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Microglia roles in synaptic plasticity and myelination in homeostatic

conditions and neurodevelopmental disorders

Article  in  Glia · May 2019

DOI: 10.1002/glia.23637

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Received: 26 January 2019 Revised: 15 April 2019 Accepted: 16 April 2019
DOI: 10.1002/glia.23637

REVIEW ARTICLE

Microglia roles in synaptic plasticity and myelination in

homeostatic conditions and neurodevelopmental disorders

Ela Bar1,2 | Boaz Barak1,3

1
The School of Psychological Sciences, Faculty
of Social Sciences, and The Sagol School of Abstract
Neuroscience, Tel Aviv University, Tel Aviv, Microglia are the immune cells of the brain, involved in synapse formation, circuit
Israel
2 sculpting, myelination, plasticity, and cognition. Being active players during early
The School of Neurobiology, Biochemistry &
Biophysics, Faculty of Life Sciences, Tel Aviv development as well as in adulthood, microglia affect other cells directly by their long
University, Tel Aviv, Israel
processes and unique receptors and indirectly by secreting growth factors and cyto-
3
The Sagol School of Neuroscience, Tel Aviv
University, Tel Aviv, Israel kines. In this review, we discuss the roles of microglia in neurodevelopmental disor-
ders, synaptic plasticity, myelination, and homeostatic conditions throughout human
Correspondence
Boaz Barak, The School of Psychological and mouse development. Within these processes, we specifically focus on the contri-
Sciences, Faculty of Social Sciences, and The bution of altered microglial interactions with neurons and oligodendrocytes, altered
Sagol School of Neuroscience, Tel Aviv
University, Tel Aviv, 69978, Israel. cytokine and growth factor activities, and alterations in the complement system. We
Email: [email protected] conclude by highlighting future perspectives and providing an overview of future
research on microglia.

KEYWORDS
autism, microglia, myelin, neurodevelopmental disorders, synaptic plasticity

1 | MICROGLIA: INNATE IMMUNE CELLS residence before the differentiation of other CNS cell types and
O F T HE C EN T R A L N E R V O U S S YST E M become critical regulators of CNS development (Kierdorf et al., 2013;
Ransohoff & Cardona, 2010).
The central nervous system (CNS) consists of neurons—specialized Microglia self-renew via proliferation and are not replaced by
cells that can receive and transmit chemical or electrical signals bone marrow-derived cells in the healthy brain (Elmore et al., 2014).
(Laughlin & Sejnowski, 2003), macroglia (astrocytes, oligodendrocytes Once in the CNS, microglial cells continually monitor their microenvi-
[OLs], ependymal cells, and radial glia), and microglia. Macroglia and ronment (Nimmerjahn, Kirchhoff, & Helmchen, 2005) and are impli-
microglia maintain the neurons' ionic milieu (Fields et al., 2014; Walz, cated in neuroplasticity, host defense, homeostasis, wound healing,
Ilschner, Ohlemeyer, Banati, & Kettenmann, 1993), modulate synaptic
debris scavenging, and peripheral immune cells recruitment (Aloisi,
activity (Tremblay, Lowery, & Majewska, 2010; Wu, Dissing-Olesen,
2001) (Figure 1). Activated microglia have the ability to migrate and
MacVicar, & Stevens, 2015), regulate conduction velocity in axons
undergo morphological and functional changes in response to a vari-
(Dutta et al., 2018), support neural development (Schafer & Stevens,
ety of stimuli, such as cytokines and growth factors (GFs) (Nayak
2013; Wu et al., 2015), and aid in recovery from CNS injury
et al., 2014; Tremblay, Lecours, Samson, Sanchez-Zafra, & Sierra,
(Kreutzberg, 1996; Pineau & Lacroix, 2009). Microglia account for
2015). The presence of activated microglia has been documented in
5–12% of the cells in the CNS (Lawson, Perry, Dri, & Gordon, 1990);
they derive from the yolk sac primitive myeloid progenitors and are a plethora of brain injury and disease conditions in humans

maintained independently of definitive hematopoiesis (Ginhoux et al., (Ransohoff & Perry, 2009) and in related animal models (Hanisch &
2010). Microglial cells arise before embryonic day 8 (E8) (Lichanska & Kettenmann, 2007). In fact, brain pathology that is not associated with
Hume, 2000) and migrate to the brain through the circulatory system microglial function is difficult to find (Faustino et al., 2011; Kim et al.,
(Nayak, Roth, & McGavern, 2014). Infiltrated microglia take up 2017; Sapp et al., 2001).

Glia. 2019;1–17. wileyonlinelibrary.com/journal/glia © 2019 Wiley Periodicals, Inc. 1

2 BAR AND BARAK

F I G U R E 1 Microglial functions and molecular signaling in a normal physiological state. (a) In a normal physiological state, microglia contact
neurons and surveille their environment using different receptors, such as CX3CR1 (Cardona et al., 2006) and TLRs (Olson & Miller, 2004). They
eliminate immature or impaired synapses using their CR3 receptor which recognizes the complement system's C3 protein, and clear debris
(Schafer et al., 2012). Microglia also secrete different cytokines and GFs to promote cell survival, maturation and proliferation (Nayak et al., 2014).
IGF-1, secreted by microglia, promotes OPC differentiation and myelination (Wlodarczyk et al., 2017) and supports layer V neurons (Ueno et al.,
2013). BDNF, also secreted by microglia, promotes survival of neurons and synaptic plasticity (Parkhurst et al., 2013), and regulates OPC
differentiation and OL survival by positively modulating promyelinating transcription factors such as olig2 and PLP (Ramos-Cejudo et al., 2015;
Zhou et al., 2015). (b) Microglia-related molecular signaling in the CNS and the outcome process

2 | M I C RO G L I A L P O L A R I Z A T I O N marked change in morphology from ramified to amoeboid (Giulian &

