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Current Molecular Medicine XXXX, XX, 1-13 1

REVIEW ARTICLE

Microglial Activation in the Neurodevelopment: A Narrative Review

Airam Barbosa de Moura1, Morgana Sonza Abitante1, Ritele Hernandez Silva1, João
Quevedo1,2,3,4 and Gislaine Zilli Réus1,*

1
Translational Psychiatry Laboratory, Graduate Program in Health Sciences, Health Sciences Unit, University
2
of Southern Santa Catarina, Criciúma, Santa Catarina, Brazil; Center for Translational Psychiatry,
Department of Psychiatry and Behavioral Sciences, Medical School, The University of Texas Health Science
3
Center at Houston, Houston, Texas, USA; Center of Excellence on Mood Disorders, Department of
Psychiatry and Behavioral Sciences, Medical School, The University of Texas Health Science Center at
4
Houston, Houston, Texas, USA; Neuroscience Graduate Program, Graduate School of Biomedical Sciences,
The University of Texas Health Science Center at Houston, Houston, Texas, USA

Abstract: Microglia are immune cells found in the central nervous system (CNS)
involved in infection combat and cellular debris clean. These glial cells are involved in
synaptogenesis during brain development by their interactions with neurons and other
glial cells. These relations are associated with the secretion of signaling molecules, such
as chemokines and neurotrophic factors. Microglia cells influence synapsis and neuron
ARTICLE HISTORY
morphology during different phases of development. Also, other systems, for example,
Received: January 08, 2021
gut microbiota, indirectly affect microglial functions and morphology. Several factors that
Revised: July 15, 2021 can occur in different development periods, including intrauterine through adult life,
Accepted: July 29, 2021
could impact microglia. Impairment in these cells could be associated with the
development of some psychiatric conditions, such as schizophrenia, autistic spectrum
DOI:
10.2174/1566524021666211018112757 disorder (ASD), and depression. This review focuses on describing microglia functions in
the maintenance of CNS and how they are associated with other systems, as the gut-
microbiota brain axis and environmental stressors, such as stress, maternal deprivation,
sleep deprivation, immune activation, and ethanol exposure, that can influence the
function of the microglia during neurodevelopment.
Keywords: Gut-microbiota-brain axis, synaptogenesis, maternal deprivation, microglia activation,
neurodevelopment, environmental stressors.

1. INTRODUCTION required for neurodevelopment maintenance. However,

an exceeding early-life inflammation may alter the
Under a stable situation, microglia act as specific
programming of the microglial amount itself, resulting in
immune cells of the central nervous system (CNS).
Similar to macrophages, these glial cells have been a lower baseline required for reactivation and
perpetuating inflammatory damage to the neuronal
involved in several CNS processes such as combating
compartment throughout life [6]. Although the role of
infection, mediating inflammation, and clearing cellular
microglia during development has been discussed,
debris via phagocytosis [1]. Admittedly, it is known by
there is little about this in the context of its positive as
the traditional macrophage-type roles. Moreover,
well negative stimulus that can influence microglia
microglia have shown to be an adjuvant in complex
neurodevelopmental programs, during which their through development. Thus, this narrative review paper
deliberates both well-established and emerging
phagocytic and signaling processes have displayed
literature and perspectives on microglia in the context
some functions, including neuronal fate determination
of neurodevelopment, with a particular emphasis on the
by regulating programmed cell death [2], neurite
relationship of the microglia in synapses, microbiome,
formation, synaptogenesis, and axonal fasciculation [3],
inflammation, and stressors during health and disease
and strip excess synapses from developing neurons to
permit the assembly of functional neuronal circuits conditions.
[4, 5]. The regulation of pro-inflammatory activity is
2. MATERIALS AND METHODS
*Address correspondence to this author at the Translational We conducted a review of computerized databases
Psychiatry Laboratory, University of Southern Santa Catarina, (i.e., PubMed) from 1919 to 2020. "Microglia" was
Criciuma, SC, 88806-000, Brazil; Tel/Fax: 55 48 3431-2792; cross-referenced with the following words: neuro-
E-mail: [email protected] development and brain development. Neuro-

1566-5240/XX $65.00+.00 © XXXX Bentham Science Publishers

2 Current Molecular Medicine, XXXX, Vol. XX, No. XX de Moura et al.

development was cross-referenced with the following and usually are the first to be activated in response to
words: microglial activation, synaptogenesis, gut- tissue damage or brain infections [11]. Microglia are
microbiota brain axis, inflammation, oxidative stress, known to have different states, including resting and
maternal deprivation, sleep deprivation, immune activated, with the capacity for phagocytosis but not
activation, ethanol exposure, immune activation. limited to it. When in the resting state, microglia cells
Bibliographies from identified papers were also verified are highly mobile even under normal inactive
to detect any other original articles associated with this conditions within the adult CNS, and it owns an ability
review's goals. to secrete neurotrophic factors such as insulin-like
growth factor 1 (IGF-1), brain-derived neurotrophic
2.1. Microglia: What are they? Origin and Function factor (BDNF), and nerve growth factor (NGF) [12, 13]
(Fig. 1). In vivo studies using two-photon microscopy
CNS has as part of its constitution neurons and glia, demonstrated that microglia are in constant movement,
which include oligodendrocytes, astrocytes, and
monitoring their microenvironment and communicating
microglia. The total of glial cells in the CNS is about
with neurons and other glial cells through motile
12% of microglia and is mostly known as a mediator of
processes and protrusions [14-16].
post-injury and inflammatory responses in the brain [7].
Besides that, these cells play an essential role in the Microglia can be activated by injury factors or any
healthy development and regulation of structural and kind of pathologic insult in the brain and produce
functional processes, from single synapses to neural several cytotoxic mediators that are involved in multiple
circuits and behavior [8]. Also, being a protector of the CNS disorders [17], such as reactive oxygen species
brain, microglia regulates neuronal precursor cell sets, (ROS), pro-inflammatory cytokines, adenosine
synaptogenesis, and the formation of neural networks triphosphate (ATP), and derivatives of arachidonic acid
in the CNS developing [9]. In recent years, vast and (AA) [18]. At the same time, adjacent cells induce
novel findings have shown that the role of microglia in microglia to release cytokines and chemokines in many
the CNS is more complicated than supposed. pathological conditions [19, 20]. After activation,
microglia change their own morphologic phenotype
Classified by Pío del Río Hortega in 1919 [10],
from a highly ramified cell to an amoeboid cell (Fig. 1).
microglia cells are essential resident immune cells of
the brain presenting a branched, ramified morphology, There are two main hypotheses of the origin of

Fig. (1). General functions of microglial cells: The resting microglial cells are involved in insulin-like growth factor 1 (IGF-1),
brain-derived-neurotrophic factor (BDNF), and nerve growth factor (NGF) release. However, when activated by stress,
pathologic insult or injury factors, such as lipopolysaccharides (LPS), pro-inflammatory cytokines, and interferon-γ, microglia
cells can be stimulated to release reactive oxygen species (ROS), pro-inflammatory cytokines, and chemokines, as well as
protective mediators like interleukin-4, -10, and -13, besides transforming growth factor b (TGF-b). Both inflammatory and anti-
inflammatory mediators secreted by microglia are essential in the central nervous system (CNS) development, synaptogenesis,
and establishment of neural networks. (A higher resolution / colour version of this figure is available in the electronic copy of the
article).
Microglia activation and neurodevelopment Current Molecular Medicine, XXXX, Vol. XX, No. XX 3

microglia: mesodermal and monocytic. The and immune processes. Besides, microglial cells from
mesodermal origin of microglia is well accepted and hippocampal tissue cultured produce pro-inflammatory
proposes that precursor cells developed in the yolk sac cytokines. When in excess, this inflammatory process
through the mesoderm invade the brain [21]. On the can trigger neuronal lesions and be associated with the
other hand, the monocytic origin indicates that development of psychiatric disorders [34].
monocytes present in the circulating blood transform
The exact timing of synaptic regulation by microglia
into amoeboid microglial cells, which consequently turn
is unclear, but some studies have indicated that the
into ramified microglial cells into CNS [22]. Microglia
postnatal period forms numerous synapses,
have been closely related to macrophages that
remodeling and removing them to construct the mature
circulate in peripheral blood [23]. Simultaneously,
circuit [4, 5]. Moreover, microglia appear to contribute
monocytic genes expressed in microglia (HLA-C, to the synaptic maturation process. In fact, in knockout
CD74, CD302, LSP1, and RUNX3) are known to have
rodents for CX3CR1 (spinal fracture receptor), which is
essential functions involved in antigen presentation and
expressed exclusively in microglia, a reduction in
lysosome action [24, 25]. During early fetal
synaptic pruning after 2-3 postnatal weeks was
development, microglia take up residence in the brain.
demonstrated, followed by an increase in postsynaptic
Runt-related transcription factor 1 (RUNX1), which
density protein 95 (PSD-95) immunoreactivity (Fig. 2).
regulates the myeloid lineage's proliferation and These results indicate that pruning defects may
differentiation, is expressed in microglia before brain
represent a function of microglial cells [4]. Another
development [21].
experimental study in mice revealed that the loss of
Microglial activation has been described as a microglia autophagy ability impairs synaptic pruning
process where the microglial cells are involved in the [35], and it is associated with abnormal social
production of protective cytokines related to essential interaction and repetitive behaviors, which are
functions in tissue repair and wound healing, like symptoms of autistic spectrum disorder (ASD).
interleukin (IL)-10, transforming growth factor b (TGF- Furthermore, the authors showed that synaptosome
b), IL-4, and IL-13, and in the secretion of inflammatory degradation and immature dendritic filopodia were
mediators, including ROS, e.g., superoxide anion damaged in the co-cultured neuron with the loss of
matrix metalloproteinase (MMP)-9, as well as pro- microglia autophagy [35]. Microglia-mediated synaptic
inflammatory cytokines and chemokines [26, 27] (Fig. changes require the release of BDNF [36].
1). This system can play a role in beneficial or
A recent pre-clinical study that exposed animals to
destructive effects depending on the stimuli, duration,
stress protocols in adolescence found that compared to
and the environment that the cells are residing; thus,
controls, stressed animals showed variations in protein
the balance between neurotrophins, inflammatory, and
expression of the ionized calcium-binding adapter
anti-inflammatory mediators released by microglia can
molecule 1 (Iba1), microglia-specific biomarker, and
be considered a desirable therapeutic goal for tumoral necrosis factor-α (TNF-α) in the prefrontal
psychiatric disorders [27].
cortex. The same study also revealed a transient
increase during stress exposure of these markers, with
2.2. Microglia, Synapses, and Neurodevelopment a subsequent gradual decrease over time, leading to
Dendritic spines are postsynaptic components of significantly reduced TNF-α in adulthood [37]. It is still
mainly excitatory synapses that play an essential role unclear how and when immune changes occur after
in synapses' function and efficacy. During exposure to stress in adolescence and whether it is
development, neuronal branches and dendritic spines possible to prevent the late occurrence of cognitive
develop and become complex and dynamic structures impairment through early immune intervention.
[28, 29]. Several neurotrophic factors are involved in Another issue that has been evaluated is the
the neurogenesis process, such as IGF-1 and BDNF, difference in synaptic pruning according to gender. One
which act on neuronal proliferation, differentiation, and study found that females, but not male mice, exhibit an
maturation. These factors are also essential for new increase in the density of axonal terminals and
synapse formation processes and the maintenance and dendritic spines in the hippocampus on the second
survival of existing dendrites [28, 30]. Synapses life's week [38]. These and other studies have shown
morphology plays a vital role in their efficiency since that the process of synaptic regulation by microglia is
the type of dendritic thorn can influence its function and necessary and performs essential functions for proper
effectiveness. Thus, the maintenance of synapses is neuronal functioning in the different periods of
fundamental for proper neuronal functioning. development.
The microglia play a role in the regulation, acting
during development by modulating the formation of 2.3. Gut-microbiota Brain Axis and Microglia in the
brain networks through their interactions with neurons, Neurodevelopment
astrocytes, and oligodendrocytes, as well as secretion
The influence of the intestinal microbiota in brain
of signaling molecules, such as chemokines and development is receiving considerable attention in the
neurotrophic factors, thus contributing to the regulation
understanding of mental health disorders. Current
of synapses [31-34]. Recent studies indicate that
research describes a bidirectional communication
microglia are involved in the elimination and refinement
between CNS and guts bacteria, the microbiota-gut-
of synaptic connections in the healthy developing brain
brain axis, which occurs through complex mechanisms
4 Current Molecular Medicine, XXXX, Vol. XX, No. XX de Moura et al.

involving neural, endocrine, immune, and metabolic an immature phenotype that results in impaired innate
pathways [39-41]. immune responses. Elimination of host-microbiota in
mice led to huge changes in microglia properties.
Microbiota dynamically changes across the lifespan.
Defective microglia are related to a limited microbiota
Infancy composition is affected by several internal and
external factors such as mode of delivery, antibodies, diversity and complexity. However, when a complex
microbiota was induced, microglia got its features
and nutrients provided by breastfeeding, maternal diet,
partially restored. Besides that, mice presenting
antibiotic or probiotic treatments, contact with parents,
deficient free fatty acid receptor 2 (FFAR2) for SCFA
siblings, and hospital staff [for reviews, see 42-46]. The
had microglial dysfunction under GF conditions. These
complex adult-like microbiome emerges by the age of
data evince that the host microbiota is vital for microglia
1-year-old and, later in the development, the
occurrence of significant shifts in the adult diet shows maintenance (Fig. 2).
dramatic changes in microbiota composition [47]. As These data support the concept that the microbiota
we age, it has been shown that the core microbiota is essential for maintaining microglia maturation, as
undergoes a dynamic shift and is reported a decrease continuous input of complex signals derived from the
in the number of probiotic Bifidobacteria strains over microbiota preserves the microglia maturation status
aging. Based on this evidence, centenarian studies actively throughout adulthood. Despite GF mice
have reinforced the importance of microbial diversity in exhibiting reduced BDNF expression levels in the
maintaining health as we age [48, 49]. cortex and hippocampus relative to SPF mice [52] and
present in adulthood increased stress response and
The intestinal microbiota provides nutritional support
marked changes in anxiety and social behavior.
for brain maturation and function [50]. Essential
However, it is unclear if these alterations are due to
vitamins are extracted from the diet, and through the
fermentation of nondigestible carbohydrates, short- changes in microglial function.
chain fatty acids (SCFA) are produced, such as
acetate, propionate, and butyrate providing an 3. INFLAMMATION, OXIDATIVE STRESS, AND
essential source of energy [51]. MICROGLIAL ACTIVATION IN THE
NEURODEVELOPMENT
Commensal gut microbes are essential for neural
networking was first demonstrated in animal studies, In recent years, the neuronal inflammatory condition
where germ-free (GF) mice exhibited an exaggerated has been the subject of studies. Many psychiatric
hypothalamic-pituitary-adrenal (HPA) axis activity, with disorders, such as major depressive disorder (MDD),
plasma adrenocorticotropic hormone (ACTH) and have been considered inflammatory events due to
significant corticosterone elevation in response to several shreds of evidence found in experimental and
restraint stress compared to specific pathogen-free clinical studies [57-60]. In MDD individuals, there is an
(SPF) mice, which was reversed by reconstitution with increase of pro-inflammatory cytokines serum levels,
commensal bacteria from control mice [52, 53]. GF such as IL-1, IL-6, IL-8, IL-12, interferon-C (IFN-C), and
mice also exhibited reduced BDNF expression levels in TNF-α. Also, rodents subjected to animal models of
the cortex and hippocampus relative to SPF mice [52]. depression showed a decrease of IL-10, an anti-
In adulthood, these mice have marked changes in inflammatory cytokine [61, 62]. Moreover, animals
neurotransmitter levels, plasticity-related proteins such subjected to stress protocols had increased damage in
as BDNF, increased stress response, and marked protein and lipid as well as altered antioxidant enzymes
changes in anxiety and social behavior [52]. [63, 64]. These data evidence the presence of inflam-
matory processes and ROS in the pathophysiological
Gut microbiome immunomodulatory effects and processes throughout the development.
possible commensal bacteria colonization can
modulate the peripheral and CNS, influencing brain Early life adverse events have repercussions over
development and function [54]. Some studies time, as identified in the study by Evans and
investigated whether gut microbiota could influence Schamberg [65], which showed an inverse relationship
microglia activation in animal models based on the between exposure to childhood poverty and/or chronic
knowledge of the role of microglia in the brain's stress events and working memory changes in young
immune defense against pathogens. Apparently, under adults. Exposure to stress in early life can induce
normal homeostatic conditions, a diverse behavioral and epigenetic changes throughout life.
gastrointestinal microbiota is necessary to maintain These alterations associated with inflammatory con-
microglia maturation and activation in a healthy ditions can lead to long-term deleterious consequences
functional state [55]. The intestinal microbiota seems to for synapses, including in the subsequent generations
control the maturation and function of microglia; [66].
therefore, gut commensal bacteria would be necessary Environmental stressors are known to activate the
to prepare the innate immune system, both in the immune system, leading to changes in behavior and
periphery and in the CNS [55, 56]. neural functions. Immune alterations can be initiated
Erny et al. [55] showed robust evidence that the from microglial activation and changes in cell plasticity,
host microbiota is essential to microglia homeostasis, resulting in the susceptibility to disrupt interactions
where GF mice demonstrated wide defects in microglia between glial cells at synapses. Microglial stimulation
with alterations in the proportion of the cell, as well as also leads to an increase of ROS and reactive nitrogen
Microglia activation and neurodevelopment Current Molecular Medicine, XXXX, Vol. XX, No. XX 5

