Pro-
inflammatory
genes

Behavioral and
cognitive deficits in
Schizophrenia

Fig. 2. Microglial activation hypothesis in the pathophysiology of schizophrenia. Pro-inammatory cytokines, HSP70s, Iba-1, DAMPs and iNOS
may activate the M1 and M2 microglia, which in turn may lead to an increase in IL-1b, IL-6, TNF-a and ROS, and IL-10 and TGF-b, respectively.
S100B protein jointly with RAGE, as well as M1 activation may induce astrocyte atrophy and lead to neural apoptosis, as well as increase gene
expression of pro-inammatory cytokines observed in schizophrenic patients. On the other hand, antipsychotic drugs used to treat schizophrenia act
by decreasing cytokines and ROS levels. DAMPS = damage-associated molecular patterns; Iba-1 = ionized calcium binding adaptor molecule 1;
iNOS = nitric oxide synthase; HSP70s = shock 70-kDa proteins; RAGE = glycation end-products receptor; ROS = reactive oxygen species;
TNF-a = tumor necrosis factor-a.

demonstrated in schizophrenic patients who had commit-
ted suicide (Steiner et al., 2008). A positron emission
tomography (PET) study showed microglial activation in
recent-onset schizophrenics within the rst 5 years of dis-
ease (van Berckel et al., 2008). Moreover, microglial acti-
vation through Iba-1 and iNOS in the hippocampus of
adult rats was observed in an animal model of schizophre-
nia induced during the neonatal period (Fig. 2). This
microglial activation was accompanied by prepulse inhibi-
tion (PPI) and working memory impairment that were
reversed by antipsychotic clozapine treatment (Ribeiro
et al., 2013). However, in the prefrontal white matter from
schizophrenic patients, Iba-1 expressing microglial cells
were found only in three out of 20 schizophrenia samples
compared to controls (Hercher et al., 2014).
Schizophrenia is known to be associated with
alterations in the immune system, such as increased
cytokine levels. In a meta-analysis, IL-1b, IL-6, and
TGF-b (which also has neuroprotective and anti-
inammatory eects in the CNS) were augmented
during an acute relapse in patients and in the rst-
episode of psychosis. These alterations in cytokines
were normalized with antipsychotic treatment (Fig. 2)
(Miller et al., 2011). Another meta-analysis revealed a link
between polymorphism in the IL-1b gene and abnormal
white and gray matter volume in schizophrenia (Najjar
and Pearlman, 2015).
Schizophrenic patients have also shown DAMPs in
the serum or in the cerebrospinal uid (CSF).
Micromolar concentrations of S100B protein (a protein
involved with cell cycle progression and dierentiation)
can induce apoptosis in neurons and astrocytes in
response to the activation of the advanced glycation
end-products receptor (RAGE) (Steiner et al., 2009).
S100B protein has been shown to be augmented in the
serum and in the CSF of untreated schizophrenic patients
(Schmitt et al., 2005).
Heat shock 70-kDa proteins (HSP70s) are molecular
chaperones and also microglial activators, which
regulate biological processes and are associated with
the pathophysiology of schizophrenia. Antibodies
against HSP70 have been found in the serum of
schizophrenic patients, which is suggestive of
inammation (Kim et al., 2001, 2008). Extracellular
HSP70 mediates the innate immune responses of brain
through toll-like receptors (TLRs). TLRs activate the
nuclear transcription factor kappa B (NF-jB), which plays
a key role in the expression of genes responsible for the
development of cell and inammation. These transcription
factors also are capable of activating the promoter region
of many pro-inammatory genes, including genes
expressed by the M1 microglial phenotype (Tato and
Hunter, 2002; Saijo and Glass, 2011).
In conclusion, inhibition of pro-inammatory cytokines
or enhancement of anti-inammatory mediators in
schizophrenic patients may be a benecial strategy to
prevent the devastating consequences of this illness
with respect to neuronal damage and function. We
propose that inhibition of the activity of DAMPs and/or
administration of specic anti-inammatory agents may
lead to amelioration of symptoms of this debilitating
illness.
 G. Z. Reus et al. / Neuroscience 300 (2015) 141154 149

MICROGLIAL ACTIVATION IN AUTISM
The autism spectrum disorders (ASD) are
neurodevelopmental disorders, which are characterized
by language and intelligence decits, as well as
impairment in social interactions (Abrahams and
Geschwind, 2008; Theoharides et al., 2013). Recent stud-
ies have demonstrated a relationship between autism and
inammation 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) reported an increase of microglial
cells in cortical areas (fronto-insular (FI) and visual cortex
(VC)) from individuals diagnosed with autism. Moreover,
in a postmortem study microglia was found to be aug-
mented in individuals with autism when compared with
healthy controls (Morgan et al., 2012), and a PET
revealed that young adults with ASD had increased mark-
ers of microglial activation in a wide range of brain areas,
including the cerebellum, brainstem, frontal cortex, ante-
rior cingulate cortex, corpus callosum, temporal cortex,
and parietal cortex (Suzuki et al., 2013). Dendritic cells,
which are important in modulating immune responses,
were found to be increased in the amygdala of individuals
with ASD in a magnetic resonance imaging (MRI) study
(Breece et al., 2013).
A study with mice lacking the chemokine receptor
CX3CR1 demonstrated decits in microglia, which were
associated with impairments in neural plasticity and
social interaction, which are linked with autism (Zhan
et al., 2014). Moreover, prenatal LPS exposure induced
autistic-like behavior and dopaminergic hypoactivity; how-
ever, the expression of glial cell markers in the striatum
was not altered (Kirsten et al., 2012). Conversely, Le
Belle et al. (2014) revealed that pregnant mice exposed
to LPS had osprings with increased forebrain microglia
and autistic behavior. In addition, LPS exacerbated glial
activation in the hippocampus and the cerebellum, as well
as behavioral changes induced by the VPA-induced ani-
mal model of autism in the gestational period (Lucchina
and Depino, 2014). Thus, it is possible that prenatal
inammation might be involved, at least in part, to micro-
glial activation in ASD (Fig. 3).
