Communicative & Integrative Biology 4:2, 220-222; March/April 2011; ©2011 Landes Bioscience

A role for microglia in synaptic plasticity?

Marie-Ève Tremblay* and Ania K. Majewska
Department of Neurobiology and Anatomy and Center for Visual Science; University of Rochester; Rochester, NY USA

R emodeling of brain circuits, includ-

ing the formation, modification and
elimination of synaptic structures, occurs
degradation, but also activation of ECM
proteins by unmasking functional epit-
opes.7 In particular, matrix metalloprote-
throughout life as animals adapt to their ase (MMP)-9 has been associated in vitro
environment. Until very recently, known with dendritic spine growth and synaptic
mechanisms for experience-dependent strength increase,8,9 and tissue-plasmino-
synaptic plasticity had placed neurons gen activator (tPA) has been associated in
and their structural interactions with vitro with synaptic plasticity10 and in vivo
astrocytes in the spotlight. However with dendritic spine motility and elimina-

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microglia, the immune cells of the brain, tion, as well as ocular-dominance plastic-
are very active even in the absence of ity.11-13 However, the cellular sources of
pathological insults and their processes MMP-9 and tPA during functional plas-
periodically contact dendritic spines and ticity, as well as their ability to achieve the
axon terminals in vivo.1-3 This intriguing spatial and temporal specificity crucial for

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electron microscopy and two-photon
in vivo imaging in the primary visual
cortex of juvenile mice, a possible role
synaptic plasticity in the face of fast pro-
tease diffusion have remained obscure.
Our recent study showed that microglial
processes can target very specific locations
for quiescent microglia in the modifica- and modify the extracellular space geome-
tion of synaptic structures.4 Our work try locally (Fig. 1A), directly or indirectly,
uncovered subtle changes in the behav- solely by their presence within the neuro-
ior of microglia during manipulations of pil.4 As a consequence, this extracellular
visual experience including regulation of remodeling could enable compartmen-
perisynaptic extracellular spaces, contact talization of proteases, ions, cytokines,
with subsets of structurally dynamic and neuromodulators and other molecules
Key words: microglia, synaptic transient dendritic spines, and phago- secreted by microglia or other cell types
plasticity, dendritic spine, visual cortex, cytic engulfment of intact synapses. nearby particular synapses. With our
critical period, development, mouse, Based on these results, here we further other observations that most microglial
electron microscopy, three-dimensional discuss three means of synapse modi- processes directly contact synaptic struc-
reconstruction, two-photon in vivo fication or elimination that could be tures4 while being extremely motile,1-4 this
imaging mediated by microglia in the context of suggests that quiescent microglia could
normal experience-dependent plasticity. regulate the dynamics of plasticity at indi-
Submitted: 12/08/10 vidual synapses as they explore the local
Accepted: 12/16/10 Proteolytic Modification environment to pursue immune surveil-
DOI: 10.4161/cib.4.2.14506 of the Perisynaptic Environment lance roles.
*Correspondence to: Marie-Ève Tremblay;
Modifications of extracellular matrix Remodeling of Dendritic Spine
Email: [email protected]
(ECM) composition have emerged as Morphology
key determinants of synaptic structural
Addendum to: Marie-Ève Tremblay, Rebecca L.
Lowery, Ania K. Majewska. Microglial interac- plasticity.5,6 Important ECM modi- Emerging evidence suggests that signal-
tions with synapses are modulated by visual fiers include extracellular proteases, ing pathways linking synaptic activity to
experience. PLoS Biology 2010; 8:1000527; PMID: either secreted by neurons, astrocytes or changes in dendritic spine morphology
21072242; DOI: 10.1371/journal.pbio.1000527 microglia, that mediate inactivation or locally influence the actin cytoskeleton.