species (RNS) as well as the expression of pro- During neurodevelopment, microglia cells and
inflammatory cytokines. Cytokines may increase the cytokines have not only an immunological function but
activity of the indolamine 2,3-dioxygenase (IDO) are also crucial for the formation of both neuronal
enzyme, responsible for the degradation of tryptophan, architecture and cellular circuits [36, 75] (Fig. 1).
a precursor of serotonin. IDO also activates pro- Microglia are probably the first CNS cells type to sense
inflammatory genes, leading to a vicious cycle, psychological stress, peripheral inflammation and
increasing neuroinflammation [62]. The process that mediate the effects of perinatal adversities during the
seems to be related to neuronal atrophy results in developing brain [76]. Data from pre-clinical studies
synaptic damage. A recent animal study showed that indicate that repeated stress exposure causes
rats undergoing maternal deprivation in the first ten morphological and functional changes in microglia
postnatal days (PND) had microglial activation markers through an activation state that appears to be mediated
identified during development, including infancy and by several factors, such as stress hormones, purines,
adolescence period, but behavioral changes were cytokines, neurotransmitters, and pattern recognition
identified when the animals were adults (PND 60), receptor (PRR) [77-79]. Moreover, experiments have
suggesting that the inflammatory process may begin at shown that stress exposure caused robust activation of
an early stage of development, but have its microglia in the prefrontal cortex (PFC), amygdala
repercussions in adulthood [64] (Fig. 2). (AMYG), and the CA3 and dentate gyrus (DG) of the
hippocampus (HPC) in mice [80-85].
Early-stage neuronal cells appear to be more
vulnerable to the effects of ROS. In fact, ROS In agreement with these findings, several animal
interferes with the neurological development process modeling studies indicate that microglial activation,
by interacting with neuronal cell lipids, proteins, and decreased hippocampal neurogenesis, and dendritic
DNA [67]. In a recent study, it was reported that alterations occur in response to prenatal immune
animals exposed to anticonvulsant valproic acid (used activation following stressors [86-89]. The most
to induce autistic behavior in animals) during replicated morphological finding appears to be cell
pregnancy it was more susceptible to peripheral and death in white matter and decreased myelin basic
neuronal inflammation associated with microglial protein immunostaining following prenatal adminis-
activation, resulting in elevated ROS production and tration of bacterial endotoxin (lipopolysaccharide, LPS)
behavioral changes. On the other hand, the and polyinosinic: polycytidylic acid (poly IC) to the
administration of minocycline, an antibiotic, was able to pregnant rodent [90-92].
reverse neuroinflammation and behavioral changes
Microglia dynamically probe the developing brain
induced by valproic acid [68].
and are highly responsive to several mediators of
Microglial cells may be "primed" in response to stress, such as corticosterone, catecholamines, and
damage, for example, in neurodegenerative diseases corticotropin-releasing hormone [93]. Researches using
and the natural aging process [69]. In normal the Brief Daily Stress (BDS) as a model of early life
physiology during microglial activation are released stress in rats observed that microglia play a critical role
inflammatory factors that act triggering immune in guiding many neurodevelopmental processes,
processes, keeping normal homeostasis. However, including synaptic pruning, synaptic maturation,
when microglia turns "primed", including after chronic neurogenesis, axonal growth, and myelination [93]. A
stress situations, the inflammatory process continues, study that explores the effects of early maternal
resulting in an excitotoxic environment, with deprivation during development through the use of Iba-
dysregulation of glutamatergic release and consequent 1 and AIF-1 microglial markers found at postnatal day
maintenance of the inflammatory process by (PND) 10, 20, and 30 the expression of Iba-1 and at 20
expression and release of pro-inflammatory genes (Fig and PND 60 the expression of AIF-1 [62]. Changes that
1). trigger an inflammatory process in animals during the
Environmental stressors: maternal deprivation, prenatal period may lead to an acceleration of the
transcriptomic maturation profile of early postnatal
sleep deprivation, and microglial activation through
microglia in a manner that persists into adulthood [94].
development.
Thereby chronic stress exposure affects not only
Human neurodevelopment is a long and dynamic microglial morphology but also microglial sensitivity
process, particularly during the fetal period, early [79]. This shift may restrict microglial physiological
childhood, puberty, and early adolescence [70]. Studies functions at crucial stages of development, leading to
on neuroplasticity and vulnerability suggest that the alterations in connectivity or excitatory/inhibitory
brain can be "shaped" by the environment, both synapses imbalance and associated behavioral deficits
positive and negative experiences [71]. Moreover, [94].
recent researches have reported a central role of the
Evidence suggests that in response to stress occurs
microglia in specific aspects of brain development,
homeostasis, and disease [72, 73]. These cells a reduction in the formation of new neurons and glia,
decreased neuronal arborization, and neuronal atrophy
mediate the interaction between the immune and
[95, 96]. Clinical studies that search for the
nervous systems, which is crucial for host perception of
pathophysiology of stress and depression report a
the external environment [74].
decreased glial number (including astrocytes and
6 Current Molecular Medicine, XXXX, Vol. XX, No. XX de Moura et al.

oligodendrocytes) in PFC in postmortem analysis of in which the mothers were exposed to ethanol, had a
depressive subjects [97, 98]. decrease in dopaminergic neurons in the ventral
tegmental area (VTA) and microglial activation. On the
Another stressor that is reported to promote
other hand, the effects of ethanol on microglia were
microglial functional alteration is sleep dysregulation.
Pre-clinical studies describe that after chronic (five normalized by the postnatal environmental intervention
[107] (Fig. 2). Strategies for decreasing the ethanol
days) rapid eye movement (REM) sleep deprivation or
effects and microglial activation have been
chronic sleep restriction, microglial activation is
investigated. For example, minocycline, an antibiotic
observed through morphological changes of microglia
drug with anti-inflammatory effects, was able to
or increased microglial expression of pro-inflammatory
attenuate ethanol-induced damage to the developing
cytokines after acute sleep deprivation [99-101]. The
evaluation of maternal sleep deprivation in rats during spinal cord by inhibiting microglial activation/
neuroinflammation and by restoring the pro-survival
the 4th, 9th, and 18th gestational days demonstrate a
signaling [108]. A cocktail of oral antibiotics reduced
cognitive impairment, anhedonic behavior, increased
the gut bacterial load and circulating endotoxin levels
inflammatory mediators, and microglial activation in the
as well as neuroinflammation (microglial activation,
hippocampus of offspring at PND 20 [102] (Fig. 2).
inflammasome and, elevated inflammatory cytokines
An animal study using serial block-face scanning levels) induced by acute or chronic alcohol
electron microscopy to analyze synapses and administration in 6- to 8-week-old C57BL/6J female
astrocytic processes in mouse frontal cortex after 6–8 h mice [109]. Resveratrol, a natural polyphenol
of sleep, spontaneous wake, or sleep deprivation and component found in plants and fruits, such as grape,
after chronic sleep restriction (∼5 days) showed that known to have antioxidant and anti-inflammatory
astrocytic phagocytosis of synaptic elements is effects, also reduced spatial memory impairment,
upregulated after a few hours of sleep deprivation and inhibited microglial activation, and reduced levels of IL-
shows an increase after prolonged and severe sleep 1ß, IL-6, and TNF- α, induced by ethanol in juvenile
loss, indicating that it can promote the maintenance of Sprague-Dawley rats [110] (Fig. 2). The inhibition of
synapses substantially used and vital to responses in chemokine monocyte chemoattractant protein 1 (MCP-
the increase of neuronal activity in the prolonged wake. 1) and its receptor C-C chemokine receptor type 2
On the other hand, chronic sleep deprivation activates (CCR2) also was able to reduce ethanol-induced
microglia, promoting an increase of their phagocytic microglial activation/neuroinflammation and
activity, even in the lack of neuroinflammation’s signs. neurodegeneration in the developing brain [111].
These data suggest that long-term sleep disturbance
Studies have been shown that immune activation
may lead to microglial activation, increasing the brain's
could lead to microglial cell change during develop-
susceptibility to neurodegeneration [100].
ment. Indeed, many studies have proposed that
Environmental stressors: immune activation, maternal immune activation during pregnancy could be
ethanol exposure, and microglial activation through related to ASD as well as other psychiatric conditions,
development. including schizophrenia [112] and depression [61,62].
The effects of ethanol exposure have been Heresi Venegas [113], in a review, proposed that these
investigated in the context of microglial activation associations could be associated with pro-inflammatory
through development. Li et al. [103] studied the effects cytokines, autoantibodies, and microglial synaptic
of ethanol exposure during adolescence and pruning during early embryonic development. Another
demonstrated an increase in the number of activated study revealed that microglial activation plays a vital
microglia and the levels of pro-inflammatory cytokines role in the development and sexual dimorphisms of
mediated by toll-like receptor 4 (TLR4). Other research neuropsychiatric disorders in humans. In fact, maternal
investigated the influence of TLR7 from the infection with live porcine reproductive and respiratory
postmortem human alcoholic hippocampus and syndrome virus leads to a fetuses' microglia increased
revealed that ethanol induces TLR7 and let-7b, as well expression, reduced phagocytic, and chemotactic
as danger signaling molecule high mobility group box-1 activity when compared to controls (Fig. 2). Moreover,
(HMGB1) expression in microglia-derived microvesicles at seven postinoculation days, an elevated microglial
[104]. density was found in the fetal amygdala, which was
sex-dependent [114].
Sanchez-Alavez et al. [105] demonstrated that rats
over adolescence period exposed to ethanol for five Maternal upregulation of type-I interferon (IFN-I) in
weeks produced an increase in microglial activation in mice, in response to maternal immune activation
different brain areas. A combination of acute ethanol induced by poly (I: C), was able to interfere with the
exposure and acute stress, as well as the combination offspring's programmed microglial developmental
of chronic ethanol exposure and acute stress, cascade, besides that increase their susceptibility to
interacted to increase plasma endotoxin and microglial postnatal stress, and led to behavioral abnormalities
CD11b in adult rats [106]. Another study analyzed the [115]. Zhang et al. [116] investigated the effects of
effects of prenatal ethanol exposure on the offspring. intrauterine endotoxin exposure at gestational day 28 in
After birth, the rats were exposed to an enriched the fetal and neonatal rabbit brain. The results revealed
environment or a standard laboratory condition. The that the maternal inflammation-induced changes in
results showed that male adult rats (8 to 12 weeks old), pathways associated with glutamate homeostasis,
astrocyte impairment, and an increase in the glutamate
Microglia activation and neurodevelopment Current Molecular Medicine, XXXX, Vol. XX, No. XX 7

Fig. (2). Microglia cells function during development and environmental factors that influence microglial activation. Microglia are
involved in brain functions and activity during development. In childhood, microglia is associated with synaptogenesis by
increasing the postsynaptic density protein 95 (PSD-95); in adolescence, microglia are required to increase the dendritic spine
in neurons mediated by the brain derived-neurotrophic factor (BDNF). Alcohol exposure during intrauterine, adolescence, or
adult life leads to microglial activation. On the other hand, resveratrol inhibits microglial activation induced by ethanol in
adolescence. An environmental enrichment (EE) during childhood can prevent microglial activation in adult life after exposure to
alcohol in prenatal life. An antibiotic cocktail also inhibits microglial activation in adult life after alcohol exposure. Maternal
immune activation, mother's sleep deprivation (SD), or valproic acid contact led to microglial activation and increased glutamate
carboxypeptidase II (GCP II) in early life periods, beyond astrocyte and glutamate homeostasis impairment. Minocycline can
inhibit microglial activation induced by SD. Maternal deprivation (MD) in early life leads to microglial activation in the childhood
period. The germ-free gut is associated with deficits in microglial maturation; however, specific pathogen-free or short-chain fatty
acids can regulate microglia cells during childhood. (A higher resolution / colour version of this figure is available in the
electronic copy of the article).

carboxypeptidase II (GCP II) in the activated microglia spinal cord in human fetuses and found that microglia
in both G29 (1-day post-injury) and PND 1 [115] (Fig. are identifiable by 9 weeks within the ventricular/sub-
2). An exquisite study using the midbrain of people with ventricular zones. In addition, the patterns of microglial
schizophrenia as well as the midbrain of mice exposed migration in the human fetal cord differ from that within
to maternal immune activation during pregnancy the cerebrum but generally conform to a route following
revealed that several inflammatory markers such as white to gray matter.
SERPINA3, TNFα, IL1β, IL6, and IL6ST transcripts A study that analyzed the initial developmental
were elevated in schizophrenia individuals compared
pattern of microglia cell invasion in the SC using
with healthy controls. Furthermore, an increase in the
immunohistochemistry on CX3CR1-eGFP mouse
transcription of microglial and astrocytic markers was
embryos showed that the invasion of microglial cells in
found, accompanied by high inflammation in offspring,
the mouse embryonic SC began at a developmental
following maternal immune activation. The authors
period corresponding to the onset of spontaneous
suggested that maternal immune activation could be a electrical activity and synaptogenesis [124]. First,
contributor factor of neuroinflammation in dopaminergic
microglial cells arrived in the SC by the peripheral
brain areas associated with schizophrenia [117].
vasculature and, after that, invaded the parenchyma at
11.5 days of embryonic age (EA 11.5). The presence of
4. MICROGLIA IN SPINAL CORD AND aggregated microglial cells was found in the
NEURODEVELOPMENT dorsolateral region near to terminal of the dying dorsal
During embryonic CNS development, the microglia root ganglia neuron at EA 12.5. After, microglia present
functions still lack information regarding spinal cord in the ventral marginal zone interacted with radial glial
(SC) colonization with microglia concerning specific cells at EA 13.5, whereas ramified microglial cells
development phases and its role in the CNS neural within the parenchyma interacted with growing
networks formation. The CNS of mammals is invaded capillaries. Also, at the same age, the lateral motor
by microglial cells in two main phases: first during the columns had an increase of microglial activation (Mac-
end of the neurogenesis in the embryonic stage and 2 staining) that led to developmental cell death of motor
the second around birth. Some species like humans, neurons, and this process continued at EA 14.5, but
rodents, and quail, have the invasion of the first with no expression of Mac-2. At the EA 15.5, the
microglial cells at early embryonic developmental presence of randomly microglial cells distributed in the
stages [118-122]. Rezaie et al. [123] investigated the parenchyma was found. This result shows that the
pattern of microglial cell distribution in the embryonic occurrence of microglia in a developing SC during
8 Current Molecular Medicine, XXXX, Vol. XX, No. XX de Moura et al.

embryonic CNS development correlates with the MCP-1 = Chemokine Monocyte Chemoattractant
presence of apoptotic cells [124]. Protein 1
In adults, the microglia present in the SC plays a AA = Derivatives of Arachidonic Acid
role in remodeling neural networks by the direct FFAR2 = Free Fatty Acid Receptor 2
interaction of synaptic elements [125]. In addition, an
increase in the number of Iba1 immunopositive GF = Germ-Free
microglia in the dorsal horns of the SC of mice that had (GCP II) = Glutamate Carboxypeptidase II
hind limb suspension was observed [125], indicating
that microglial cells can create a response to the HMGB1 = High Mobility Group Box-1
decrease in the afferent stimulation of neurons in the HPA = Hypothalamic-Pituitary-Adrenal
related region. The accumulation of microglial cells
number in the central canal may be linked to the IDO = Indolamine 2,3-dioxygenase
heterogeneity of microglia in this region [126] and IGF-1 = Insulin-like Growth Factor 1
alterations in the cerebrospinal fluid dynamic, in which
subependymal microglia react to processes that can IFN-C = Interferon-C
interact with the cerebrospinal fluid [127]. IL = Interleukin
Iba1 = Ionized Calcium-binding Adapter
CONCLUSION Molecule 1
Microglial cells have long been called guardians of MDD = Major Depressive Disorder
the CNS, acting as a defense system against
pathogens. In recent years, many studies have shown NGF = Nerve Growth Factor
different roles of microglia, and now we know that PRR = Pattern Recognition Receptor
these cells play a critical role in the shape and
functioning of other glial cells and mainly neurons. The PND = Postnatal Days
exact mechanisms and functions of microglia during PSD-95 = Postsynaptic Density Protein 95
development are not still known, but it is acknowledged
RNS = Reactive Nitrogen Species
that these cells can influence synaptogenesis and
dendritic spine processes during childhood and ROS = Reactive Oxygen Species
adolescence. Exposure to unfavorable environmental
RUNX1 = Runt-related Transcription Factor 1
conditions, such as maternal/sleep deprivation,
maternal immune activation, and ethanol exposure, SCFA = Short-chain Fatty Acids
leads to several changes in microglial cells during SPF = Specific Pathogen-free
development, including from intrauterine to adult life.
On the other hand, favorable conditions, such as SC = Spinal Cord
environmental enrichment and chemical compound or MMP = Superoxide Anion Matrix
drug medicine, could be protective alternatives against Metalloproteinase
neuroinflammation and microglial activation through
life. The source of strategies for protecting microglia is TLR4 = Toll-like Receptor 4
important since changes or exacerbated activation of TGF-b = Transforming Growth Factor b
these cells is associated with the development of
psychiatric conditions. In addition, this narrative review TNF-α = Tumoral Necrosis Factor-α
has flaws in explaining in detail the role of microglia VTA = Ventral Tegmental Area
during development, specifically in pathological
conditions, since there are few experimental and AUTHORS’ CONTRIBUTIONS
clinical studies in this area. Future studies showing the
importance of microglia in the development of Airam B. de Moura, Morgana S. Abitante, Ritele H.
neuropathologies and mood disorders, as well as da Silva, and Gislaine Z. Réus contributed to writing
environmental factors and other systems that influence the manuscript. Airam B. de Moura and Gislaine Z.
its normal functioning, are suggested. Réus prepared the figures. Gislaine Z. Réus and João
Quevedo contributed to study design, manuscript
revision, and editing.
LIST OF ABBREVIATIONS
ATP = Adenosine Triphosphate CONSENT FOR PUBLICATION
ACTH = Adrenocorticotropic Hormone Not applicable.
ASD = Autistic Spectrum Disorder
BDNF = Brain-Derived Neurotrophic Factor FUNDING
BDS = Brief Daily Stress The Translational Psychiatry Program (USA) is
funded by the Department of Psychiatry and Behavioral
CCR2 = C-C Chemokine Receptor Type 2 Sciences, McGovern Medical School, The University of
CNS = Central Nervous System Texas Health Science Center at Houston (UTHealth).
Microglia activation and neurodevelopment Current Molecular Medicine, XXXX, Vol. XX, No. XX 9

The Center of Excellence on Mood Disorders (USA) is [13] Sanagi T, Yuasa S, Nakamura Y, et al. Appearance of
funded by the Pat Rutherford Jr. Chair in Psychiatry, phagocytic microglia adjacent to motoneurons in spinal cord
tissue from a presymptomatic transgenic rat model of
John S. Dunn Foundation, and Anne and Don Fizer amyotrophic lateral sclerosis. J Neurosci Res 2010; 88(12):
Foundation Endowment for Depression Research. 2736-46.
http://dx.doi.org/10.1002/jnr.22424 PMID: 20648658
[14] Davalos D, Grutzendler J, Yang G, et al. ATP mediates rapid
CONFLICT OF INTEREST microglial response to local brain injury in vivo. Nat Neurosci
The authors declare no conflict of interest, financial 2005; 8(6): 752-8.
or otherwise. http://dx.doi.org/10.1038/nn1472 PMID: 15895084
[15] Ladeby R, Wirenfeldt M, Garcia-Ovejero D, et al. Microglial
cell population dynamics in the injured adult central nervous
ACKNOWLEDGEMENTS system. Brain Res Brain Res Rev 2005; 48(2): 196-206.
http://dx.doi.org/10.1016/j.brainresrev.2004.12.009 PMID:
We would like to thank the Translational Psychiatry 15850658
Laboratory (Brazil) from CNPq (JQ and GZR), FAPESC [16] Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial
(JQ and GZR), CAPES (JQ and GZR), Instituto cells are highly dynamic surveillants of brain parenchyma in
Cérebro e Mente (JQ and GZR), and UNESC (JQ and vivo. Science 2005; 308(5726): 1314-8.
http://dx.doi.org/10.1126/science.1110647 PMID: 15831717
GZR). JQ is a 1A and GZR is a 2 CNPq Researches [17] Gao Y, Xu X, Chang S, et al. Totarol prevents neuronal injury
Fellow. ABM and RHS are CAPES Researches Fellow. in vitro and ameliorates brain ischemic stroke: Potential roles
of Akt activation and HO-1 induction. Toxicol Appl Pharmacol
2015; 289(2): 142-54.
REFERENCES http://dx.doi.org/10.1016/j.taap.2015.10.001 PMID: 26440581
[1] Salter MW, Stevens B. Microglia emerge as central players in [18] Bhatia HS, Baron J, Hagl S, Eckert GP, Fiebich BL. Rice bran
brain disease. Nat Med 2017; 23(9): 1018-27. derivatives alleviate microglia activation: Possible
http://dx.doi.org/10.1038/nm.4397 PMID: 28886007 involvement of MAPK pathway. J Neuroinflammation 2016;
[2] Marín-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, 13: 148.
Mallat M. Microglia promote the death of developing Purkinje [19] Hanisch UK. Microglia as a source and target of cytokines.
cells. Neuron 2004; 41(4): 535-47. Glia 2002; 40(2): 140-55.
http://dx.doi.org/10.1016/S0896-6273(04)00069-8 PMID: http://dx.doi.org/10.1002/glia.10161 PMID: 12379902
14980203 [20] Zhang F, Liu J, Shi JS. Anti-inflammatory activities of
[3] Pont-Lezica L, Beumer W, Colasse S, Drexhage H, Versnel resveratrol in the brain: role of resveratrol in microglial
M, Bessis A. Microglia shape corpus callosum axon tract activation. Eur J Pharmacol 2010; 636(1-3): 1-7.
fasciculation: functional impact of prenatal inflammation. Eur http://dx.doi.org/10.1016/j.ejphar.2010.03.043 PMID:
J Neurosci 2014; 39(10): 1551-7. 20361959
http://dx.doi.org/10.1111/ejn.12508 PMID: 24593277 [21] Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping
[4] Paolicelli RC, Bolasco G, Pagani F, et al. Synaptic pruning by analysis reveals that adult microglia derive from primitive
microglia is necessary for normal brain development. Science macrophages. Science 2010; 330(6005): 841-5.
2011; 333(6048): 1456-8. http://dx.doi.org/10.1126/science.1194637 PMID: 20966214
http://dx.doi.org/10.1126/science.1202529 PMID: 21778362 [22] Kaur C, Wu CH, Wen CY, Ling EA. The effects of
[5] Schafer DP, Lehrman EK, Kautzman AG, et al. Microglia subcutaneous injections of glucocorticoids on amoeboid
sculpt postnatal neural circuits in an activity and complement- microglia in postnatal rats. Arch Histol Cytol 1994; 57(5): 449-
dependent manner. Neuron 2012; 74(4): 691-705. 59.
http://dx.doi.org/10.1016/j.neuron.2012.03.026 PMID: http://dx.doi.org/10.1679/aohc.57.449 PMID: 7734174
22632727 [23] Saijo K, Glass CK. Microglial cell origin and phenotypes in
[6] Bilbo SD, Smith SH, Schwarz JM. A lifespan approach to health and disease. Nat Rev Immunol 2011; 11(11): 775-87.
neuroinflammatory and cognitive disorders: a critical role for http://dx.doi.org/10.1038/nri3086 PMID: 22025055
glia. J Neuroimmune Pharmacol 2012; 7(1): 24-41. [24] Inoue K, Ozaki S, Shiga T, et al. Runx3 controls the axonal
http://dx.doi.org/10.1007/s11481-011-9299-y PMID: projection of proprioceptive dorsal root ganglion neurons. Nat
21822589 Neurosci 2002; 5(10): 946-54.
[7] Gomez-Nicola D, Perry VH. Microglial dynamics and role in http://dx.doi.org/10.1038/nn925 PMID: 12352981
the healthy and diseased brain: a paradigm of functional [25] Zusso M, Methot L, Lo R, Greenhalgh AD, David S, Stifani S.
plasticity. Neuroscientist 2015; 21(2): 169-84. Regulation of postnatal forebrain amoeboid microglial cell
http://dx.doi.org/10.1177/1073858414530512 PMID: proliferation and development by the transcription factor
24722525 Runx1. J Neurosci 2012; 32(33): 11285-98.
[8] Wake H, Moorhouse AJ, Miyamoto A, Nabekura J. Microglia: http://dx.doi.org/10.1523/JNEUROSCI.6182-11.2012 PMID:
actively surveying and shaping neuronal circuit structure and 22895712
function. Trends Neurosci 2013; 36(4): 209-17. [26] Rodriguez-Pallares J, Rey P, Parga JA, Muñoz A, Guerra MJ,
http://dx.doi.org/10.1016/j.tins.2012.11.007 PMID: 23260014 Labandeira-Garcia JL. Brain angiotensin enhances
[9] Nayak D, Roth TL, McGavern DB. Microglia development and dopaminergic cell death via microglial activation and NADPH-
function. Annu Rev Immunol 2014; 32: 367-402. derived ROS. Neurobiol Dis 2008; 31(1): 58-73.
http://dx.doi.org/10.1146/annurev-immunol-032713-120240 http://dx.doi.org/10.1016/j.nbd.2008.03.003 PMID: 18499466
PMID: 24471431 [27] Slyepchenko A, Brunoni AR, McIntyre RS, Quevedo J,
[10] Pío DR. El tercer elemento de los centros nerviosos. Biol Soc Carvalho AF. The adverse effects of smoking on health
Esp Biol 1919; 9: 69-129. outcomes in bipolar disorder: a review and synthesis of
[11] Stertz L, Magalhães PV, Kapczinski F. Is bipolar disorder an biological mechanisms. Curr Mol Med 2016; 16(2): 187-205.
inflammatory condition? The relevance of microglial http://dx.doi.org/10.2174/1566524016666160126144601
activation. Curr Opin Psychiatry 2013; 26(1): 19-26. PMID: 26812916
http://dx.doi.org/10.1097/YCO.0b013e32835aa4b4 PMID: [28] Qiao H, An SC, Xu C, Ma XM. Role of proBDNF and BDNF in
23196997 dendritic spine plasticity and depressive-like behaviors
[12] Bessis A, Béchade C, Bernard D, Roumier A. Microglial induced by an animal model of depression. Brain Res 2017;
control of neuronal death and synaptic properties. Glia 2007; 1663: 29-37.
55(3): 233-8. http://dx.doi.org/10.1016/j.brainres.2017.02.020 PMID:
http://dx.doi.org/10.1002/glia.20459 PMID: 17106878 28284898
10 Current Molecular Medicine, XXXX, Vol. XX, No. XX de Moura et al.