Baker, 1986). Once activated, microglia have been implicated in both
Microglia are able to polarize into an activated state, such that their mode protective and destructive functions (Ekdahl et al., 2009; Hanisch &
of action is situation-dependent (Ransohoff & Perry, 2009), resulting in Kettenmann, 2007), with their action depending on the perceived sig-
varied and context-dependent microglial transcriptome profiles (Wes, nals. Therefore, microglia are equipped with numerous pattern-
Holtman, Boddeke, Moller, & Eggen, 2016). Microglial function results recognition receptors (PRRs) (Kigerl, de Rivero Vaccari, Dietrich,
from a combination of variables, such as age, neuropathological condition, Popovich, & Keane, 2014), such as toll-like receptors (TLRs) and the
disease stage, and environmental factors (Colonna & Butovsky, 2017; mannose receptor expressed on innate immune cells (Barak,
Gosselin et al., 2017) (Figure 2). Microglia can produce and secrete Feldman, & Okun, 2014; Bianchi, 2007).
proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor To perform their diverse functions, microglia express all types of
necrosis factor-α (TNF-α), which have been shown to be beneficial during TLRs, as shown in mice (Olson & Miller, 2004), rats (Zhang et al.,
development (Shigemoto-Mogami, Hoshikawa, Goldman, Sekino, & Sato, 2013), and humans (Barak et al., 2014; Bsibsi, Ravid, Gveric, & van
2014) but harmful in several pathological states in the CNS (Kim & Joh, Noort, 2002). Damage-specific microglial activation and reaction, also
2006; Patterson, 2015). Conversely, microglia can produce and secrete mediated by the PRRs, is an essential early cellular response to brain
anti-inflammatory cytokines and neurotrophic factors, including IL-4, injury (Giulian & Baker, 1985). For instance, TLR2 has a high affinity
IL-10, insulin-like growth factor-1 (IGF-1), and brain-derived neurotrophic for many pathogen-associated molecular patterns (PAMPs) (Drouin-
factor (BDNF) (Cherry, Olschowka, & O'Banion, 2014). Microglia are Ouellet & Cicchetti, 2012), whereas TLR4 can be triggered by
affected by cytokines such as IL-4 and IL-13, leading to suppressed pro- lipopolysaccharide and recognizes damage-associated molecular pat-
duction of the proinflammatory cytokines IL-1β, IL-6, and TNF-α, reduced terns (DAMPs)—endogenous molecules released by injured tissue
nitric oxide production, and enhanced tissue remodeling/repair (Colton, (Bianchi & Manfredi, 2009; Okun et al., 2012). As there is strong over-
2009). Importantly, microglia may not display a significant bias toward lap between the signaling pathways (Zhang et al., 2013), microglia
pro- or anti-inflammatory phenotypes. It is increasingly accepted that this may not be able to discriminate between invading pathogens, stress,
dichotomy is inadequate to describe microglia in vivo (Ransohoff, 2016). or aberrant endogenous molecular patterns (Mariani & Kielian, 2009).
Many studies have characterized microglia and their roles in dif- Overall, the activation of microglia through TLRs and their
ferent brain pathologies (Perry, Nicoll, & Holmes, 2010; Prinz, Priller, coreceptors initiates an immune response that is geared toward
Sisodia, & Ransohoff, 2011), where activated microglia demonstrate a protecting the brain (Fellner et al., 2013; Latz, Xiao, & Stutz, 2013).
BAR AND BARAK 3

F I G U R E 2 Alteration of microglial properties and molecular signaling in pathology. Upon pathological stimulation, microglia may change from a
ramified to amoeboid form, secrete anti- or proinflammatory factors, and phagocytose harmful debris (Tremblay, 2014). However, in disorders
involving myelination deficits, microglia may be compromised in their ability to phagocytose myelin debris and support OLs (Butovsky et al., 2006b;
Zhou et al., 2015). In other pathological conditions, microglia can be overactivated and secrete high levels of inflammatory factors and radicals (Ekdahl,
Kokaia, & Lindvall, 2009; Groh, Klein, Berve, West, & Martini, 2018; Kim, Hong, & Bae, 2018). This excess inflammation may eventually lead to
neurotoxicity and neuronal death. Microglia-related treatments that result in microglial regulation have been shown to be effective in ameliorating
deficits and promoting remyelination in pathological conditions (Butovsky et al., 2006a; Groh et al., 2018; Janova et al., 2018)

However, under certain circumstances (Fu, Shen, Xu, Luo, & Tang, matter, along with morphological abnormalities and altered neuronal
2014; Jones et al., 2015; Nair & Bonneau, 2006), microglia might be interactions in ASD subjects (Morgan et al., 2010). A study examining
exposed to nonphysiological levels of immune stimulators (Ekdahl the prefrontal cortex (PFC) in ASD subjects demonstrated a neuron-
et al., 2009; Yao et al., 2013), affecting their typical responses. directed microglial activation response in ASD (Morgan et al., 2012).
Impaired microglial activity at different stages of life can severely Microglial activation, which leads to neuroinflammation, was reported
impair plasticity-related processes and cognitive functions (Morris, in autistic children, with increased levels of oxidative stress mediators
Clark, Zinn, & Vissel, 2013). For instance, elevated microglial activa- and proinflammatory cytokines such as IL-6, TNF-α, and interferon-
tion has been shown in response to a range of psychosocial stressors gamma (IFN-γ) (Vargas et al., 2005). Increased protein levels of micro-
in early life, as well as in adulthood (Calcia et al., 2016), known to glial IL-6 were measured in the cerebellar cortex of subjects with ASD
increase the risk of mental illness mediated by microglial inflammatory (Wei et al., 2011), disrupting neuronal migration, an important process
activation (Frick, Williams, & Pittenger, 2013; Nair & Bonneau, 2006). in establishing proper brain wiring (Wei et al., 2011). Finally, using
transcriptome analysis, it was shown that genes related to microglial
activation are upregulated in autistic subjects (Gupta et al., 2014;
2.1 | Microglial polarization in autism spectrum
Voineagu et al., 2011).
disorder
Alterations in microglial activity, morphology, and gene expression
2.2 | Maternal immune activation and ASD
have been associated with neurodevelopmental disorders (Garey,
2010; Gupta et al., 2014; Tetreault et al., 2012) (Figure 3). This is logi- One of the proposed risk factors for ASD involves maternal immune
cal, given the crucial role played by microglia during development and activation (MIA) (Ponzio, Servatius, Beck, Marzouk, & Kreider, 2007;
adulthood in the elimination and maturation of synapses (Paolicelli Smith, Li, Garbett, Mirnics, & Patterson, 2007). A recent study
et al., 2011). Several studies have shown that children with autism modeled MIA by acute administration of lipopolysaccharide to E12
spectrum disorder (ASD) suffer from an ongoing neuroinflammatory mouse embryos and found significant elevation of IL-1β, TNF-α, and
process in different regions of the brain mediated by microglial activa- IL-6 in the fetal brain, suggesting long-term microglial activation
tion (Chez, Dowling, Patel, Khanna, & Kominsky, 2007; Vargas (O'Loughlin, Pakan, Yilmazer-Hanke, & McDermott, 2017). Another
et al., 2005). study modeled MIA by viral infection and similarly found alterations in
Indeed, microglial activation has been reported in multiple studies microglial activation, density, migration, and maturation properties in
focusing on ASD. For example, neuroimaging studies using positron- the rat offspring (Zhang, Jing, Zhang, Bilkey, & Liu, 2018). Interest-
emission tomography or magnetic resonance imaging (MRI) found ingly, both studies suggested prolonged microglial activation, as it was
putative inflammation in the brains of ASD subjects (Pardo, Vargas, & also evident postnatally. The potential link between MIA and micro-
Zimmerman, 2005; Suzuki et al., 2013; Vargas et al., 2005). Similarly, glial activation was also examined using a few novel treatments in
postmortem studies found increased density of microglia in the gray human and animal trials. Microglial inhibition using luteolin decreased
4 BAR AND BARAK

F I G U R E 3 Alteration of microglial properties and molecular signaling in neurodevelopmental disorders. Microglial alterations, such as
morphological abnormalities, altered microglial density and cell number (Morgan et al., 2010), high levels of inflammatory cytokines (Vargas,
Nascimbene, Krishnan, Zimmerman, & Pardo, 2005) and glutamate (Maezawa & Jin, 2010), compromised phagocytosis (Sekar et al., 2016), excess
synapses, and altered connectivity (Filipello et al., 2018; Sellgren et al., 2019), have been shown to occur in neurodevelopmental disorders.
Moreover, molecular alterations, such as upregulation of SHANK proteins and Psd95 in neurons (Kim et al., 2017), altered TREM2 expression
(Edmonson, Ziats, & Rennert, 2014; Filipello et al., 2018), and elevated levels of CX3CR1 and BDNF in microglia have been associated with ASD
(Edmonson et al., 2014; Ricci et al., 2013). Conversely, a reduction in microglial BDNF levels is seen in RTT (Katz, 2014), and a reduction in
myelin-related genes (CNP) has been measured in postmortem brains of schizophrenic and major depressive subjects (Aston, Jiang, & Sokolov,
2005; Peirce et al., 2006). Microglia-related treatments, such as inhibition of microglial activity, have been shown to be effective in ameliorating
deficits in neurodevelopmental disorders (Bertolino et al., 2017; Taliou, Zintzaras, Lykouras, & Francis, 2013)

their inflammatory effect, improved sociability in humans (Taliou et al., provide optimal levels of IL-1β, IFN-γ, and IL-6 to stimulate both neuro-
2013; Theoharides, Asadi, & Panagiotidou, 2012), and attenuated genesis and oligodendrogenesis (Shigemoto-Mogami et al., 2014; Wong,
autistic-like behaviors in mice (Bertolino et al., 2017). Interestingly, Stowell, & Majewska, 2017). Accordingly, inhibition of microglia with
gastrointestinal disturbances have also been suggested to influence minocycline decreased microglial activation, reduced proinflammatory
the severity of symptoms in children with ASD (Adams, Johansen, cytokine levels (i.e., IL-1β, IL-6, TNF-α, and IFN-γ), and subsequently sig-
Powell, Quig, & Rubin, 2011). Of relevance, a MIA-induced ASD nificantly inhibited neurogenesis and oligodendrogenesis in the SVZ
mouse model presented altered gut microbiota which was reversed after (Shigemoto-Mogami et al., 2014).
treatment with Bacteroides fragilis (Hsiao et al., 2013). The gut microbiota Overall, these findings suggest that microglial activation status
was suggested to reduce microglial secretion of proinflammatory cyto- affects the proliferation of SVZ neural progenitor cells (Matarredona,
kines in ASD (Kim et al., 2018), and specifically, microbiota-derived bac- Talaveron, & Pastor, 2018). Specifically, it was shown that IL-1β, IFN-
terial fermentation products were suggested to regulate microglial γ, and IGF-1 enhance neurogenesis, whereas only IL-1β and IL-6
homeostasis (Erny et al., 2015). Apart from their role in development, enhance oligodendrogenesis (Shigemoto-Mogami et al., 2014). There-
microglial actions play a crucial part in maintaining CNS homeostasis and fore, it can be concluded that the cytokines' roles and functions
synaptic plasticity (Napoli & Neumann, 2009) (Figure 4). depend on their context.

3 | M I C RO G L I A , N E U R O N , A N D O L 3.2 | Microglial fine sculpting of neuronal

CROSSTALK UNDER HOMEOSTATIC connections during development and in the
C O N D I T I O N S A ND I N S Y N A P T I C P L A S T I C I T Y mature CNS
Following their establishment in the CNS, microglia are highly mobile
3.1 | Microglia promote neurogenesis and
and primarily use an amoeboid morphology to regulate neural circuits
oligodendrogenesis
(Nayak, Roth, & McGavern, 2014). For example, most of the cerebellar
Neurogenesis and oligodendrogenesis in the CNS serve to maintain Purkinje cells that undergo developmental apoptosis are engulfed by
its function. In the rat subventricular zone (SVZ), from postnatal days amoeboid microglia, which release superoxide ions to trigger this pro-
1 through 10 (P1–P10), activated microglia are densely populated and cess (Marin-Teva et al., 2004).
BAR AND BARAK 5

F I G U R E 4 Microglial functions and molecular signaling in synaptic plasticity. Microglia regulate the molecular signaling that can affect
synaptic plasticity processes such as LTP and LTD (Arnoux & Audinat, 2015; Maggi et al., 2009; Rogers et al., 2011). Microglia can also mediate
the removal of impaired or inhibitory synapses from neurons (Arnoux & Audinat, 2015; Trapp et al., 2007), and however, induce spine formation
(Ji, Akgul, Wollmuth, & Tsirka, 2013). These modifications can alter neuron survival and activity, which may lead to altered neuronal network
activity and synchronicity

During brain development, neurons form an excess number of undergoing remodeling based on experience, resulting in synaptic
synaptic connections; many of these are subsequently removed dur- plasticity (Tremblay et al., 2010). Connectivity-refinement deficits
ing synapse sculpting (Figure 1), a critical process for appropriate brain may lead to the impairment of brain wiring as implicated in the etiol-
connectivity (Kettenmann, Kirchhoff, & Verkhratsky, 2013; Paolicelli ogy of several neurodevelopmental disorders (Sekar et al., 2016;
et al., 2011). Microglia are key regulators of synapse elimination dur- Thion, Ginhoux, & Garel, 2018; Zhan et al., 2014), including ASD
ing development via refinement of immature synapses (Schafer & (Filipello et al., 2018) and schizophrenia (McGlashan & Hoffman,
Stevens, 2013; Sierra, Abiega, Shahraz, & Neumann, 2013) (Figure 4). 2000) (Figure 3). A recent study utilized microglia-like cells through
Microglia were shown to engulf presynaptic (i.e., axonal terminals) and cellular reprogramming of monocytes from schizophrenia subjects
postsynaptic elements during developmental periods of circuit refine- (Sellgren et al., 2019). Excessive synaptic pruning was shown to occur
ment in the CNS (Bilimoria & Stevens, 2015; Paolicelli et al., 2011). in this subject-derived cellular model (Sellgren et al., 2019). Moreover,
Contradictory results showed no evidence of elimination of postsyn- synaptic elimination affects age-associated cognitive decline and the
aptic material, although microglial contact on dendritic spines was development of several neurodegenerative disorders (Kim & Joh,
suggested (Weinhard et al., 2018). Using in vivo two-photon imaging, 2006). Interestingly, synapse connectivity might also be affected by
it was suggested that the microglial contact on spines can increase the alterations in myelination (Schain, Hill, & Grutzendler, 2014). Similar
synchronization of neuronal populations by enhancing synaptic activ- to synaptic elimination, demyelination might disrupt the communica-
ity (Akiyoshi et al., 2018). Furthermore, it was shown in vitro that tion between neurons and has also been suggested to play a role in
adding microglia to neuronal cultures decreases synaptic activity, syn- neurodegenerative disorders (Nave & Ehrenreich, 2014; Trapp &
apse density, spine numbers, expression of AMPA receptor (GluA1), Nave, 2008).
and levels of synaptic adhesion molecules (Ji et al., 2013). These find-
ings demonstrate that “surveilling” microglia can modulate synaptic
3.3 | Microglia–OL crosstalk in myelination
activity by regulating the number of synapses.
In the adult brain, microglia remove synapses from damaged neu- Microglial interactions with OLs can affect OL functionality and mye-
rons (Cullheim & Thams, 2007; Trapp et al., 2007) and are also key lination properties. A recent study (Wlodarczyk et al., 2017) identified
regulators of neuronal and synapse function in the healthy brain a CD11c + microglial subset that predominates in primary myelinating
(Bilimoria & Stevens, 2015; Paolicelli & Ferretti, 2017) (Figure 1). Such areas of the developing brain, and expresses genes for neuronal and
remodeling of neuronal synapses occurs constantly throughout life glial survival, migration, and differentiation. In contrast to healthy
(Wu et al., 2015), with synaptic connections in many areas constantly adult and inflammation-activated cells, neonatal CD11c + microglia
6 BAR AND BARAK

show unique myelinogenic and neurogenic phenotypes (Wlodarczyk myelin debris clearance by microglia was demonstrated by blocking
et al., 2017). These cells are the major source of IGF-1 (Rodriguez- microglia-specific phagocytosis through inhibition of Rab7 (a key regu-
Perez, Borrajo, Diaz-Ruiz, Garrido-Gil, & Labandeira-Garcia, 2016), lator in endolysosomal trafficking (Kiral, Kohrs, Jin, & Hiesinger,
and its selective depletion from CD11c + microglia leads to impair- 2018)). This manipulation resulted in enhanced accumulation of mye-
ment of primary myelination (Wlodarczyk et al., 2017). Interestingly, lin fragments in microglial endosomes and prevented remyelination
microglia produce and secrete IGF-1 to support the survival of layer V (Safaiyan et al., 2016), emphasizing the microglia's key role in synaptic
cortical neurons during postnatal development (Ueno et al., 2013), yet plasticity.
OLs do this as well (Wilkins, Chandran, & Compston, 2001). There-
fore, microglia could be contributing to cell survival indirectly by
3.5 | Microglia and myelin-associated proteins
supporting oligodendrogenesis or through an additive effect on
OL-derived GFs. Early studies using microglia and OL cocultures showed that microglia
Evidence of the microglia's role in oligodendrogenesis can be stimulate the expression of myelin basic protein (Mbp) and proteolipid
found in rodents with acute or chronic experimental autoimmune protein (Plp) in OLs, suggesting a positive role for microglia in mye-
encephalomyelitis (EAE)—an experimental model of brain inflamma- lination (Hamilton & Rome, 1994).
tion and multiple sclerosis (MS). Injection of IL-4-activated microglia A recent study showed that in a Plp1-mutant mouse model for
into the cerebrospinal fluid of rodents with EAE resulted in increased progressive MS, targeting microglia by oral administration of colony
oligodendrogenesis in the spinal cord and improved clinical symptoms stimulating factor-1 receptor (CSF-1R) inhibitor substantially reduced
(Butovsky, Landa, et al., 2006a). The newly formed OLs were spatially inflammation-related demyelination, axonopathic alterations, and neu-
associated with microglia expressing major histocompatibility complex ronal degeneration (Groh et al., 2018).
class II proteins and IGF-1 (Butovsky, Landa, et al., 2006a). Treatment 20 ,30 -Cyclic-nucleotide 30 -phosphodiesterase (CNP) is another
with IGF-1 was also suggested to restore spine density and synaptic myelin-associated gene whose mRNA levels are significantly reduced
amplitude, increase Psd95-expression levels, and stabilize cortical in postmortem brains of schizophrenic and major depressive subjects
plasticity in a mouse model for Rett syndrome (RTT) (Tropea et al., (Aston et al., 2005; Flynn et al., 2003; Peirce et al., 2006). Moreover, a
2009). Moreover, a reduced number of IGF-1-expressing microglia significant decrease in CNP protein levels has been shown in postmor-
was implicated in a mouse model of Tourette syndrome and was tem brains of schizophrenic patients (Flynn et al., 2003).
suggested to mediate neuronal loss, although such a reduction was In humans and mice, reduced expression of CNP is associated with
not shown in human subjects (Frick & Pittenger, 2016). Thus, benefi- catatonic signs in an age-dependent manner (Hagemeyer et al., 2012).
cial consequences of microglia on the pathological conditions in which Depletion of microglia in Cnp-deficient mice prevented catatonia
myelin is impaired, being mediated by GF secretion, should be consid- onset in young and mature mice (Janova et al., 2018). These findings,
ered as a possible therapeutic approach (Hagemeyer et al., 2012). from postmortem tissues and the mouse model, revealed microglia
and low-grade inflammation of myelinated tracts as the triggers for
3.4 | Roles of microglia and myelination in synaptic this previously unexplained mental condition (Janova et al., 2018).
plasticity Thus, specific microglia-targeting anti-inflammatory therapies might
help in treating other disorders associated with catatonia, such as
Aside from the well-known myelin-related neurological disorders, such
mood-induced psychotic disorders and malignant neuroleptic syn-
as MS (Trapp & Nave, 2008) and central pontine myelinolysis (Lampl &
drome (Tandon et al., 2013).
Yazdi, 2002), myelin deficits resulting from altered glia–neuron interac-
tions are associated with altered neuronal plasticity and cognitive
impairments (McKenzie et al., 2014; Nave & Ehrenreich, 2014). 4 | MICROGLIAL ALTERATIONS IN
Microglia secrete cytokines and GFs and eliminate synapses in WI L LI A M S SY N DR OM E A N D N E U R OL OGI CA L
part by monitoring synaptic transmission (Wake, Moorhouse, CONDITIONS
Miyamoto, & Nabekura, 2013; Ziv et al., 2006); as such, they play a
key role in neuronal connection properties, in accordance with neuro- We recently showed multifaceted myelin deficits in Williams syndrome
nal function (Schafer et al., 2012). OLs greatly increase the speed of (WS) subjects and a mouse model for WS (Barak et al., accepted to
electrical transmission through nerve axons by forming the axonal Nature Neuroscience, in press; Barak, B. et al., 2019), a genetic neu-
myelin sheath and clustering ion channels at the nodes of Ranvier, rodevelopmental disorder that affects social behavior and fine motor
where action potentials are propagated (10.1038/nature09614, skills (Barak & Feng, 2016). These myelination-related deficits, a result
2010). Myelination is finely and locally modified to orchestrate the of Gtf2i deletion in forebrain excitatory neurons, are mediated by abnor-
timing of action potentials that may require both high and low con- mal neuron–glia interactions and are ameliorated following administra-
duction velocities (Waxman, 1997). Microglia are also involved in tion of FDA-approved drugs such as 4-aminopyridine and clemastine.
myelin debris clearance in normal aging (Shobin et al., 2017) and in We also measured a significantly increased number of microglia
disease conditions, as shown in cuprizone-induced demyelination (Iba1-positive cells) in the mutant mouse cortex (data not published),
models (Poliani et al., 2015; Skripuletz et al., 2010). The importance of where we characterized myelination deficits. This opens an exciting
BAR AND BARAK 7

research avenue that connects the interplay between myelination and (Sekar et al., 2016). The C4A variant is significantly upregulated in
microglial abnormalities to other neurodevelopmental disorders, as postmortem tissue of schizophrenic subjects (Gandal et al., 2018). The
increased microglial density has also been shown in ASD (Morgan et al., frequency of C4B variant deficiency is significantly higher in ASD sub-
2010), schizophrenia (Garey, 2010), and WS (Wilder, Hanson, Lew, Bel- jects compared to controls (Odell et al., 2005), and the mRNA levels
lugi, & Semendeferi, 2018) (Figure 3). of C1q, C3, and C4 are significantly decreased in the PFC of ASD sub-
Moreover, activated microglia-mediated brain inflammation has jects (Fagan, Crider, Ahmed, & Pillai, 2017). Overall, these alterations
been observed in attention deficit hyperactivity disorder (Anand, Colpo, might affect the microglia's ability to recognize and engulf defective
Zeni, Zeni, & Teixeira, 2017) and Tourette syndrome (Lennington et al., synapses.
2016), whereas impaired synapse refinement has been seen in schizo- Further studies are needed on the C3 on C4 risk variants and
phrenia (Sekar et al., 2016), and significant microgliosis has been other complement system components, to reveal how they shape
observed in subjects with depression who committed suicide (Steiner behaviors relevant to psychiatric disorders. A transgenic animal model
et al., 2008). that conditionally overexpresses C3 or C4 in the CNS has yet to be
examined. Such a transgenic model would enable studying whether
overtagging of synapses for microglial engulfment can enhance synap-
5 | CO NS EQ UENCES OF ALTERED
tic elimination, shedding light on neuropsychiatric disorders with
MICROGLIAL ACTIVITY ON COGNITION AND
altered connectivity.
S Y N A P TI C P L A S T I CI T Y I N T H E C N S

5.1 | Microglia and the complement system in 5.3 | Autophagy and the functional role of TREM2–
synaptic plasticity DAP12 in development and ASD
The complement system is an evolutionarily conserved branch of the Triggering receptor expressed on myeloid cells 2 (TREM2) and its
innate immune system. The mammalian complement family consists adapter protein DAP12 are expressed exclusively by microglia in the
of more than 30 soluble and cell-associated factors. These factors are CNS (Bechade, Cantaut-Belarif, & Bessis, 2013; Chertoff, Shrivastava,
engaged in a cascade that converges in the cleavage of C3 to release Gonzalez, Acarin, & Gimenez-Llort, 2013). TREM2 interacts with
the anaphylactic peptide C3a and the opsonin C3b, followed by DAP12 and stimulates microglial migration, cytoskeletal reorganiza-
downstream events (Zipfel & Skerka, 2009). Several studies have tion, and increased phagocytosis associated with secretion/reduction
suggested that microglia participate in synapse elimination through a of cytokines, depending on the ligand to which the complex binds
phagocytic engulfment mechanism involving complement receptor (endogenous or exogenous) (Takahashi, Rochford, & Neumann, 2005).
3 (CR3) (Fu et al., 2012; Ramaglia et al., 2012; Schafer et al., 2012). TREM2 signaling has a variable impact in different brain regions,
CRs bind to the complement fragments C3b and C4b—hub molecules depending on their myelin content, their level of TREM2 expression,
of the complement-activation cascade—and regulate clearance of and the presence of alternative TREM2 ligands (Mecca, Giambanco,
immune complexes and cell debris (Groves, Dart, Covarelli, & Caron, Donato, & Arcuri, 2018; Poliani et al., 2015). In Trem2−/− mice, micro-
2008; Khera & Das, 2009). CRs are also involved in activity- glial reduction was significant in the hippocampus, accompanied by
dependent synapse sculpting, where key proteins of the complement defective synapse elimination (Filipello et al., 2018). In the cuprizone
cascade, namely C1q and C3, were implicated in tagging “weaker” model, which mainly affects the corpus callosum, TREM2 was
synapses that are normally pruned (Stevens et al., 2007). required for microglial response to prolonged demyelination, removal
Microglia-mediated synaptic elimination depends on neuronal of damaged myelin sheaths, and secretion of trophic factors that sup-
activity, as microglia preferentially phagocytose less active presynap- port differentiation of OL precursor cells (OPCs) (Poliani et al., 2015).
tic inputs (Stevens et al., 2007). C1q- and C3-mutant mice have excess Consistent with these findings, in an EAE mouse model, blocking
synaptic connections in the mouse retinogeniculate system, a com- TREM2 function resulted in the accumulation of myelin debris that
monly studied area in research on developmental synaptic elimination continuously recruited non-engulfing microglia (Piccio et al., 2007).
(Stevens et al., 2007). This complement-dependent synaptic sculpting Dap12-deficient microglia in embryos resulted in upregulation of
is significantly downregulated in the mature visual thalamus, immune gene expression, and downregulated expression of genes
suggesting a highly regulated process that is likely restricted to the involved in nervous system development and function (Pont-Lezica
refinement stages of development (Schafer et al., 2012; Xavier, et al., 2014). This included neurite development and function, demon-
Menezes, Goldman, & Nedergaard, 2014). strating a key role for microglia in corpus callosum development.
Interestingly, defective synaptic refinement and dysfunctional
microglia are associated with ASD (Kim et al., 2017; Tang et al., 2014;
5.2 | Microglial CR3 and CR4 in neuropsychiatric
Wang et al., 2017).
disorders
Findings from postmortem brains of subjects with idiopathic ASD
C4 promotes C3 activation, allowing the latter to covalently attach to displayed a significant reduction in TREM2 compared to healthy sub-
its targets and promote their engulfment by phagocytic cells (Fu et al., jects (Filipello et al., 2018). This was particularly evident in 5- to
2012). C4 deficiency compromises synaptic elimination in mice 23-year-old subjects, an age range that represents the developmental
8 BAR AND BARAK

period coinciding with synapse refinement in humans (Stiles & showed decreased functional brain connectivity and weak synaptic
Jernigan, 2010). Trem2−/− mice show increased expression of synaptic transmission, leading to deficits in social interactions and increased
proteins such as Psd95 and Shank2, an increased number of dendritic repetitive behavior (Paolicelli et al., 2011; Zhan et al., 2014), traits
spines, increased functional connectivity between multiple brain linked to ASD in humans (Barak & Feng, 2016). In juvenile Cx3cr1-
regions, and increased miniature excitatory postsynaptic currents deficient mice, this behavior was correlated with the observed tran-
(mEPSCs) (Filipello et al., 2018). sient circuit-sculpting deficits (Zhan et al., 2014).
These changes in Trem2−/− mice suggest circuit hyperexcitability Fractalkine is also involved in synaptic plasticity processes. For
and reduced long-range functional connectivity, converging in the instance, fractalkine expression is upregulated in the hippocampus
observed altered sociability and repetitive behaviors that parallel during memory-associated synaptic plasticity (Sheridan & Murphy,
those of human ASD symptoms (Filipello et al., 2018). Interestingly, an 2013). Yet, in Cx3cr1-deficient mice, reduced long-term potentiation
autistic-like behavior was observed in mice lacking the Atg7 gene, a (LTP) was recorded (Rogers et al., 2011), whereas another study
key component in autophagy, in cells of the myeloid lineage, including showed increased LTP (Maggi et al., 2011). Moreover, deletion or
microglia (Kim et al., 2017). This was accompanied by significantly reduction of Cx3cr1 also led to elevated levels of the inflammatory
higher levels of Psd95 and Shank3 proteins and a significant elevation cytokine IL-1β, which triggered a reduction of LTP in the brain
in the number of dendritic spines, attributed to an impairment in syn- (Wu et al., 2015). Ventricular infusion of an IL-1β receptor antagonist
apse elimination by microglia (Kim et al., 2017). for 4 weeks reversed this reduction (Rogers et al., 2011), whereas
SHANK proteins encode a family of postsynaptic scaffolding pro- infusion of an inactivated antagonist did not (Rogers et al., 2011).
teins present at glutamatergic synapses in the CNS (Amal et al., 2018; Therefore, intact chemokine signaling between neurons and microglia
Barak & Feng, 2016; Bozdagi et al., 2010; Monteiro & Feng, 2017; and appropriate levels of CNS cytokines are crucial for the mainte-
Peca et al., 2011; Zhou et al., 2016). Impairments in microglia's ability nance of normal plasticity mechanisms.
to sculpt synapses by phagocytic function could potentially lead to
abnormal expression of SHANK proteins in the synapses, perturbing
6 | R O L E S OF M I C R O G L I A L CY T O K I N E S
neurodevelopment. Interestingly, conflicting results showed a signifi-
A ND B D NF I N SY N A P T I C P L A ST I CI T Y A N D
cant increase in TREM2, DAP12, and CX3CR1 gene expression in the
COGNITION
PFC of idiopathic ASD subjects (Edmonson et al., 2014).
Together, these findings suggest that the TREM2–DAP12 axis is
6.1 | BDNF in synaptic plasticity
essential for CNS homeostasis (Neumann & Takahashi, 2007) and may
be fundamental in regulating microglial phagocytic function during BDNF is one of the most important neurotrophins secreted by neu-
their lifespan. rons and glial cells, contributing to many aspects of CNS function,
including cell differentiation, normal developmental apoptosis, brain
connectivity, neuronal survival and migration, dendritic arborization,
5.4 | Role of microglial fractalkine receptor in
synaptogenesis, and activity-dependent forms of synaptic plasticity
synaptic plasticity and ASD
(Coull et al., 2005; Teng et al., 2005; Wu et al., 2015). Specifically,
CX3CR1 is a Gi-protein-coupled receptor that is encoded by the microglial BDNF can be released to directly affect the structure and
Cx3cr1 gene and is expressed mostly by microglia in the brain function of nearby synapses (Parkhurst et al., 2013). Uncleaved pro-
(Cardona et al., 2006). However, its ligand, CX3CL1, also known as BDNF expression levels at early postnatal stages (<4 weeks) are high,
fractalkine, is largely expressed in neurons (Tarozzo et al., 2003) and is leading to neuronal death and the removal of unnecessary neurons
considered an OFF signal, keeping microglia in a nonactivated state (Deinhardt & Chao, 2014). Pro-BDNF selectively activates its high-
(Biber, Neumann, Inoue, & Boddeke, 2007; Cardona et al., 2006). affinity receptor, the neurotrophin receptor p75 (p75NTR), leading
CX3CL1–CX3CR1 signaling represents a substantial communication mainly to the induction of proapoptotic signaling pathways and has
channel between neurons and microglia, mediating fundamental been shown to facilitate LTD in the mouse hippocampus (Rosch,
microglial functions (Limatola & Ransohoff, 2014; Paolicelli, Bisht, & Schweigreiter, Bonhoeffer, Barde, & Korte, 2005; Woo et al., 2005).
Tremblay, 2014) (Figures 1 and 4). In adult mice, mature BDNF is the prominent isoform (Greenberg,
Cx3cr1-deficient mice at different stages of development (P8, Xu, Lu, & Hempstead, 2009), and secretion of mature BDNF by
P15, and P28) presented a transient decrease in the density of micro- microglia increases phosphorylation of neuronal tropomyosin kinase
glial cells, which were compromised in their capacity to engulf synap- receptor type B (TrkB) (Parkhurst et al., 2013), a key mediator of syn-
tic material (Paolicelli et al., 2011). In addition, a transient increase in aptic plasticity. Mature BDNF binds to its highly specific receptor
dendritic spine density and a higher density of Psd95 were measured TrkB, increasing neuronal survival, and facilitating LTP (Deinhardt &
in microglial processes in the mouse hippocampus (Paolicelli et al., Chao, 2014) (Figure 4). These actions are determined via interactions
2011). These alterations led to immature connectivity, augmented between the two transmembrane receptors, separately or together,
long-term depression (LTD), and impaired functionality of the excit- determining cell fate. Indeed, in human studies, polymorphism in the
atory synaptic network during postnatal development in the hippo- BDNF gene has been associated with variations in hippocampal vol-
campus (Arnoux & Audinat, 2015). Both juvenile and adult mice ume (Pezawas et al., 2004), memory performance (Egan et al., 2003),
BAR AND BARAK 9