Rett syndrome, which is a X-linked ASD and is a
devastating neurodevelopmental disorder, was also
shown to be related to microglial alteration. In fact,
Derecki et al. (2012) demonstrated brain microglial activa-
tion in a murine model of Rett syndrome. This eect was
inhibited by annexin V, which blocks phosphatydilserine
residues on apoptotic targets. In addition, damages in
dendrites and synapses and microglial activation due to
high levels of glutamate were found in an animal model
of Rett syndrome (Maezawa and Jin, 2010). The same
authors demonstrated that inhibition of microglial gluta-
mate synthase, release or antagonism was able to block
its neurotoxicity activity in the hippocampus (Maezawa
and Jin, 2010). Glutamate dysfunction has been reported
also in ASD. A study showed that autistic patients
exhibited higher glutamate concentration; however,
higher GABA and lower GABA/glutamate have been
found in the patients (El-Ansary and Al-Ayadhi, 2014).
Additionally, a decrease in TNF-a and IL-6 and an
increase in IFN-c and IFI16 (a neuroinammatory marker)
were demonstrated (El-Ansary and Al-Ayadhi, 2014).
Altogether, these results suggest that an imbalance in
GABA and glutamate neurotransmission might be related
to neuroinammation in ASD. Thus, glutamatergic
modulators could be promising to treat ASD spectrum to
ultimately reduce glutamatergic excitotoxicity and conse-
quently microglial activation (Fig. 3).

Autism and Rett syndrome

LPS Microglial disease and neuroprogression
activation
Glutaminase
Inhibitor

Inhibitor

Glu NMDA 2+
Ca
Neuroinflammatory
proteins

Postsynaptic
Presynaptic
Antagonists neuron
neuron

Fig. 3. The role of neuron-glia, glutamatergic signaling and immune system interactions in the pathophysiology of ASD and Rett syndrome.
Prenatal infection with LPS may lead to microglial activation. Microglia may be also activated by higher levels of Glu, as well as increase in Glu
levels. Elevated glutamate levels from presynaptic neuron and microglia may increase Glu levels in the synaptic cleft and consequently
intraneuronal Ca2+ levels via NMDA receptors, which may be involved with neuroinammatory protein activation, thus leading to a vicious cycle with
elevation of proinammatory cytokine levels. These toxic eects could be involved with autism and Rett syndrome disease and neuroprogression.
On the other hand, decrease in Glu levels by glutamatergic modulators act to reduce microglial activation and pro-inammatory cytokine production.
Glu = glutamate; LPS = lipopolysaccharide; NMDA = N-methyl-D-aspartate.
150 G. Z. Reus et al. / Neuroscience 300 (2015) 141154
Recent studies show that there is a potential role of
microglial activation in autism and Rett syndrome, and
the pathways linked to microglial activation may be
involved with the neurodevelopment of both autism and
Rett syndrome. Moreover, preclinical studies in this area
may help to comprehend the mechanisms by which
microglial activation may be involved with the autistic
spectrum.
CONCLUSION
Microglial activation and neuroinammation 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
neuroinammatory process. More specically, even
though microglial activation can present two opposite
phenotypes, the majority of the studies do not take
these phenotypes into account when assessing
microglial activation in dierent disorders. In other
words, we can only infer whether a particular disorder is
associated with the M1 or M2 phenotype based on the
reported inammatory markers that the patients present.
In addition, many studies show peripheral inammation
in psychiatric disorders; however, increased
inammatory markers in the periphery are not synonyms
of microglial activation in the CNS. Thus, future studies
are needed to better characterize peripheral
inammatory markers involved with microglial activation
and to describe the role of microglia and their key
regulators in the symptomatic manifestations of
psychiatric disorders. Future studies may also help in
the development of new therapeutic targets, both for
prevention and for treatment.
AcknowledgmentsLaboratory 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 Cerebro e
Mente, UNESC (J.Q.), and LOreal/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 Translational
Psychiatry (USA) is funded by Department of Psychiatry and
Behavioral Sciences, The University of Texas Medical School
at Houston.
REFERENCES
Abelaira HM, Reus GZ, Quevedo J (2013) Animal models as tools to
study the pathophysiology of depression. Rev Bras Psiquiatr
35(Suppl 2):S112S120.
Abelaira HM, Reus GZ, Neotti MV, Quevedo J (2014a) The role of
mTOR in depression and antidepressant responses. Life Sci
101:1014.
Abelaira HM, Reus GZ, Quevedo J (2014b) Animal models as tools to
study the pathophysiology of depression. Rev Bras Psiquiatr
35:112120.
Abrahams BS, Geschwind DH (2008) Advances in autism genetics:
on the threshold of a new neurobiology. Nat Rev Genet
9:341355.
Acosta SA, Diamond DM, Wolfe S, Tajiri N, Shinozuka K, Ishikawa H,
et al. (2013) Inuence of post-traumatic stress disorder on
neuroinammation and cell proliferation in a rat model of
traumatic brain injury. PLoS One 8:e81585.
Arakawa S, Shirayama Y, Fujita Y, Ishima T, Horio M, Muneoka K,
Iyo M, Hashimoto K (2012) Minocycline produced antidepressant-
like eects on the learned helplessness rats with alterations in
levels of monoamine in the amygdala and no changes in BDNF
levels in the hippocampus at baseline. Pharmacol Biochem Behav
100:601606.
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS (2006)
Prenatal exposure to maternal genital and reproductive infections
and adult schizophrenia. Am J Psychiatry 163:927929.
Barbosa IG, Nogueira CR, Rocha NP, Queiroz AL, Vago JP, Tavares
LP, Assis F, Fagundes CT, Huguet RB, Bauer ME, Teixeira AL,
de Sousa LP (2013) Altered intracellular signaling cascades in
peripheral blood mononuclear cells from BD patients. J Psychiatr
Res 47:19491954.