[29] Duman CH, Duman RS. Spine synapse remodeling in the http://dx.doi.org/10.4161/gmic.28681 PMID: 24685620
pathophysiology and treatment of depression. Neurosci Lett [44] Dominguez-Bello MG, Costello EK, Contreras M, et al.
2015; 601: 20-9. Delivery mode shapes the acquisition and structure of the
http://dx.doi.org/10.1016/j.neulet.2015.01.022 PMID: initial microbiota across multiple body habitats in newborns.
25582786 Proc Natl Acad Sci USA 2010; 107(26): 11971-5.
[30] Lim SH, Park E, You B, et al. Neuronal synapse formation http://dx.doi.org/10.1073/pnas.1002601107 PMID: 20566857
induced by microglia and interleukin 10. PLoS One 2013; [45] Yatsunenko T, Rey FE, Manary MJ, et al. Human gut
8(11): e81218. microbiome viewed across age and geography. Nature 2012;
http://dx.doi.org/10.1371/journal.pone.0081218 PMID: 486(7402): 222-7.
24278397 http://dx.doi.org/10.1038/nature11053 PMID: 22699611
[31] Shigemoto-Mogami Y, Hoshikawa K, Goldman JE, Sekino Y, [46] Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut
Sato K. Microglia enhance neurogenesis and microbiome in obese and lean twins. Nature 2009;
oligodendrogenesis in the early postnatal subventricular 457(7228): 480-4.
zone. J Neurosci 2014; 34(6): 2231-43. http://dx.doi.org/10.1038/nature07540 PMID: 19043404
http://dx.doi.org/10.1523/JNEUROSCI.1619-13.2014 PMID: [47] Bäckhed F, Roswall J, Peng Y, et al. Dynamics and
24501362 stabilization of the human gut microbiome during the first year
[32] Nicholas RS, Wing MG, Compston A. Nonactivated microglia of life. Cell Host Microbe 2015; 17(5): 690-703. [Erratum in:
promote oligodendrocyte precursor survival and maturation Cell Host Microbe. 2015;17]. [6]. [:852. Jun, Wang ].
through the transcription factor NF-kappa B. Eur J Neurosci [corrected to Wang, Jun]. [. Erratum in: Cell Host Microbe.
2001; 13(5): 959-67. 2015;17]. [6]. [:852. PMID: 25974306].
http://dx.doi.org/10.1046/j.0953-816x.2001.01470.x PMID: http://dx.doi.org/10.1016/j.chom.2015.04.004 PMID:
11264668 25974306
[33] Heese K, Fiebich BL, Bauer J, Otten U. NF-kappaB [48] Claesson MJ, Cusack S, O'Sullivan O, Greene-Diniz R, de
modulates lipopolysaccharide-induced microglial nerve Weerd H, Flannery E. Composition, variability, and temporal
growth factor expression. Glia 1998; 22(4): 401-7. stability of the intestinal microbiota of the elderly. Proc Natl
http://dx.doi.org/10.1002/(SICI)1098- Acad Sci U S A 2011; 108(Suppl 1): 4586-91.
1136(199804)22:4<401::AID-GLIA9>3.0.CO;2-5 PMID: http://dx.doi.org/10.1073/pnas.1000097107
9517572 [49] Biagi E, Nylund L, Candela M, et al. Through ageing, and
[34] Peng J, Wang P, Ge H, Qu X, Jin X. Effects of cordycepin on beyond: gut microbiota and inflammatory status in seniors
the microglia-overactivation-induced impairments of growth and centenarians. PLoS One 2010; 5(5): e10667. [Erratum in:
and development of hippocampal cultured neurons. PLoS PLoS One. 2010;5].
One 2015; 10(5): e0125902. http://dx.doi.org/10.1371/journal.pone.0010667 PMID:
http://dx.doi.org/10.1371/journal.pone.0125902 PMID: 20498852
25932642 [50] Cryan JF, Dinan TG. Gut microbiota: Microbiota and
[35] Kim HJ, Cho MH, Shim WH, et al. Deficient autophagy in neuroimmune signalling-Metchnikoff to microglia. Nat Rev
microglia impairs synaptic pruning and causes social Gastroenterol Hepatol 2015; 12(9): 494-6.
behavioral defects. Mol Psychiatry 2017; 22(11): 1576-84. http://dx.doi.org/10.1038/nrgastro.2015.127 PMID: 26215386
http://dx.doi.org/10.1038/mp.2016.103 PMID: 27400854 [51] Henning SJ, Hird FJ. Transport of acetate and butyrate in the
[36] Parkhurst CN, Yang G, Ninan I, et al. Microglia promote hind-gut of rabbits. Biochem J 1972; 130(3): 791-6.
learning-dependent synapse formation through brain-derived http://dx.doi.org/10.1042/bj1300791 PMID: 4664933
neurotrophic factor. Cell 2013; 155(7): 1596-609. [52] Sudo N, Chida Y, Aiba Y, et al. Postnatal microbial
http://dx.doi.org/10.1016/j.cell.2013.11.030 PMID: 24360280 colonization programs the hypothalamic-pituitary-adrenal
[37] Zhang Y, Xu H, Wang J, et al. Transient upregulation of system for stress response in mice. J Physiol 2004; 558(Pt
immune activity induced by adolescent social stress is 1): 263-75.
involved in cognitive deficit in adult male mice and early http://dx.doi.org/10.1113/jphysiol.2004.063388 PMID:
intervention with minocycline. Behav Brain Res 2019; 374: 15133062
112136. [53] Clarke G, Grenham S, Scully P, et al. The microbiome-gut-
http://dx.doi.org/10.1016/j.bbr.2019.112136 PMID: 31381975 brain axis during early life regulates the hippocampal
[38] Weinhard L, Neniskyte U, Vadisiute A, et al. Sexual serotonergic system in a sex-dependent manner. Mol
dimorphism of microglia and synapses during mouse Psychiatry 2013; 18(6): 666-73.
postnatal development. Dev Neurobiol 2018; 78(6): 618-26. http://dx.doi.org/10.1038/mp.2012.77 PMID: 22688187
http://dx.doi.org/10.1002/dneu.22568 PMID: 29239126 [54] Forsythe P, Kunze WA. Voices from within: gut microbes and
[39] Org E, Mehrabian M, Parks BW, et al. Sex differences and the CNS. Cell Mol Life Sci 2013; 70(1): 55-69.
hormonal effects on gut microbiota composition in mice. Gut http://dx.doi.org/10.1007/s00018-012-1028-z PMID:
Microbes 2016; 7(4): 313-22. 22638926
http://dx.doi.org/10.1080/19490976.2016.1203502 PMID: [55] Erny D, Hrabě de Angelis AL, Jaitin D, et al. Host microbiota
27355107 constantly control maturation and function of microglia in the
[40] Kiliaan AJ, Saunders PR, Bijlsma PB, et al. Stress stimulates CNS. Nat Neurosci 2015; 18(7): 965-77.
transepithelial macromolecular uptake in rat jejunum. Am J http://dx.doi.org/10.1038/nn.4030 PMID: 26030851
Physiol 1998; 275(5): G1037-44. [56] Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser
http://dx.doi.org/10.1152/ajpgi.1998.275.5.G1037 PMID: JN. Recognition of peptidoglycan from the microbiota by
9815034 Nod1 enhances systemic innate immunity. Nat Med 2010;
[41] Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria 16(2): 228-31.
from the gut microbiota regulate host serotonin biosynthesis. http://dx.doi.org/10.1038/nm.2087 PMID: 20081863
Cell 2015; 161(2): 264-76. [Erratum in: Cell. 2015;163:258. [57] Chourbaji S, Urani A, Inta I, et al. IL-6 knockout mice exhibit
PMID: 25860609; PMCID: PMC4393509]. resistance to stress-induced development of depression-like
http://dx.doi.org/10.1016/j.cell.2015.02.047 PMID: 25860609 behaviors. Neurobiol Dis 2006; 23(3): 587-94.
[42] Douglas-Escobar M, Elliott E, Neu J. Effect of intestinal http://dx.doi.org/10.1016/j.nbd.2006.05.001 PMID: 16843000
microbial ecology on the developing brain. JAMA Pediatr [58] Yue N, Huang H, Zhu X, et al. Activation of P2X7 receptor
2013; 167(4): 374-9. and NLRP3 inflammasome assembly in hippocampal glial
http://dx.doi.org/10.1001/jamapediatrics.2013.497 PMID: cells mediates chronic stress-induced depressive-like
23400224 behaviors. J Neuroinflammation 2017; 14(1): 102.
[43] Selkrig J, Wong P, Zhang X, Pettersson S. Metabolic http://dx.doi.org/10.1186/s12974-017-0865-y PMID:
tinkering by the gut microbiome: Implications for brain 28486969
development and function. Gut Microbes 2014; 5(3): 369-80.
Microglia activation and neurodevelopment Current Molecular Medicine, XXXX, Vol. XX, No. XX 11

