Review
Microglia: actively surveying and shaping neuronal circuit structure and function

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The traditional role of microglia has been in brain infection and disease, phagocytosing debris and secreting factors to modify disease progression. Recent evidence extends their role to healthy brain homeostasis, including the regulation of cell death, synapse elimination, neurogenesis, and neuronal surveillance. These actions contribute to the maturation and plasticity of neural circuits that ultimately shape behavior. Here we review microglial contributions to the development, plasticity, and maintenance of neural circuits with a focus on interactions with synapses. We introduce this topic by reviewing recent studies on the migration and proliferation of microglia within the brain, and conclude with the proposal that microglia dysfunction may adversely affect brain function, and thereby contribute to the development of psychiatric and neurological disorders.

Introduction

Microglia were first characterized by Pio del Rio-Hortega in the 1920s and 1930s, who described their distinct morphological phenotypes [1]. Many subsequent studies have focused on microglia and their roles in different brain pathologies 2, 3, where a marked transformation of microglia takes place from a ramified to an amoeboid morphology, associated with the secretion of neuroactive compounds, the expression of various cell-surface receptors, proliferation, and phagocytosis. This has resulted in the traditional view that microglial function is largely associated with disease, but with the implication that microglial involvement in any pathology is secondary to disease formation and progression. Indeed, the observed phenotypic changes have led to a concept of dormant ramified or ‘resting’ microglia in the healthy adult brain, and that only amoeboid or ‘activated’ microglia influence brain function and pathology. However, this is clearly not entirely true, and recent studies indicate that both ‘resting’ and ‘activated’ microglia (as defined by this morphological phenotype) have physiological functions even in the absence of pathologies. Consequently the concept of resting and activated is misleading because multiple phenotypic stages of microglia can influence neuronal structure and function. In this review we highlight recent findings that have advanced our understanding of microglia in normal central nervous system (CNS) homeostasis, and suggest that microglia function to maintain neural circuits. We further speculate that dysfunction of this normal homeostatic role may contribute to disease.

Section snippets

Immigrants to the CNS take up long-term residence

The embryonic origins of microglia have been hotly debated over the past several decades [4]. The genetic and immunohistochemical fingerprint of microglia strongly supports the consensus that they are not derived from the same embryonic lineage (neuroectoderm) as neurons and astrocytes, but instead share the same mesodermal origin as macrophages and other hematopoietic cells 5, 6, 7, 8. For example, mice deficient in PU.1, a transcription factor which controls the differentiation of myeloid

Source of microglial expansion in disease

An increase in the number of microglia occurs in response to brain injuries. Such reactive microgliosis is a feature of both acute injury and chronic or recurring neuronal diseases, including infections, facial nerve axotomy, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and stroke 1, 19, 21. The increased microglial population stems from a variable mix of infiltration of circulating monocytes, proliferation of the resident population, and/or from

Developmental programmed cell death

Following their establishment in the CNS, microglia regulate neuronal circuit development. Programmed cell death (PCD) is an integral part of the refinements that take place during CNS development [26]. Amoeboid microglia have long been known to phagocytose the apoptotic neurons associated with PCD 10, 27, 28, but the role of microglia extends beyond simply cleaning up the debris. In developing vertebrate spinal cord, cerebellum, and hippocampus, microglia play a more active role in that they

Interactions between microglia and synapses in neural circuit formation and maintenance

The discussion above has focused on the role of microglia in regulating neuronal numbers during development and in the adult CNS. Neurons also need to be correctly wired up in neuronal circuits to mediate brain functions. This occurs during development in an activity-dependent fashion as excessive synapses are eliminated or pruned, while key functional synapses are strengthened 47, 48. Incorrect wiring of synapses and altered synapse morphology can be associated with developmental disorders

Immune/complement molecules and microglia–synapse interactions

Studies on the molecular mechanisms mediating these tight interactions between microglia and synapses have demonstrated some homologies with the peripheral immune system. Proteins of the major histocompatibility complex class I (MHC-1) and complement cascade (C1q and C3) are expressed in various neurons in an activity-dependent fashion 73, 74. A classic model of developmental synaptic pruning is the segregation of projections from retinal ganglion cells (RGCs) of each eye into the appropriate

Microglia and psychiatric disorders

The neurotoxic or neuroprotective roles of microglia in neurodegenerative diseases have been well documented (e.g., 1, 78). Microglia also play an important role in shaping synapses and neuronal circuits during development and neurogenesis, and survey the resting adult brain, as described above (Figure 3). If these microglial functions are disrupted, one can predict that this will result in dysfunction of the brain and in the emergence of psychiatric and neurological disorders (Figure 3).

Concluding remarks

In this review we have highlighted recent observations regarding the CNS migration and proliferation of microglia, and the subsequent physiological roles that these resident microglia mediate. In addition to their neuronal immune function in reacting to infections and clearing debris by phagocytosis, both resting and challenged microglia play an active role in neuronal circuit homeostasis. They contribute to PCD and synapse elimination during maturation of neuronal circuits and in response to

Note added in proof

A recent paper by Li et al. [96] confirmed and extended in zebrafish larvae the characterisation of resting microglia-neuron contacts that has been described previously in mouse brain [65]. Microglial processes made frequent brief (5–6 mins) contacts with neuronal somata in the optic tectum of the larvae. Orientated movement towards neurons was activity-dependent and subsequent contacts were associated with an enlargment of the microglia process end into a bulbous tip. Both these steps were

Acknowledgments

We gratefully acknowledge Wai T. Wong, R. Douglas Fields, and Olena Bukalo for critical reading of the manuscript. This work was supported by a Japan Society for the Promotion of Science fellowship (to H.W.) and the Japan Science and Technology Agency for Core Research for Evolutional Science and Technology (to J.N.).

