Review
Little cells of the little brain: microglia in cerebellar development and function

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Highlights

  • Microglia, the innate immune cells of the CNS, directly shape and influence neural development and function.

  • Much of our knowledge of microglia–neuron interactions derives from the study of cortical or hippocampal microglia, which may not fully represent other microglial populations. Microglia in the cerebellum represent an extreme case of regional specification and differ from microglia residing in the cortex and hippocampus phenotypically and functionally.

  • Cerebellar microglia show distinctive functional dynamics compared with other microglial populations studied to date, and their properties may stem from their gene expression profiles, which are enriched for immune pathways.

  • Microglia play cerebellum-specific roles in development, phagocytosing apoptotic Purkinje cells and facilitating the development of the cerebellar circuit.

  • The developmental roles of cerebellar microglia, such as pronounced phagocytic activity, likely influence their distinctive adult phenotype; however, the cerebellar environment in adulthood may also play a role in maintaining microglial characteristics.

Microglia are long-lived resident macrophages of the brain with diverse roles that span development, adulthood, and aging. Once thought to be a relatively homogeneous population, there is a growing recognition that microglia are highly specialized to suit their specific brain region. Cerebellar microglia represent an example of such specialization, exhibiting a dynamical, transcriptional, and immunological profile that differs from that of other microglial populations. Here we review the evidence that cerebellar microglia shape the cerebellar environment and are in turn shaped by it. We examine the roles microglia play in cerebellar function, development, and aging. The emerging findings on cerebellar microglia may also provide insights into disease processes involving cerebellar dysfunction.

Section snippets

Cerebellar microglia in the light of microglial heterogeneity

Microglia, the innate immune cells of the CNS, directly shape and influence neural development and function. