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Page 24 Benusa et al. Neuroimmunol Neuroinflammation 2020;7:23-39 I http://dx.doi.org/10.20517/2347-8659.2019.28

the peripheral blood-derived monocytes/macrophages that reside outside the CNS and mediate the
[4,5]
peripheral inflammatory response . Peripheral blood-derived immune cells are not typically found in
the healthy CNS. However, peripheral monocytes/macrophages can infiltrate the CNS and exacerbate the
neuroinflammatory response under pathological conditions. The distinct developmental origin of microglia
from peripheral monocyte-derived macrophages and the exclusion of peripheral immune cells from the
CNS underscores the immunological privilege of the CNS and the unique functions microglia might exert
[6]
in the healthy brain and in pathological processes .
Microglia are cells with highly dynamic process networks that rapidly remodel to survey the
[7-9]
microenvironment and maintain tissue homeostasis . The surveying processes of microglia respond to
CNS perturbations through rapid protrusion onto the site of insult/interest [7,10] and microglia undergo
“activation”, a complex series of alterations including changes in enzyme, receptor, and immune factor
expression and altered cellular morphology [3,11,12] . Microglia exhibit a variety of morphologies ranging from
small cell bodies with long highly-branched processes to enlarged cell bodies with short, thick processes [3,13] .
The spectrum of microglial morphologies is indicative of their activation state and is commonly used
to characterize activated vs. non-activated microglia in histological samples. Surveying (non-activated)
microglia exhibit long, highly-branched or “ramified” processes that sample the surrounding environment.
However, upon activation, microglia retract their processes and increase their cell body size, exhibiting
morphologies defined by short, thick processes and large somas [3,14] . Highly activated, phagocytic microglia
tend to lose distinctive processes all together and exhibit an ameboid shape [3,14] .

Many studies have investigated microglial-neuronal interactions via secreted factors. Activated microglia
[15]
exhibit extensive changes in the expression of their inflammatory profile . While some of these secreted
factors may provide neurotrophic functions, pro-inflammatory factors exhibit deleterious effects [16,17] .
Various neurotrophic secreted factors released from microglia induce neurite outgrowth and have been
shown to be involved in regulating the cytoarchitecture of the developing brain [18-20] . Pro-inflammatory
microglia, however, up-regulate cytokines and enzymes that produce reactive oxygen species, which have
been implicated in axonal injury and disruption [16,21-32] .

Microglia also interact with neurons through physical contact under homeostatic conditions [7,9,11,33-36] .
Microglia have recently been shown to contact dendrites and neuronal cell bodies in the normal adult
brain [37,38] . Both contact types require purinergic signaling through the P2Y12 receptor and appear to be
protective in nature [37-40] . In the developing somatosensory cortex, it was recently found that microglial
process contacts onto dendrites precipitates filipodia formation, linking microglia process contacts with
[38]
synaptic formation . Microglia are also key mediators of synaptic pruning, which alters the neuronal
[41]
excitatory/inhibitory balance . Microglia contact pre- and postsynaptic neuronal elements in an activity-
dependent manner, and synapses that are contacted by microglia more frequently and for longer durations
of time are subsequently removed [Figure 1A] [9,42,43] . Specifically, studies have demonstrated that early
during development (Postnatal Day 5 in mice) phagocytic microglia engulf synapses of neurons with
reduced activity/input in a complement-dependent manor [42,43] . Alternatively, later during development
(Postnatal Day 15 in mice) microglia only appear to remove parts of synapses in a process called
[44]
“trogocytosis” . Another study using zebrafish larva demonstrated that microglial-synaptic contacts
increased with increased neuronal spontaneous activity. Further, the zebrafish neurons that were contacted
by microglia exhibited a decrease in activity, while noncontacted neurons maintained an increased firing
[36]
rate .
Microglia may also influence neuronal excitability through contact with the axon initial segment (AIS), the
[45]
axonal domain responsible for action potential initiation and modulation [Figure 1A] . Microglia appear
to establish contact with the AIS early in development and maintain this contact through adulthood,