Barger SW, Basile AS (2001) Activation of microglia by secreted
amyloid precursor protein evokes release of glutamate by cystine
exchange and attenuates synaptic function. J Neurochem
76:846854.
Barger SW, Goodwin ME, Porter MM, Beggs ML (2007) Glutamate
release from activated microglia requires the oxidative burst and
lipid peroxidation. J Neurochem 101:12051213.
Barichello T, Generoso JS, Milioli G, Elias SG, Teixeira AL (2013)
Pathophysiology of bacterial infection of the central nervous
system and its putative role in the pathogenesis of behavioral
changes. Rev Bras Psiquiatr 35:8187.
Bayer TA, Buslei R, Havas L, Falkai P (1999) Evidence for activation
of microglia in patients with psychiatric illnesses. Neurosci Lett
271:126128.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney
DS, et al. (2000) Antidepressant eects of ketamine in depressed
patients. Biol Psychiatry 47:351354.
Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J,
Klein HC, et al. (2012) The immune theory of psychiatric
diseases: a key role for activated microglia and circulating
monocytes. J Leuk Biol 92:959975.
Boche D, Perry VH, Nicoll JA (2013) Review: activation patterns of
microglia and their identication in the human brain. Neuropathol
Appl Neurobiol 39:318.
Breece E, Paciotti B, Nordahl CW, Ozono S, Van de Water JA,
Rogers SJ, et al. (2013) Myeloid dendritic cells frequencies are
increased in children with autism spectrum disorder and
associated with amygdala volume and repetitive behaviors.
Brain Behav Immun 31:6975.
Brown AS (2011) Exposure to prenatal infection and risk of
schizophrenia. Front Psychiatry 2:63.
Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ,
Bresnahan M, Babulas VP, Susser ES (2004) Serologic evidence
of prenatal inuenza in the etiology of schizophrenia. Arch Gen
Psychiatry 61:774780.
Burke NN, Kerr DM, Moriarty O, Finn DP, Roche M (2014)
Minocycline modulates neuropathic pain behaviour and cortical
M1M2 microglial gene expression in a rat model of depression.
Brain Behav Immun 42:147156.
Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra
IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN,
Jung S, Lira SA, Littman DR, Ransoho RM (2006) Control of
microglial neurotoxicity by the fractalkine receptor. Nat Neurosci
9(7):917924.
Carrillo-de Sauvage MA, Maatouk L, Arnoux I, Pasco M, Sanz Diez A,
Delahaye M, et al. (2013) Potent and multiple regulatory actions of
microglial glucocorticoid receptors during CNS inammation. Cell
Death Dier 20:15461557.
Catanzaro JM, Hueston CM, Deak MM, Deak T (2014) The impact of
the P2X7 receptor antagonist A-804598 on neuroimmune and
 G. Z. Reus et al. / Neuroscience 300 (2015) 141154
behavioral consequences of stress. Behav Pharmacol
25:582598.
Ceretta LB, Reus GZ, Abelaira HM, Jornada LK, Schwalm MT, et al.
(2012) Increased prevalence of mood disorders and suicidal
ideation in type 2 diabetic patients. Acta Diabetol 49:227234.
Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC, et al. (2006)
Valproate protects dopaminergic neurons in midbrain neuron/glia
cultures by stimulating the release of neurotrophic factors from
astrocytes. Mol Psychiatry 11:11161125.
Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H, et al.
(2007) Valproic acid and other histone deacetylase inhibitors
induce microglial apoptosis and attenuate lipopolysaccharide-
induced dopaminergic neurotoxicity. Neuroscience 149:203212.
Choi JH, Won MH (2011) Microglia in the normally aged
hippocampus. Lab Anim Res 27:181187.
Chung ES, Chung YC, Bok E, Baik HH, Park ES, Park JY, et al.
(2010) Fluoxetine prevents LPS-induced degeneration of nigral
dopaminergic neurons by inhibiting microglia-mediated oxidative
stress. Brain Res 1363:143150.
Chung YC, Kim SR, Park JY, Chung ES, Park KW, Won SY, et al.
(2011) Fluoxetine prevents MPTP-induced loss of dopaminergic
neurons by inhibiting microglial activation. Neuropharmacology
60:963974.
Colton CA, Wilcock DM (2010) Assessing activation states in
microglia. CNS Neurol Dis Drug Targ 9:174191.
Correa F, Mallard C, Nilsson M, Sandberg M (2011) Activated
microglia decrease histone acetylation and Nrf2-inducible anti-
oxidant defence in astrocytes: restoring eects of inhibitors of
HDACs, p38 MAPK and GSK3beta. Neurobiol Dis 44:142151.
Couch Y, Anthony DC, Dolgov O, Revischin A, Festo B, Santos AI,
Steinbusch HW, et al. (2013) Microglial activation, increased TNF
and SERT expression in the prefrontal cortex dene stress-
altered behaviour in mice susceptible to anhedonia. Brain Behav
Immun 29:136146.
Dahl J, Ormstad H, Aass HC, Malt UF, Bendz LT, Sandvik L, Brundin
L, Andreassen OA (2014) The plasma levels of various cytokines
are increased during ongoing depression and are reduced to
normal levels after recovery. Psychoneuroendocrinology
45:7786.
Dantzer R, OConnor JC, Freund GG, Johnson RW, Kelley KW
(2008) From inammation to sickness and depression: when the
immune system subjugates the brain. Nat Rev Neurosci 9:4656.
Derecki NC, Cronk JC, Lu Z, Xu E, Abbott SB, Guyenet PG, Kipnis J
(2012) Wild-type microglia arrest pathology in a mouse model of
Rett syndrome. Nature 484:105109.
Dheen ST, Kaur C, Ling EA (2007) Microglial activation and its
implications in the brain diseases. Curr Med Chem
14:11891197.
Di Benedetto B, Rupprecht R (2013) Targeting glia cells: novel
perspectives for the treatment of neuropsychiatric diseases. Curr
Neuropharmacol 11:171185.
Diz-Chaves Y, Astiz M, Bellini MJ, Garcia-Segura LM (2013) Prenatal
stress increases the expression of proinammatory cytokines and
exacerbates the inammatory response to LPS in the
hippocampal formation of adult male mice. Brain Behav Immun
28:196206.
Diz-Chaves Y, Pernia O, Carrero P, Garcia-Segura LM (2012)
Prenatal stress causes alterations in the morphology of microglia
and the inammatory response of the hippocampus of adult
female mice. J Neuroinammation 9:71.
Dong H, Zhang X, Dai X, Lu S, Gui B, Jin W, et al. (2014) Lithium
ameliorates lipopolysaccharide-induced microglial activation via
inhibition of toll-like receptor 4 expression by activating the PI3K/
Akt/FoxO1 pathway. J Neuroinammation 11:140.
Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM,
Irwin MR (2010) Inammation-induced anhedonia: endotoxin
reduces ventral striatum responses to reward. Biol Psychiatry
68:748754.
Ekdahl CT (2012) Microglial activation tuning and pruning adult
neurogenesis. Front Pharmacol 3:41.
151
El-Ansary A, Al-Ayadhi L (2014) GABAergic/glutamatergic imbalance
relative to excessive neuroinammation in autism spectrum
disorders. J Neuroinammation 11:189.
Ferguson JM, Shingleton RN (2007) An open-label, exible-dose
study of memantine in major depressive disorder. Clin
Neuropharmacol 30:136144.
Frank MG, Hershman SA, Weber MD, Watkins LR, Maier SF (2014)
Chronic exposure to exogenous glucocorticoids primes microglia
to pro-inammatory stimuli and induces NLRP3 mRNA in the
hippocampus. Psychoneuroendocrinology 40:191200.
Frank MG, Thompson BM, Watkins LR, Maier SF (2012)
Glucocorticoids mediate stress-induced priming of microglial
pro-inammatory responses. Brain Behav Immun 26:337345.
Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM,
Andreazza AC, et al. (2008a) Acute administration of ketamine
induces antidepressant-like eects in the forced swimming test
and increases BDNF levels in the rat hippocampus. Prog
Neuropsychopharmacol Biol Psychiatry 32:140144.
Garcia LS, Comim CM, Valvassori SS, Reus GZ, Andreazza AC,
Stertz L, et al. (2008b) Chronic administration of ketamine elicits
antidepressant-like eects in rats without aecting hippocampal
brain-derived neurotrophic factor protein levels. Basic Clin
Pharmacol Toxicol 103:502506.
Garcia LS, Comim CM, Valvassori SS, Reus GZ, Stertz L, Kapczinski
F, et al. (2009) Ketamine treatment reverses behavioral and
physiological alterations induced by chronic mild stress in rats.
Prog Neuropsychopharmacol Biol Psychiatry 33:450455.
Gigante AD, Young LT, Yatham LN, Andreazza AC, Nery FG,
Grinberg LT, et al. (2011) Morphometric post-mortem studies in
bipolar disorder: possible association with oxidative stress and
apoptosis. Int J Neuropsychopharmacol 14:10751089.
Girgis RR, Kumar SS, Brown AS (2014) The cytokine model of
schizophrenia: emerging therapeutic strategies. Biol Psychiatry
75:292299.
Gomez-Gonzalez B, Escobar A (2010) Prenatal stress alters
microglial development and distribution in postnatal rat brain.
Acta Neuropathol 119:303315.
Graeber MB, Li W, Rodriguez ML (2011) Role of microglia in CNS
inammation. FEBS Lett 585:37983805.
Gubert C, Fries GR, Aguiar BW, Rosa AR, Busnello JV, Ribeiro L,
Morrone FB, Battastini AMO, Kapczinski F (2013) The P2X7
purinergic receptor as a molecular target in Bipolar Disorder.
Neuropsychiat Neuropsychol 8:17.
Haarman BC, Riemersma-Van der Lek RF, de Groot JC, Ruhe HG,
Klein HC, et al. (2014) Neuroinammation in bipolar disorder A
[(11)C]-(R)-PK11195 positron emission tomography study. Brain
Behav Immun 40:219225.
Hamidi M, Drevets WC, Price JL (2004) Glial reduction in amygdala in
major depressive disorder is due to oligodendrocytes. Biol
Psychiatry 55:563569.
Haroon E, Raison CL, Miller AH (2012) Psychoneuroimmunology
meets neuropsychopharmacology: translational implications of
the impact of inammation on behavior.
Neuropsychopharmacology 37:137162.
Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD
(2009) Inammation causes mood changes through alterations in
subgenual cingulate activity and mesolimbic connectivity. Biol
Psychiatry 66:407414.
Hercher C, Chopra V, Beasley CL (2014) Evidence for morphological
alterations in prefrontal white matter glia in schizophrenia and
bipolar disorder. J Psychiatry Neurosci 39:130277.
Heyes MP, Achim CL, et al. (1996) Human microglia convert l-
tryptophan into the neurotoxin quinolinic acid. Biochem
J 320:595597.
Hinwood M, Morandini J, Day TA, Walker FR (2012) Evidence that
microglia mediate the neurobiological eects of chronic
psychological stress on the medial prefrontal cortex. Cereb
Cortex 22:14421454.
Hoyo-Becerra C, Schlaak JF, Hermann DM (2014) Insights from
interferon-alpha-related depression for the pathogenesis of
152 G. Z. Reus et al. / Neuroscience 300 (2015) 141154
depression associated with inammation. Brain Behav Immun
42:222231.
Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J (2015)
Microglial and macrophage polarization new prospects for brain
repair. Nat Rev Neurol 11:5664.
Hu X, Liou AK, Leak RK, Xu M, An C, Suenaga J, et al. (2014)
Neurobiology of microglial action in CNS injuries: receptor-
mediated signaling mechanisms and functional roles. Progr
Neurobiol 19120:6084.
Ignacio ZM, Reus GZ, Abelaira HM, Quevedo J (2014) Epigenetic
and epistatic interactions between serotonin transporter and
brain-derived neurotrophic factor genetic polymorphism: insights
in depression. Neuroscience 275:455468.
Imai Y, Ibata I, Ito D, Ohsawa K, Kohsaka S (1996) 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 224:855862.
Iseme RA, McEvoy M, Kelly B, Agnew L, Attia J, Walker FR (2014)
Autoantibodies and depression: evidence for a causal link?
Neurosci Biobehav Rev 40:6279.
Jinno S, Fleischer F, Eckel S, Schmidt V, Kosaka T (2007) Spatial
arrangement of microglia in the mouse hippocampus: a
stereological study in comparison with astrocytes. Glia
55:13341347.
Kim JJ, Lee SJ, Toh KY, Lee CU, Lee C, Paik IH (2001) Identication
of antibodies to heat shock proteins 90 kDa and 70 kDa in patients
with schizophrenia. Schizophr Res 52:127135.
Kim JJ, Mandelli L, Lim S, Lim HK, Kwon OJ, Pae CU, et al. (2008)
Association analysis of heat shock protein 70 gene
polymorphisms in schizophrenia. Eur Archiv Psychiatry Clin
Neurosci 258:239244.
Kim JS, Schmid-Burgk W, Claus D, Kornhuber HH (1982) Increased
serum glutamate in depressed patients. Arch Psychiatr Nervenkr
23:299304.
Kirsten TB, Chaves-Kirsten GP, Chaible LM, Silva AC, Martins DO,
Britto LR, et al. (2012) Hypoactivity of the central dopaminergic
system and autistic-like behavior induced by a single early
prenatal exposure to lipopolysaccharide. J Neurosci Res
90:19031912.
Le Belle JE, Sperry J, Ngo A, Ghochani Y, Laks DR, Lopez-Aranda
M, Silva AJ, Kornblum HI (2014) Maternal inammation
contributes to brain overgrowth and autism-associated
behaviors through altered redox signaling in stem and
progenitor cells. Stem Cell Rep 3:725734.
Leboyer M, Soreca I, Scott J, Frye M, Henry C, Tamouza R, Kupfer
DJ (2012) Can bipolar disorder be viewed as a multi-system
inammatory disease? J Aec Dis 141:110.
Lu B, Wang C, Wang M, Li W, Chen F, Tracey KJ, et al. (2014)
Molecular mechanism and therapeutic modulation of high mobility
group box 1 release and action: an updated review. Expt Rev Clin
Immunol 10:713727.
Lucchina L, Depino AM (2014) Altered peripheral and central
inammatory responses in a mouse model of autism. Autism
Res 7:273289.
Ma M, Ren Q, Zhang JC, Hashimoto K (2014) Eects of brilliant blue
g on serum tumor necrosis factor-alpha levels and depression-like
behavior in mice after lipopolysaccharide administration. Clin
Psychopharmacol Neurosci 12:3136.
Maezawa I, Jin LW (2010) Rett syndrome microglia damage
dendrites and synapses by the elevated release of glutamate. J
Neurosci 30:53465356.
Maiorino C, Khorooshi R, Runi F, Lbner M, Bergami A, Garzetti L,
Martino G, Owens T, Furlan R (2013) Lentiviral-mediated
administration of IL-25 in the CNS induces alternative activation
of microglia. Gene Ther 20:487496.
Marshall SA, McClain JA, Kelso ML, Hopkins DM, Pauly JR, Nixon K
(2013) Microglial activation is not equivalent to neuroinammation
in alcohol-induced neurodegeneration: the importance of
microglia phenotype. Neurobiol Dis 54:239251.
McInnis OA, Matheson K, Anisman H (2014) Living with the
unexplained: coping, distress, and depression among women
with chronic fatigue syndrome and/or bromyalgia compared to an
autoimmune disorder. Anx Stress Cop 27:601618.
McNally L, Bhagwagar Z, Hannestad J (2008) Inammation,
glutamate, and glia in depression: a literature review. CNS
Spect 13:501510.
Meyer U (2013) Developmental neuroinammation and
schizophrenia. Progr Neuropsychopharmacol Biol Psychiatry
42:2034.
Miller AH (2013) Conceptual conuence: the kynurenine pathway as
a common target for ketamine and the convergence of the
inammation and glutamate hypotheses of depression.
Neuropsychopharmacology 38:16071608.
Miller AH, Maletic V, Raison CL (2009) Inammation and its
discontents: the role of cytokines in the pathophysiology of
major depression. Biol Psychiatry 65:732741.
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B (2011) Meta-
analysis of cytokine alterations in schizophrenia: clinical status
and antipsychotic eects. Biol Psychiatry 70:663671.
Missault S, Van den Eynde K, Vanden Berghe W, Fransen E, Weeren
A, Timmermans JP, Kumar-Singh S, Dedeurwaerdere S (2014)
The risk for behavioural decits is determined by the maternal
immune response to prenatal immune challenge in a
neurodevelopmental model. Brain Behav Immun 42:138146.
Mitani H, Shirayama Y, Yamada T, Maeda K, Ashby Jr CR, Kawahara
R (2006) Correlation between plasma levels of glutamate, alanine
and serine with severity of depression. Progr
Neuropsychopharmacol Biol Psychiatry 30:11551158.
Monfrim X, Gazal M, De Leon PB, Quevedo L, Souza LD, Jansen K,
et al. (2014) Immune dysfunction in bipolar disorder and suicide
risk: is there an association between peripheral corticotropin-
releasing hormone and interleukin-1b? Bipolar Disord 16:
741747.
Monji A, Kato T, Kanba S (2009) Cytokines and schizophrenia:
microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci
63:257265.
Morgan JT, Chana G, Abramson I, Semendeferi K, Courchesne E,
Everall IP (2012) Abnormal microglial-neuronal spatial
organization in the dorsolateral prefrontal cortex in autism. Brain
Res 1456:7281.