and susceptibility to plasticity-inducing brain-stimulation protocols Moriuchi, Nag, Mellot, & Berger-Sweeney, 2010). Moreover, impaired
(Cheeran et al., 2008). phagocytosis of apoptotic cell debris along with a toxic increase in
The importance of BDNF secretion by microglia was also demon- glutamate release by microglia has been suggested in the RTT mouse
strated in a study (Parkhurst et al., 2013) showing that depletion of model (Derecki et al., 2012; Maezawa & Jin, 2010). In contrast, BDNF
microglia leads to impaired activity of AMPA and NMDA receptors. was found to be elevated in subjects with ASD (Ricci et al., 2013),
This suggests a role for microglia in regulating the level of synaptic although conflicting results showed an association between reduced
proteins that are associated with the glutamatergic excitatory synapse BDNF release from neurons and ASD (Sadakata et al., 2012).
function. Moreover, microglial depletion led to severe deficits in multi- Taken together, these findings underscore the importance of
ple learning tasks and motor learning-induced synaptic remodeling microglial BDNF as an essential regulator of learning-induced synaptic
(Parkhurst et al., 2013). Similar effects were discovered in genetically formation, functional connectivity, myelination, and behavioral perfor-
depleted microglial BDNF (Parkhurst et al., 2013). Elevated levels of mance (Barrientos et al., 2003; Chen, Dowlatshahi, MacQueen,
the proinflammatory cytokine IL-1β (experimentally or induced by Wang, & Young, 2001; McTigue et al., 1998) and suggest that BDNF
social isolation) were shown to decrease BDNF mRNA levels following may have significant potential in therapeutic approaches.
learning, inhibit LTP in several regions of the hippocampus in young
animals, and impair performance in behavioral paradigms such as the
Morris water maze (Morris, 1984) and contextual fear conditioning
7 | C O N C L U D I N G R E M A R K S A ND F U T U R E
(Barrientos et al., 2003), commonly used to examine hippocampus-
PERSPECTI V ES
dependent memory (Yirmiya & Goshen, 2011). Importantly, adminis-
Microglia are sensors of the CNS and playing a crucial role in health
tration of IL-1 receptor antagonist before the social-isolation period
and in pathological conditions (Napoli & Neumann, 2009) (Figures 1
prevented both BDNF downregulation and memory impairments
and 2). Numerous studies have implicated microglia in supporting neu-
produced by the isolation (Barrientos et al., 2003).
rons (Ueno et al., 2013), OLs and remyelination (Miron, 2017),
highlighting these cells as an important therapeutic target. Equipped
6.2 | BDNF involvement in myelination and with PRRs, CRs, GFs, and cytokines, microglia take part in many pro-
neurodevelopmental disorders cesses occurring in the CNS, with their response fitting the specific

BDNF was shown to affect growth in neurons by stimulating axonal conditions encountered (Olson & Miller, 2004; Stevens et al., 2007;

sprouting toward a wound edge (Batchelor et al., 2002). Deficiency of Ueno et al., 2013). In this review, we summarize microglial functions

BDNF can lead to a reduced number of neuron/glial antigen 2-positive in synaptic plasticity processes and neurological disorders, with special

OPCs and decreased expression of MBP and PLP in the CNS emphasis on ASD. However, this is just the tip of the iceberg. During

(Vondran, Clinton-Luke, Honeywell, & Dreyfus, 2010). In subjects with development and throughout life, microglia promote myelination
MS lesions, BDNF is primarily present in immune cells, such as (Wlodarczyk et al., 2017), sculpt neural circuits (Yirmiya & Goshen,
microglia and reactive astrocytes (Stadelmann et al., 2002). The number 2011), and help shape proper connectivity by remodeling based on
of BDNF-immunopositive cells correlates with lesion demyelinating experience, resulting in synaptic plasticity (Paolicelli et al., 2014)
activity. In an EAE mouse model, administration of 18β-glycyrrhetinic (Figures 1 and 4). Impairments in microglial components can have
acid (GRA) significantly reduced disease severity, mediated by a regula- major consequences for the CNS, such as effects on circuit connectiv-
tory effect on microglia (Zhou et al., 2015). In addition, GRA treatment ity, homeostasis, immunological response, debris clearance, and
promoted remyelination by reducing inflammation that might inhibit remyelination (Kim et al., 2017; Lampron et al., 2015; Streit, Braak,
BDNF expression in microglia and enhancing OPC proliferation (Zhou Xue, & Bechmann, 2009). Impaired microglial activity at different
et al., 2015). stages of life can severely impair plasticity processes and cognitive
Furthermore, following CNS injury, BDNF becomes a potent functions, as seen in a variety of disorders, such as ASD (Suzuki et al.,
extrinsic regulator of OPC differentiation and OL survival by positively 2013), Alzheimer's disease (Wendt et al., 2017), MS (Zrzavy et al.,
modulating promyelinating transcription factors such as Olig2 and 2017), and schizophrenia (Fillman et al., 2013).
promoting expression of PLP (Ramos-Cejudo et al., 2015). BDNF in
the injured spinal cord induced the formation of new OLs and pro-
7.1 | Which comes first? Microglial alterations
moted upregulation of MBP protein levels and prompt behavior
or ASD?
recovery (Ikeda et al., 2002; McTigue, Horner, Stokes, & Gage, 1998).
BDNF might also play a role in RTT and ASD (Katz, 2014; Ricci The microglia's contribution to primary damage in neurodevelopmental
et al., 2013), disorders with several intriguing differences, as well as disorders is still not fully understood. In this review, we mention a few
similarities (Castro, Mellios, & Sur, 2013; Fombonne, 2009). There is microglial alterations that are suggested to occur in ASD: MIA, increased
evidence for immune system dysregulation early in life and altered secretion of inflammatory cytokines (Vargas et al., 2005; Wei et al.,
myelination in both conditions (Ameis & Catani, 2015; Nguyen et al., 2011), increased density (Morgan et al., 2010), and increased expression
2013; Ricci et al., 2013). Decreased levels of BDNF have been impli- of microglial activation-related genes (Gupta et al., 2014). However,
cated in RTT in both humans and mice (Katz, 2014; Schaevitz, these abnormalities might act as secondary effects. Some of the factors
10 BAR AND BARAK