220 Communicative & Integrative Biology Volume 4 Issue 2

 article addendum

Figure 1. Possible means of synapse modification or elimination by quiescent microglia. In (A), a synapse between an axon terminal (blue) and a
dendritic spine (pink) is simultaneously contacted by an astrocytic (green) and microglial (taupe) process. Note the astrocytic and microglial contacts
with the synaptic cleft (arrowheads) and the pocket of microglia-associated extracellular space (asterisk), which suggests microglial remodeling of the
extracellular environment in the vicinity of synapses. Surrounding elements of neuropil are shown in grey. (B) Microglial process displaying end-feet
morphological specializations. Here, these end-feet contact a dendritic spine (end-foot 1) and an axon terminal (end-foot 2), at two different synapses.
Such direct cell-cell interaction between microglia and synaptic elements could contribute to local remodeling of the actin cytoskeleton during epi-
sodes of plasticity. (C) Engulfment by a microglial process of an intact synapse between an axon terminal and a dendritic spine suggesting microglial
phagocytosis of synaptic elements during experience-dependent plasticity.

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These changes are not limited to forma-
tion and elimination of dendritic spines
but also include their subtle morphologi-
cal remodeling in terms of size, shape and
perisynaptic astrocytic processes,4 sug-
gesting direct communication between
quiescent microglia and synapses through
trans-endocytic exchange of various
physical separation of pre- and post-synap-
tic elements in pathological conditions,24,25
a recent EM with three-dimensional (3D)
reconstruction study failed to show any

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motility. The actin cytoskeleton addition-
ally plays an important role in maintain-
ing synaptic structures by facilitating the
trafficking of synaptic cargos, regrouping
membranous or cytoplasmic molecules.
Taken together, these findings dictate that
cell-cell interactions involving extremely
motile microglial processes must be taken
evidence of synaptic stripping in a mouse
model of neurodegeneration.26 Whether
synaptic stripping is linked to the elimina-
tion or degeneration of synaptic elements,
the translation machinery, organizing into account when considering the mecha- and is an initial stage of phagocytosis or
the postsynaptic density and anchoring nisms of rapid dendritic spine remodeling an advanced form of synaptic ensheath-
postsynaptic receptors to the membrane14 during experience-driven plasticity. ment also remains unknown. In this con-
suggesting that structural remodeling text, while we have shown direct contacts
is tightly linked to synapse function.15 Phagocytic Engulfment between microglia and axon terminals,
Regulation of the actin cytoskeleton can of Dendritic Spines dendritic spines, as well as synaptic clefts,
be initiated by molecular interactions and Axon Terminals with both immunocytochemical EM and
between dendritic spines and the ECM serial section EM with 3D reconstruction,
or by coordinated interactions between Although phagocytic engulfment is in line which could suggest synaptic stripping, we
dendritic spines and dynamic astrocytic with the macrophagic nature of microglia, never saw instances of microglial processes
processes which also promote the stabili- their participation in synapse elimination penetrating into the cleft to separate pre-
zation of dendritic protrusions and their during early postnatal development and and post-synaptic elements.4 However,
subsequent maturation into dendritic neurodegenerative disease has remained cellular inclusions resembling dendritic
spines in vitro.16,17 Using high spatial controversial.19,20 Recent studies have spines, axon terminals or entire synapses
resolution electron microscopy (EM), we demonstrated the involvement of the com- between dendritic spines and axon termi-
have observed that microglial processes plement cascade in developmental prun- nals, were frequently encountered inside
directly contact synaptic elements, either ing21,22 but whether microglia are the cell microglial cell bodies and their processes,
extensively or focally (Fig. 1B; see Fig. 4C type performing the elimination of com- especially during adaptation to a new
in the original paper for an example of plement-tagged axon terminals remains to visual environment when plastic changes
microglial process displaying an end-feet be confirmed.23 While EM observations of are prominent. We also reported microg-
specialization where it contacts an axon microglial processes intervening between lial processes with phagocytic structures4
terminal4). Clathrin-coated pits reminis- axon terminals and neuronal cells bodies using two-photon in vivo imaging after
cent of spinules18 were also observed with or proximal dendrites have long ago sug- visual manipulations. These observa-
EM, at sites of contact between microglia gested microglial elimination of synapses tions add to the evidence that microg-
and dendritic spines, axon terminals or by “synaptic stripping,” defined as the lia may phagocytose synaptic elements,

www.landesbioscience.com Communicative & Integrative Biology 221

 13. Muller CM, Griesinger CB. Tissue plasminogen acti-
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(FRSQ) postdoctoral training award.

222 Communicative & Integrative Biology Volume 4 Issue 2