Mortensen PB, Norgaard-Pedersen B, Waltoft BL, Sorensen TL,
Hougaard D, Torrey EF, Yolken RH (2007) Toxoplasma gondii as
a risk factor for early-onset schizophrenia: analysis of lter paper
blood samples obtained at birth. Biol Psychiatry 61:688693.
Muller A, Brandenburg S, Turkowski K, Muller S, Vajkoczy P (2015)
Resident microglia, and not peripheral macrophages, are the
main source of brain tumor mononuclear cells. Int J Cancer
137(2):278288. http://dx.doi.org/10.1002/ijc.29379.
Najjar S, Pearlman DM (2015) Neuroinammation and white matter
pathology in schizophrenia: systematic review. Schizophrenia
Res 161:102112.
Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O (2013)
Neuroinammation and psychiatric illness. J Neuroinammation
10:43.
Nakagawa Y, Chiba K (2014) Role of microglial m1/m2 polarization in
relapse and remission of psychiatric disorders and diseases.
Pharmaceuticals 7:10281048.
Nimmerjahn A, Kirchho F, Helmchen F (2005) Resting microglial
cells are highly dynamic surveillants of brain parenchyma in vivo.
Science 308:13141318.
OBrien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG (2007)
Plasma cytokine proles in depressed patients who fail to respond
to selective serotonin reuptake inhibitor therapy. J Psychiatr Res
41:326331.
OConnor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon
N, et al. (2009) Lipopolysaccharide-induced depressive-like
behavior is mediated by indoleamine 2,3-dioxygenase activation
in mice. Mol Psychiatry 14:511522.
Ohgi Y, Futamura T, Kikuchi T, Hashimoto K (2013) Eects of
antidepressants on alternations in serum cytokines and
depressive-like behavior in mice after lipopolysaccharide
administration. Pharmacol Biochem Behav 103:853859.
 G. Z. Reus et al. / Neuroscience 300 (2015) 141154
Peng GS, Li G, Tzeng NS, Chen PS, Chuang DM, Hsu Y, et al. (2005)
Valproate pretreatment protects dopaminergic neurons from LPS-
induced neurotoxicity in rat primary midbrain cultures: role of
microglia. Brain Res Mol Brain Res 134:162169.
Phillips AC, Carroll D, Der G (2015) Negative life events and
symptoms of depression and anxiety: stress causation and/or
stress generation. Anxiety Stress Cop 9:130.
Piani D, Spranger M, Frei K, Schaner A, Fontana A (1992)
Macrophage-induced cytotoxicity of N-methyl-D-aspartate
receptor positive neurons involves excitatory amino acids rather
than reactive oxygen intermediates and cytokines. Eur J Immunol
22:24292436.
Radewicz K, Garey LJ, Gentleman SM, Reynolds R (2000) Increase
in HLA-DR immunoreactive microglia in frontal and temporal
cortex of chronic schizophrenics. J Neuropathol Exp Neurol
59:137150.
Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg
GW (1999) Neuroglial activation repertoire in the injured brain:
graded response, molecular mechanisms and cues to
physiological function. Brain Res Brain Res Rev 30:77105.
Ransoho RM, Perry VH (2009) Microglial physiology: unique stimuli,
specialized responses. Annual Rev Immunol 27:119145.
Rao JS, Harry GJ, Rapoport SI, Kim HW (2010) Increased
excitotoxicity and neuroinammatory markers in postmortem
frontal cortex from bipolar disorder patients. Mol Psychiatry
15:384392.
Rege S, Hodgkinson SJ (2013) Immune dysregulation and
autoimmunity in bipolar disorder: synthesis of the evidence and
its clinical application. Aust N Z J Psychiatry 47:11361151.
Reininghaus EZ, McIntyre RS, Reininghaus B, Geisler S, Bengesser
SA, Lackner N, et al. (2014) Tryptophan breakdown is increased
in euthymic overweight individuals with bipolar disorder: a
preliminary report. Bipolar Disord 16:432440.
Reisinger S, Khan D, Kong E, Berger A, Pollak A, Pollak DD (2015)
The Poly(I:C) induced maternal immune activation model in
preclinical neuropsychiatric drug discovery. Pharmacol Ther
149:213226. http://dx.doi.org/10.1016/
j.pharmthera.2015.01.001.
Reus GZ, Stringari RB, Kirsch TR, Fries GR, Kapczinski F, Roesler
R, et al. (2010) Neurochemical and behavioural eects of acute
and chronic memantine administration in rats: further support for
NMDA as a new pharmacological target for the treatment of
depression? Brain Res Bul 81:585589.
Reus GZ, Abelaira HM, Stringari RB, Fries GR, Kapczinski F,
Quevedo J (2012) Memantine treatment reverses anhedonia,
normalizes corticosterone levels and increases BDNF levels in
the prefrontal cortex induced by chronic mild stress in rats. Met
Brain Dis 27:175182.
Reus GZ, Abelaira HM, dos Santos MA, Carlessi AS, Tomaz DB,
Neotti MV, et al. (2013a) Ketamine and imipramine in the nucleus
accumbens regulate histone deacetylation induced by maternal
deprivation and are critical for associated behaviors. Behav Brain
Res 256:451456.
Reus GZ, Dos Santos MA, Abelaira HM, Ribeiro KF, Petronilho F,
Vuolo F, et al. (2013b) Imipramine reverses alterations in
cytokines and BDNF levels induced by maternal deprivation in
adult rats. Behav Brain Res 242:4046.
Reus GZ, Vieira FG, Abelaira HM, Michels M, Tomaz DB, dos Santos
MA, et al. (2014) MAPK signaling correlates with the
antidepressant eects of ketamine. J Psychiatr Res 55:1521.
Reus GZ, Nacif MP, Abelaira HM, Tomaz DB, Dos Santos MAB,
Carlessi AS, et al. (2015a) Ketamine ameliorates depressive-like
behaviors and immune alterations in adult rats following maternal
deprivation. Neurosci Lett 584:8387.