References (96)

  • J.L. Marin-Teva

    Microglia promote the death of developing Purkinje cells

    Neuron

    (2004)
  • H. Wei

    Alteration of brain volume in IL-6 overexpressing mice related to autism

    Int. J. Dev. Neurosci.

    (2012)
  • E. Gould et al.

    Neuronal birth and death

    Curr. Opin. Neurobiol.

    (1993)
  • A. Sierra

    Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis

    Cell Stem Cell

    (2010)
  • S.H. Choi

    Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation

    Neuron

    (2008)
  • K. Inokuchi

    Adult neurogenesis and modulation of neural circuit function

    Curr. Opin. Neurobiol.

    (2011)
  • J.W. Lichtman et al.

    Synapse elimination and indelible memory

    Neuron

    (2000)
  • L.B. Moran et al.

    The facial nerve axotomy model

    Brain Res. Brain Res. Rev.

    (2004)
  • J. Yamada

    Differential involvement of perineuronal astrocytes and microglia in synaptic stripping after hypoglossal axotomy

    Neuroscience

    (2011)
  • X. Li

    MEK is a key regulator of gliogenesis in the developing brain

    Neuron

    (2012)
  • W. Denk et al.

    Photon upmanship: why multiphoton imaging is more than a gimmick

    Neuron

    (1997)
  • G. Feng

    Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP

    Neuron

    (2000)
  • D.P. Schafer

    Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner

    Neuron

    (2012)
  • R.A. Corriveau

    Regulation of class I MHC gene expression in the developing and mature CNS by neural activity

    Neuron

    (1998)
  • B. Stevens

    The classical complement cascade mediates CNS synapse elimination

    Cell

    (2007)
  • S. Cullheim et al.

    The microglial networks of the brain and their role in neuronal network plasticity after lesion

    Brain Res. Rev.

    (2007)
  • I.B. Van den Veyver et al.

    Methyl-CpG-binding protein 2 mutations in Rett syndrome

    Curr. Opin. Genet. Dev.

    (2000)
  • S.K. Chen

    Hematopoietic origin of pathological grooming in Hoxb8 mutant mice

    Cell

    (2010)
  • T. Dierks

    Activation of Heschl's gyrus during auditory hallucinations

    Neuron

    (1999)
  • Y. Li

    Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo

    Dev. Cell

    (2012)
  • H. Kettenmann

    Physiology of microglia

    Physiol. Rev.

    (2011)
  • V.H. Perry

    Microglia in neurodegenerative disease

    Nat. Rev. Neurol.

    (2010)
  • M. Prinz

    Heterogeneity of CNS myeloid cells and their roles in neurodegeneration

    Nat. Neurosci.

    (2011)
  • C. Kaur

    Origin of microglia

    Microsc. Res. Tech.

    (2001)
  • U.K. Hanisch

    Microglia as a source and target of cytokines

    Glia

    (2002)
  • M. Prinz et al.

    Microglia in the CNS: immigrants from another world

    Glia

    (2011)
  • D.R. Beers

    Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis

    Proc. Natl. Acad. Sci. U.S.A.

    (2006)
  • F. Ginhoux

    Fate mapping analysis reveals that adult microglia derive from primitive macrophages

    Science

    (2010)
  • E. Gomez Perdiguero

    Development and homeostasis of ‘resident’ myeloid cells: the case of the microglia

    Glia

    (2013)
  • C. Schulz

    A lineage of myeloid cells independent of Myb and hematopoietic stem cells

    Science (New York, N.Y.)

    (2012)
  • B. Ajami

    Local self-renewal can sustain CNS microglia maintenance and function throughout adult life

    Nat. Neurosci.

    (2007)
  • M. Zusso

    Regulation of postnatal forebrain amoeboid microglial cell proliferation and development by the transcription factor runx1

    J. Neurosci.

    (2012)
  • A. Rappert

    CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion

    J. Neurosci.

    (2004)
  • I. Bechmann

    Circulating monocytic cells infiltrate layers of anterograde axonal degeneration where they transform into microglia

    FASEB J.

    (2005)
  • B. Ajami

    Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool

    Nat. Neurosci.

    (2011)
  • C.M. Hulette

    Microglioma, a histiocytic neoplasm of the central nervous system

    Mod. Pathol.

    (1996)
  • J.L. Marin-Teva

    Naturally occurring cell death and migration of microglial precursors in the quail retina during normal development

    J. Comp. Neurol.

    (1999)
  • S. Rakic et al.

    Programmed cell death in the developing human telencephalon

    Eur. J. Neurosci.

    (2000)
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    *

    Current address: Division of Brain Circuits, National Institute for Basic Biology, Okazaki, Japan.

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