[59] Fagundes CP, Glaser R, Hwang BS, Malarkey WB, Kiecolt- [74] Thion MS, Low D, Silvin A, et al. Microbiome Influences
Glaser JK. Depressive symptoms enhance stress-induced Prenatal and Adult Microglia in a Sex-Specific Manner. Cell
inflammatory responses. Brain Behav Immun 2013; 31: 172- 2018; 172(3): 500-516.
6. http://dx.doi.org/10.1016/j.cell.2017.11.042 PMID: 29275859
http://dx.doi.org/10.1016/j.bbi.2012.05.006 PMID: 22634107 [75] Beattie EC, Stellwagen D, Morishita W, et al. Control of
[60] Chen MH, Li CT, Lin WC, et al. Rapid inflammation synaptic strength by glial TNFalpha. Science 2002;
modulation and antidepressant efficacy of a low-dose 295(5563): 2282-5.
ketamine infusion in treatment-resistant depression: A http://dx.doi.org/10.1126/science.1067859 PMID: 11910117
randomized, double-blind control study. Psychiatry Res 2018; [76] Mattei D, Ivanov A, Ferrai C, et al. Maternal immune
269: 207-11. activation results in complex microglial transcriptome
http://dx.doi.org/10.1016/j.psychres.2018.08.078 PMID: signature in the adult offspring that is reversed by minocycline
30153598 treatment. Transl Psychiatry 2017; 7(5): e1120.
[61] Réus GZ, Fernandes GC, de Moura AB, et al. Early life http://dx.doi.org/10.1038/tp.2017.80 PMID: 28485733
experience contributes to the developmental programming of [77] Frank MG, Thompson BM, Watkins LR, Maier SF.
depressive-like behaviour, neuroinflammation and oxidative Glucocorticoids mediate stress-induced priming of microglial
stress. J Psychiatr Res 2017; 95: 196-207. pro-inflammatory responses. Brain Behav Immun 2012;
http://dx.doi.org/10.1016/j.jpsychires.2017.08.020 PMID: 26(2): 337-45.
28886447 http://dx.doi.org/10.1016/j.bbi.2011.10.005 PMID: 22041296
[62] Réus GZ, Silva RH, de Moura AB, et al. Early maternal [78] Frank MG, Miguel ZD, Watkins LR, Maier SF. Prior exposure
deprivation induces microglial activation, alters glial fibrillary to glucocorticoids sensitizes the neuroinflammatory and
acidic protein immunoreactivity and indoleamine 2,3- peripheral inflammatory responses to E. coli
dioxygenase during the development of offspring rats. Mol lipopolysaccharide. Brain Behav Immun 2010; 24(1): 19-30.
Neurobiol 2019; 56(2): 1096-108. http://dx.doi.org/10.1016/j.bbi.2009.07.008 PMID: 19647070
http://dx.doi.org/10.1007/s12035-018-1161-2 PMID: [79] Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF.
29873040 Microglia serve as a neuroimmune substrate for stress-
[63] Réus GZ, Carlessi AS, Titus SE, et al. A single dose of S- induced potentiation of CNS pro-inflammatory cytokine
ketamine induces long-term antidepressant effects and responses. Brain Behav Immun 2007; 21(1): 47-59.
decreases oxidative stress in adulthood rats following http://dx.doi.org/10.1016/j.bbi.2006.03.005 PMID: 16647243
maternal deprivation. Dev Neurobiol 2015; 75(11): 1268-81. [80] Hinwood M, Morandini J, Day TA, Walker FR. Evidence that
http://dx.doi.org/10.1002/dneu.22283 PMID: 25728399 microglia mediate the neurobiological effects of chronic
[64] Réus GZ, Maciel AL, Abelaira HM, et al. ω-3 and folic acid psychological stress on the medial prefrontal cortex. Cereb
act against depressive-like behavior and oxidative damage in Cortex 2012; 22(6): 1442-54.
the brain of rats subjected to early- or late-life stress. Nutrition http://dx.doi.org/10.1093/cercor/bhr229 PMID: 21878486
2018; 53: 120-33. [81] Tynan RJ, Naicker S, Hinwood M, et al. Chronic stress alters
http://dx.doi.org/10.1016/j.nut.2018.03.006 PMID: 29783176 the density and morphology of microglia in a subset of stress-
[65] Evans GW, Schamberg MA. Childhood poverty, chronic responsive brain regions. Brain Behav Immun 2010; 24(7):
stress, and adult working memory. Proc Natl Acad Sci USA 1058-68.
2009; 106(16): 6545-9. http://dx.doi.org/10.1016/j.bbi.2010.02.001 PMID: 20153418
http://dx.doi.org/10.1073/pnas.0811910106 PMID: 19332779 [82] Wohleb ES, Hanke ML, Corona AW, Powell ND, Stiner LM,
[66] Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Bailey MT. beta-Adrenergic receptor antagonism prevents
Synaptic plasticity and depression: new insights from stress anxiety-like behavior and microglial reactivity induced by
and rapid-acting antidepressants. Nat Med 2016; 22(3): 238- repeated social defeat. J Neurosci 2011; 31: 6277-88.
49. [83] Wohleb ES, McKim DB, Shea DT, Powell ND, Tarr AJ,
http://dx.doi.org/10.1038/nm.4050 PMID: 26937618 Sheridan JF. Re-establishment of anxiety in stress-sensitized
[67] Bell KFS, Al-Mubarak B, Martel M-A, et al. Neuronal mice is caused by monocyte trafficking from the spleen to the
development is promoted by weakened intrinsic antioxidant brain. Biol Psychiatry 2014; 75: 970-81.
defences due to epigenetic repression of Nrf2. Nat Commun http://dx.doi.org/10.1016/j.biopsych.2013.11.029
2015; 6: 7066. [84] Wohleb ES, Patterson JM, Sharma V, Quan N, Godbout JP,
http://dx.doi.org/10.1038/ncomms8066 PMID: 25967870 Sheridan JF. Knockdown of interleukin-1 receptor type-1 on
[68] Lucchina L, Depino AM. Altered peripheral and central endothelial cells attenuated stress-induced
inflammatory responses in a mouse model of autism. Autism neuroinflammation and prevented anxiety-like behavior. J
Res 2014; 7(2): 273-89. Neurosci 2014; 34: 2583-91.
http://dx.doi.org/10.1002/aur.1338 PMID: 24124122 [85] Wohleb ES, Powell ND, Godbout JP, Sheridan JF. Stress-
[69] Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, induced recruitment of bone marrow-derived monocytes to
Mechawar N. Evidence for increased microglial priming and the brain promotes anxietylike behavior. J Neurosci 2013; 33:
macrophage recruitment in the dorsal anterior cingulate white 13820-33.
matter of depressed suicides. Brain Behav Immun 2014; 42: [86] Ling Z, Zhu Y, Tong CW, Snyder JA, Lipton JW, Carvey PM.
50-9. Progressive dopamine neuron loss following supra-nigral
http://dx.doi.org/10.1016/j.bbi.2014.05.007 PMID: 24858659 lipopolysaccharide (LPS) infusion into rats exposed to LPS
[70] Lima-Ojeda JM, Rupprecht R, Baghai TC. Neurobiology of prenatally. Exp Neurol 2006; 199(2): 499-512.
depression: A neurodevelopmental approach. World J Biol http://dx.doi.org/10.1016/j.expneurol.2006.01.010 PMID:
Psychiatry 2018; 19(5): 349-59. 16504177
http://dx.doi.org/10.1080/15622975.2017.1289240 PMID: [87] Ling Z, Zhu Y, Tong CW, Snyder JA, Lipton JW, Carvey PM.
28155577 Prenatal lipopolysaccharide does not accelerate progressive
[71] Costa JC. Neurodesenvolvimento e os primeiros anos de dopamine neuron loss in the rat as a result of normal aging.
vida: genética vs. ambiente. RELAdEI 2018; 7: 52-60. Exp Neurol 2009; 216(2): 312-20.
[72] Ueno M, Fujita Y, Tanaka T, et al. Layer V cortical neurons http://dx.doi.org/10.1016/j.expneurol.2008.12.004 PMID:
require microglial support for survival during postnatal 19133261
development. Nat Neurosci 2013; 16(5): 543-51. [88] Cui K, Ashdown H, Luheshi GN, Boksa P. Effects of prenatal
http://dx.doi.org/10.1038/nn.3358 PMID: 23525041 immune activation on hippocampal neurogenesis in the rat.
[73] Abud EM, Ramirez RN, Martinez ES, et al. iPSC-derived Schizophr Res 2009; 113(2-3): 288-97.
human microglia-like cells to study neurological diseases. http://dx.doi.org/10.1016/j.schres.2009.05.003 PMID:
Neuron 2017; 94(2): 278-293. 19464151
http://dx.doi.org/10.1016/j.neuron.2017.03.042 PMID: [89] Baharnoori M, Brake WG, Srivastava LK. Prenatal immune
28426964 challenge induces developmental changes in the morphology
12 Current Molecular Medicine, XXXX, Vol. XX, No. XX de Moura et al.