Reus GZ, Abelaira HM, Maciel AL, Dos Santos MA, Carlessi AS,
Steckert AV, et al. (2015b) Minocycline protects against oxidative
damage and alters energy metabolism parameters in the brain of
rats subjected to chronic mild stress. Met Brain Dis 30:545553.
Ribeiro BM, do Carmo MR, Freire RS, Rocha NF, Borella VC, de
Menezes AT, et al. (2013) Evidences for a progressive microglial
activation and increase in iNOS expression in rats submitted to a
153
neurodevelopmental model of schizophrenia: reversal by
clozapine. Schizophr Res 151:1219.
Rinwa P, Kumar A (2013) Quercetin suppress microglial
neuroinammatory response and induce antidepressent-like
eect in olfactory bulbectomized rats. Neuroscience 255:8698.
Ritter PS, Kretschmer K, Pfennig A, Soltmann B (2013) Disturbed
sleep in bipolar disorder is related to an elevation of IL-6 in
peripheral monocytes. Med Hypot 81:10311033.
Roman A, Rogoz Z, Kubera M, Nawrat D, Nalepa I (2009)
Concomitant administration of uoxetine and amantadine
modulates the activity of peritoneal macrophages of rats
subjected to a forced swimming test. Pharmacol Rep
61:10691077.
Rosenblat JD, Cha DS, Mansur RB, McIntyre RS (2014) Inamed
moods: a review of the interactions between inammation and
mood disorders. Progr Neuropsychopharmacol Biol Psychiatry
53:2334.
Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in
health and disease. Nat Rev Immunol 11:775787.
Santello M, Volterra A (2012) TNFa in synaptic function: switching
gears. Trends Neurosci 35:638647.
Savitz JB, Price JL, Drevets WC (2014) Neuropathological and
neuromorphometric abnormalities in bipolar disorder: view from
the medial prefrontal cortical network. Neurosci Biobehav Rev
42:132147.
Schiepers OJ, Wichers MC, Maes M (2005) Cytokines and major
depression. Progr Neuropsychopharmacol Biol Psychiatry
29:201217.
Schinder AF, Olson EC, Spitzer NC (1996) Montal M. Mitochondrial
dysfunction is a primary event in glutamate neurotoxicity. J
Neurosci 16:61256133.
Schmitt A, Bertsch T, Henning U, Tost H, Klimke A, Henn FA, Falkai
P (2005) Increased serum S100B in elderly, chronic
schizophrenic patients: negative correlation with decit
symptoms. Schizophr Res 80:305313.
Schnieder TP, Trencevska I, Rosoklija G, Stankov A, Mann JJ,
Smiley J, Dwork AJ (2014) Microglia of prefrontal white matter in
suicide. J Neuropathol Exp Neurol 3:880890.
Schroeter ML, Steiner J, Mueller K (2011) Glial pathology is modied
by age in mood disorders a systematic meta-analysis of serum
S100B in vivo studies. J Aect Dis 134:3238.
Serrats J, Schiltz JC, Garcia-Bueno B, van Rooijen N, Reyes TM,
Sawchenko PE (2010) Dual roles for perivascular macrophages in
immune-to-brain signaling. Neuron 65:94106.
Soczynska JK, Mansur RB, Brietzke E, Swardfager W, Kennedy SH,
Woldeyohannes HO, et al. (2012) Novel therapeutic targets in
depression: minocycline as a candidate treatment. Behav Brain
Res 235:302317.
Song C, Halbreich U, Han C, Leonard BE, Luo H (2009) Imbalance
between pro- and anti-inammatory cytokines, and between Th1 and
Th2 cytokines in depressed patients: the eect of electroacupuncture
or uoxetine treatment. Pharmacopsychiatry 42:182188.
Stanciu M, Wang Y, Kentor R, Burke N, Watkins S, Kress G,
Reynolds I, Klann E, Angiolieri MR, Johnson JW, DeFranco DB
(2000) Persistent activation of ERK contributes to glutamate-
induced oxidative toxicity in a neuronal cell line and primary
cortical neuron cultures. J Biol Chem 275:1220012206.
Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, et al.
(2008) Immunological aspects in the neurobiology of suicide:
elevated microglial density in schizophrenia and depression is
associated with suicide. J Psychiatr Res 42:151157.
Steiner J, Walter M, Wunderlich MT, Bernstein HG, Panteli B,
Brauner M, et al. (2009) A new pathophysiological aspect of
S100B in schizophrenia: potential regulation of S100B by its
scavenger soluble RAGE. Biol Psychiatry 65:11071110.
Stertz L, Magalhaes PV, Kapczinski F (2013) Is bipolar disorder an
inammatory condition? The relevance of microglial activation.
Curr Opin Psychiatry 26:1926.
Sugama S, Fujita M, Hashimoto M, Conti B (2007) Stress induced
morphological microglial activation in the rodent brain:
involvement of interleukin-18. Neuroscience 146:13881399.
154 G. Z. Reus et al. / Neuroscience 300 (2015) 141154
Sugama S, Takenouchi T, Fujita M, Kitani H, Conti B, Hashimoto M
(2012) Corticosteroids limit microglial activation occurring during
acute stress. Neuroscience 232:1320.
Sugama S, Takenouchi T, Fujita M, Kitani H, Hashimoto M (2011)
Cold stress induced morphological microglial activation and
increased IL-1beta expression in astroglial cells in rat brain. J
Neuroimmunol 233:2936.
Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M,
Takebayashi K, et al. (2013) Microglial activation in young adults
with autism spectrum disorder. JAMA Psychiatry 70:4958.
Takaki J, Fujimori K, Miura M, Suzuki T, Sekino Y, Sato K (2012) L-
glutamate released from activated microglia downregulates
astrocytic L-glutamate transporter expression in
neuroinammation: the collusion hypothesis for increased
extracellular L-glutamate concentration in neuroinammation. J
Neuroinammation 9:275.