supporting this are: (i) the above-cited studies measured activity and Meitar Grad, Gilad Levy, Sari Trangle, and Ariel Nir, for their help and
density using markers that are not specific to microglial cells (Vargas support.
et al., 2005; Wei et al., 2011). For example, infiltrating macrophages can
also be detected using those markers and are also able to secrete the
OR CID
detected cytokines (Arango Duque & Descoteaux, 2014); (ii) cytokines
from the peripheral immune system have already been suggested to be Boaz Barak https://orcid.org/0000-0001-9724-4578
involved in ASD (Masi et al., 2017); and (iii) studies examining MIA
reported no obvious changes in microglial activation (Garay, Hsiao,
RE FE RE NCE S
Patterson, & McAllister, 2013; Giovanoli, Weber-Stadlbauer, Schedlowski,
Meyer, & Engler, 2016). Adams, J. B., Johansen, L. J., Powell, L. D., Quig, D., & Rubin, R. A. (2011).
Gastrointestinal flora and gastrointestinal status in children with
Nevertheless, malfunctioning microglia have the potential to cause
autism--comparisons to typical children and correlation with autism
damage, such as connectivity problems and impaired myelination,
severity. BMC Gastroenterology, 11, 22. https://doi.org/10.1186/
which might result in behavioral changes (Akiyoshi et al., 2018; 1471-230X-11-22
Bennett & Barres, 2017). As already noted, a reduction in TREM2 pro- Akiyoshi, R., Wake, H., Kato, D., Horiuchi, H., Ono, R., Ikegami, A., …
tein was observed in postmortem brains of autistic subjects (Filipello Nabekura, J. (2018). Microglia enhance synapse activity to promote
local network synchronization. eNeuro, 5. https://doi.org/10.1523/
et al., 2018), and increased connectivity was detected in Trem2−/−
ENEURO.0088-18.2018
mice (Filipello et al., 2018). Conversely, another study showed ele- Aloisi, F. (2001). Immune function of microglia. Glia, 36, 165–179.
vated TREM2 gene expression in postmortem brains of autistic sub- Amal, H., Barak, B., Bhat, V., Gong, G., Joughin, B. A., Wang, X., …
jects (Edmonson et al., 2014). Tannenbaum, S. R. (2018). Shank3 mutation in a mouse model of
autism leads to changes in the S-nitroso-proteome and affects key
Therefore, it is important to further investigate both transcription
proteins involved in vesicle release and synaptic function. Molecular
and translation levels, to get a better perspective on the source of the Psychiatry. https://doi.org/10.1038/s41380-018-0113-6
problem: to better define the microglia's role in ASD, or in any disor- Ameis, S. H., & Catani, M. (2015). Altered white matter connectivity as a
der for that manner, microglial-specific genes should be detected and neural substrate for social impairment in autism spectrum disorder.
Cortex, 62, 158–181. https://doi.org/10.1016/j.cortex.2014.10.014
recognized as risk factors. Interestingly, a recent study identified a
Anand, D., Colpo, G. D., Zeni, G., Zeni, C. P., & Teixeira, A. L. (2017). Atten-
rare variant of the microglia-specific CX3CR1 gene and suggested its tion-deficit/hyperactivity disorder and inflammation: What does cur-
role in some pathophysiological mechanisms of ASD and schizophre- rent knowledge tell us? A systematic review. Frontiers in Psychiatry, 8,
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Arango Duque, G., & Descoteaux, A. (2014). Macrophage cytokines:
populations (Wlodarczyk et al., 2017), specific genes (Bennett et al.,
Involvement in immunity and infectious diseases. Frontiers in Immunol-
2016), and proteins (Satoh et al., 2016). Use of advanced trans- ogy, 5, 491. https://doi.org/10.3389/fimmu.2014.00491
criptomic and proteomic techniques will help distinguish microglia Arnoux, I., & Audinat, E. (2015). Fractalkine signaling and microglia func-
from peripheral immune cells and might give a clearer picture of their tions in the developing brain. Neural Plasticity, 689404. https://doi.
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Aston, C., Jiang, L., & Sokolov, B. P. (2005). Transcriptional profiling reveals
on sorting subpopulations, manipulating genetic microglial aspects, evidence for signaling and oligodendroglial abnormalities in the tempo-
and examining whether this might lead to behavioral defects. ral cortex from patients with major depressive disorder. Molecular Psy-
Evidence has emerged showing that microglia do not consist of chiatry, 10, 309–322. https://doi.org/10.1038/sj.mp.4001565
one identical population. Using a variety of methods, such as single- Barak, B., et al. (2019). Neuronal deletion of Gtf2i, associated with Wil-
liams syndrome, causes behavioral and myelin alterations rescuable by
cell RNA-Seq, fractal analysis, and mass cytometry (Karperien,
a remyelinating drug. Nature Neuroscience, https://doi.org/10.1038/
Ahammer, & Jelinek, 2013; Keren-Shaul et al., 2017; Mrdjen et al., s41593-019-0380-9
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better defined, emphasizing the importance of the microglia's location in autism and Williams syndrome. Nature Neuroscience, 19, 647–655.
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produce local trophic gradients that stimulate axonal sprouting toward
The authors gratefully acknowledge Mr. Tobias Kaiser for insightful but not beyond the wound edge. Molecular and Cellular Neurosciences,
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BAR AND BARAK 11

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18beta-glycyrrhetinic acid suppresses experimental autoimmune

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