of pyramidal neurons of the prefrontal cortex and [104] Coleman LG Jr, Zou J, Crews FT. Microglial-derived miRNA
hippocampus in rats. Schizophr Res 2009; 107(1): 99-109. let-7 and HMGB1 contribute to ethanol-induced neurotoxicity
http://dx.doi.org/10.1016/j.schres.2008.10.003 PMID: via TLR7. J Neuroinflammation 2017; 14(1): 22.
19004618 http://dx.doi.org/10.1186/s12974-017-0799-4 PMID:
[90] Kumral A, Baskin H, Yesilirmak DC, et al. Erythropoietin 28118842
attenuates lipopolysaccharide-induced white matter injury in [105] Sanchez-Alavez M, Nguyen W, Mori S, et al. Time course of
the neonatal rat brain. Neonatology 2007; 92(4): 269-78. blood and brain cytokine/chemokine levels following
http://dx.doi.org/10.1159/000105493 PMID: 17627093 adolescent alcohol exposure and withdrawal in rats. Alcohol
[91] Yesilirmak DC, Kumral A, Baskin H, et al. Activated protein C Clin Exp Res 2019; 43(12): 2547-58.
reduces endotoxin-induced white matter injury in the http://dx.doi.org/10.1111/acer.14209 PMID: 31589333
developing rat brain. Brain Res 2007; 1164: 14-23. [106] Walter TJ, Vetreno RP, Crews FT. Alcohol and stress
http://dx.doi.org/10.1016/j.brainres.2007.04.083 PMID: activation of microglia and neurons: brain regional effects.
17644074 Alcohol Clin Exp Res 2017; 41(12): 2066-81.
[92] Makinodan M, Tatsumi K, Manabe T, et al. Maternal immune http://dx.doi.org/10.1111/acer.13511 PMID: 28941277
activation in mice delays myelination and axonal [107] Aghaie CI, Hausknecht KA, Wang R, et al. Prenatal ethanol
development in the hippocampus of the offspring. J Neurosci exposure and postnatal environmental intervention alter
Res 2008; 86(10): 2190-200. dopaminergic neuron and microglia morphology in the ventral
http://dx.doi.org/10.1002/jnr.21673 PMID: 18438922 tegmental area during adulthood. Alcohol Clin Exp Res 2020;
[93] Delpech JC, Wei L, Hao J, et al. Early life stress perturbs the 44(2): 435-44.
maturation of microglia in the developing hippocampus. Brain http://dx.doi.org/10.1111/acer.14275 PMID: 31872887
Behav Immun 2016; 57: 79-93. [108] Ren Z, Wang X, Xu M, Frank JA, Luo J. Minocycline
http://dx.doi.org/10.1016/j.bbi.2016.06.006 PMID: 27301858 attenuates ethanol-induced cell death and microglial
[94] Matcovitch-Natan O, Winter DR, Giladi A, et al. Microglia activation in the developing spinal cord. Alcohol 2019; 79: 25-
development follows a stepwise program to regulate brain 35.
homeostasis. Science 2016; 353(6301): aad8670. http://dx.doi.org/10.1016/j.alcohol.2018.12.002 PMID:
http://dx.doi.org/10.1126/science.aad8670 PMID: 27338705 30529756
[95] Radley JJ, Rocher AB, Janssen WG, Hof PR, McEwen BS, [109] Lowe PP, Gyongyosi B, Satishchandran A, et al. Reduced
Morrison JH. Reversibility of apical dendritic retraction in the gut microbiome protects from alcohol-induced
rat medial prefrontal cortex following repeated stress. Exp neuroinflammation and alters intestinal and brain
Neurol 2005; 196(1): 199-203. inflammasome expression. J Neuroinflammation 2018; 15(1):
http://dx.doi.org/10.1016/j.expneurol.2005.07.008 PMID: 298.
16095592 http://dx.doi.org/10.1186/s12974-018-1328-9 PMID:
[96] Liu RJ, Aghajanian GK. Stress blunts serotonin- and 30368255
hypocretin-evoked EPSCs in prefrontal cortex: role of [110] Qi B, Shi C, Meng J, Xu S, Liu J. Resveratrol alleviates
corticosterone-mediated apical dendritic atrophy. Proc Natl ethanol-induced neuroinflammation in vivo and in vitro:
Acad Sci USA 2008; 105(1): 359-64. Involvement of TLR2-MyD88-NF-κB pathway. Int J Biochem
http://dx.doi.org/10.1073/pnas.0706679105 PMID: 18172209 Cell Biol 2018; 103: 56-64.
[97] Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al. Morphometric http://dx.doi.org/10.1016/j.biocel.2018.07.007 PMID:
evidence for neuronal and glial prefrontal cell pathology in 30107238
major depression. Biol Psychiatry 1999; 45(9): 1085-98. [111] Zhang K, Wang H, Xu M, Frank JA, Luo J. Role of MCP-1
http://dx.doi.org/10.1016/S0006-3223(99)00041-4 PMID: and CCR2 in ethanol-induced neuroinflammation and
10331101 neurodegeneration in the developing brain. J
[98] Hayashi Y, Nihonmatsu-Kikuchi N, Yu X, Ishimoto K, Neuroinflammation 2018; 15(1): 197.
Hisanaga SI, Tatebayashi Y. A novel, rapid, quantitative cell- http://dx.doi.org/10.1186/s12974-018-1241-2 PMID:
counting method reveals oligodendroglial reduction in the 29976212
frontopolar cortex in major depressive disorder. Mol [112] Laskaris LE, Di Biase MA, Everall I, et al. Microglial activation
Psychiatry 2011; 16(12): 1155-8. and progressive brain changes in schizophrenia. Br J
http://dx.doi.org/10.1038/mp.2011.152 PMID: 21747396 Pharmacol 2016; 173(4): 666-80.
[99] Hsu JC, Lee YS, Chang CN, Chuang HL, Ling EA, Lan CT. http://dx.doi.org/10.1111/bph.13364 PMID: 26455353
Sleep deprivation inhibits expression of NADPH-d and NOS [113] Heresi Venegas C. Maternal immune activation and risk of
while activating microglia and astroglia in the rat Autism Spectrum Disorder. Rev Chil Pediatr 2019; 90: 555-8.
hippocampus. Cells Tissues Organs 2003; 173(4): 242-54. [114] Antonson AM, Lawson MA, Caputo MP, Matt SM, Leyshon
http://dx.doi.org/10.1159/000070380 PMID: 12766354 BJ, Johnson RW. Maternal viral infection causes global
[100] Bellesi M, de Vivo L, Chini M, Gilli F, Tononi G, Cirelli C. alterations in porcine fetal microglia. Proc Natl Acad Sci USA
Sleep loss promotes astrocytic phagocytosis and microglial 2019; 116(40): 20190-200.
activation in mouse cerebral cortex. J Neurosci 2017; 37(21): http://dx.doi.org/10.1073/pnas.1817014116 PMID: 31527230
5263-73. [115] Ben-Yehuda H, Matcovitch-Natan O, Kertser A, Spinrad A,
http://dx.doi.org/10.1523/JNEUROSCI.3981-16.2017 PMID: Prinz M, Amit I, Maternal Type-I interferon signaling adversely
28539349 affects the microglia and the behavior of the offspring
[101] Wisor JP, Schmidt MA, Clegern WC. Evidence for accompanied by increased sensitivity to stress. Mol
neuroinflammatory and microglial changes in the cerebral Psychiatry 2020; 25: 1050-67.
response to sleep loss. Sleep 2011; 34(3): 261-72. http://dx.doi.org/10.1038/s41380-019-0604-0 PMID:
http://dx.doi.org/10.1093/sleep/34.3.261 PMID: 21358843 31772304
[102] Zhao Q, Peng C, Wu X, Chen Y, Wang C, You Z. Maternal [116] Zhang Z, Bassam B, Thomas AG, et al. Maternal
sleep deprivation inhibits hippocampal neurogenesis inflammation leads to impaired glutamate homeostasis and
associated with inflammatory response in young offspring up-regulation of glutamate carboxypeptidase II in activated
rats. Neurobiol Dis 2014; 68: 57-65. microglia in the fetal/newborn rabbit brain. Neurobiol Dis
http://dx.doi.org/10.1016/j.nbd.2014.04.008 PMID: 24769004 2016; 94: 116-28.
[103] Li Q, Liu D, Pan F, Ho CSH, Ho RCM. Ethanol exposure http://dx.doi.org/10.1016/j.nbd.2016.06.010 PMID: 27326668
induces microglia activation and neuroinflammation through [117] Purves-Tyson TD, Weber-Stadlbauer U, Richetto J,
TLR4 activation and SENP6 modulation in the adolescent rat Rothmond DA, Labouesse MA, Polesel M, et al. Increased
hippocampus. Neural Plast 2019; 2019: 1648736. levels of midbrain immune-related transcripts in
http://dx.doi.org/10.1155/2019/1648736 PMID: 31781182 schizophrenia and in murine offspring after maternal immune
activation. Mol Psychiatry 2021; 26: 849-63.
Microglia activation and neurodevelopment Current Molecular Medicine, XXXX, Vol. XX, No. XX 13

http://dx.doi.org/10.1038/s41380-019-0434-0 PMID: [123] Rezaie P, Patel K, Male DK. Microglia in the human fetal
31168068 spinal cord--patterns of distribution, morphology and
[118] Ashwell K. Development of microglia in the albino rabbit phenotype. Brain Res Dev Brain Res 1999; 115(1): 71-81.
retina. J Comp Neurol 1989; 287(3): 286-301. http://dx.doi.org/10.1016/S0165-3806(99)00043-7 PMID:
http://dx.doi.org/10.1002/cne.902870303 PMID: 2674209 10366704
[119] Ashwell KW, Holländer H, Streit W, Stone J. The appearance [124] Rigato C, Buckinx R, Le-Corronc H, Rigo JM, Legendre P.
and distribution of microglia in the developing retina of the rat. Pattern of invasion of the embryonic mouse spinal cord by
Vis Neurosci 1989; 2(5): 437-48. microglial cells at the time of the onset of functional neuronal
http://dx.doi.org/10.1017/S0952523800012335 PMID: networks. Glia 2011; 59(4): 675-95.
2487081 http://dx.doi.org/10.1002/glia.21140 PMID: 21305616
[120] Billiards SS, Haynes RL, Folkerth RD, et al. Development of [125] Mukhamedshina YO, Povysheva TV, Nigmetzyanova MV, et
microglia in the cerebral white matter of the human fetus and al. Astrocytes and microglia of the mouse spinal cord during
infant. J Comp Neurol 2006; 497(2): 199-208. hind limb suspension. Dokl Biol Sci 2014; 456(1): 157-9.
http://dx.doi.org/10.1002/cne.20991 PMID: 16705680 http://dx.doi.org/10.1134/S001249661403003X PMID:
[121] Dalmau I, Vela JM, González B, Finsen B, Castellano B. 24985504
Dynamics of microglia in the developing rat brain. J Comp [126] Chelyshev YA, Muhamedshina YO, Povysheva TV, et al.
Neurol 2003; 458(2): 144-57. Characterization of spinal cord glial cells in a model of
http://dx.doi.org/10.1002/cne.10572 PMID: 12596255 hindlimb unloading in mice. Neuroscience 2014; 280: 328-39.
[122] Sánchez-López A, Cuadros MA, Calvente R, Tassi M, Marín- http://dx.doi.org/10.1016/j.neuroscience.2014.09.004 PMID:
Teva JL, Navascués J. Radial migration of developing 25218808
microglial cells in quail retina: a confocal microscopy study. [127] Kirik OV, Sukhorukova EG, Alekseeva OS, Korzhevskiĭ DÉ.
Glia 2004; 46(3): 261-73. Subependymal microgliocytes of the third ventricle of the
http://dx.doi.org/10.1002/glia.20007 PMID: 15048849 brain. Morfologiia 2014; 145(2): 67-9.
PMID: 25282829

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