Tanaka J, Fujita H, Matsuda S, Toku K, Sakanaka M, Maeda N
(1997) Glucocorticoid- and mineralocorticoid receptors in
microglial cells: the two receptors mediate dierential eects of
corticosteroids. Glia 20:2337.
Tandon R, Keshavan MS, Nasrallah HA (2008) Schizophrenia, just
the facts what we know in 2008. 2. Epidemiology and etiology.
Schizophr Res 102:118.
Tato CM, Hunter CA (2002) Host-pathogen interactions: subversion
and utilization of the NF-kappa B pathway during infection. Infec
Immun 70:33113317.
Tetreault NA, Hakeem AY, Jiang S, Williams BA, Allman E, Wold BJ,
Allman JM (2012) Microglia in the cerebral cortex in autism. J Aut
Development Disord 42:25692584.
Theoharides TC, Asadi S, Patel AB (2013) Focal brain inammation
and autism. J Neuroinammation 10:46.
Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N
(2014) Evidence for increased microglial priming and macrophage
recruitment in the dorsal anterior cingulate white matter of
depressed suicides. Brain Behav Immun 42:5059.
Tynan RJ, Beynon SB, Hinwood M, Johnson SJ, Nilsson M, Woods
JJ, et al. (2013) Chronic stress-induced disruption of the astrocyte
network is driven by structural atrophy and not loss of astrocytes.
Acta Neuropathol 126:7591.
Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker
FR (2012) A comparative examination of the anti-inammatory
eects of SSRI and SNRI antidepressants on LPS stimulated
microglia. Brain Behav Immun 26:469479.
van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A,
Caspers E, et al. (2008) Microglia activation in recent-onset
schizophrenia: a quantitative (R)-[11C]PK11195 positron
emission tomography study. Biol Psychol 64:820822.
Van den Eynde K, Missault S, Fransen E, Raeymaekers L, Willems
R, Drinkenburg W, Timmermans JP, Kumar-Singh S,
Dedeurwaerdere S (2014) Hypolocomotive behaviour
associated with increased microglia in a prenatal immune
activation model with relevance to schizophrenia. Behav Brain
Res 258:179186.
Ventura-Junca R, Symon A, Lopez P, Fiedler JL, Rojas G, Heskia C,
et al. (2014) Relationship of cortisol levels and genetic
polymorphisms to antidepressant response to placebo and
uoxetine in patients with major depressive disorder: a
prospective study. BMC Psychol 14:220.
(Accepted 7 May 2015)
(Available online 14 May 2015)
Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B,
et al. (2013a) NMDA receptor blockade by ketamine abrogates
lipopolysaccharide-induced depressive-like behavior inC57BL/6J
mice. Neuropsychopharmacology 38:16091616.
Walker FR, Nilsson M, Jones K (2013b) Acute and chronic stress-
induced disturbances of microglial plasticity, phenotype and
function. Curr Drug Targets 14:12621276.
Watkins CC, Sawa A, Pomper MG (2014) Glia and immune cell signaling
in bipolar disorder: insights from neuropharmacology and molecular
imaging to clinical application. Transl Psychiatry 4:e350.
Weber MD, Frank MG, Tracey KJ, Watkins LR, Maier SF (2015)
Stress induces the danger-associated molecular pattern HMGB-1
in the hippocampus of male Sprague Dawley rats: a priming
stimulus of microglia and the NLRP3 inammasome. J Neurosci
35:316324.
Weisman GA, Camden JM, Peterson TS, et al. (2012) P2 receptors
for extracellular nucleotides in the central nervous system: role of
P2x7 and P2y2 receptor interactions in neuroinammation. Mol
Neurobiol 46:96113.
Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T (2014)
Host innate immune responses to sepsis. Virulence 5:3644.
Wischhof L, Irrsack E, Osorio C, Koch M (2015) Prenatal LPS-
exposure a neurodevelopmental rat model of schizophrenia
dierentially aects cognitive functions, myelination and
parvalbumin expression in male and female ospring. Progr
Neuropsychopharmacol Biol Psychiatry 57:1730.
World Health Organization (2012) Media Centre Fact Sheet No. 369.
http://www.who.int/mediacentre/factsheets/fs369/en/.
Wu GJ, Chen TL, Ueng YF, Chen RM (2008) Ketamine inhibits tumor
necrosis factor-a and interleukin-6 gene expressions in
lipopolysaccharide-stimulated macrophages through
suppression of toll-like receptor 4-mediated c-Jun N-terminal
kinase phosphorylation and activator protein-1 activation. Toxicol
Appl Pharmacol 228:105113.
Xanthos DN, Sandkuhler J (2014) Neurogenic neuroinammation:
inammatory CNS reactions in response to neuronal activity. Nat
Rev Neurosci 15:4353.
Xie N, Wang C, Lin Y, Li H, Chen L, Zhang T, et al. (2010) The role of
p38 MAPK in valproic acid induced microglia apoptosis. Neurosci
Lett 482:5156.
Young AM, Campbell E, Lynch S, Suckling J, Powis SJ (2011)
Aberrant NF-kappaB expression in autism spectrum condition: a
mechanism for neuroinammation. Front Psychiatry 2:27.
Zarate Jr CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R,
Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized
trial of an N-methyl-D-aspartate antagonist in treatment-resistant
major depression. Arch Gen Psychiatry 63(8):856864.
Zeidan-Chulia F, Salmina AB, Malinovskaya NA, Noda M,
Verkhratsky A, Moreira JC (2014) The glial perspective of
autism spectrum disorders. Neurosci Biobehav Rev 38:160172.
Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani
F, et al. (2014) Decient neuron-microglia signaling results in
impaired functional brain connectivity and social behavior. Nat
Neurosci 17:400406.
Zhao Q, Peng C, Wu X, Chen Y, Wang C, You Z (2014) Maternal
sleep deprivation inhibits hippocampal neurogenesis associated
with inammatory response in young ospring rats. Neurobiol Dis
68:5765.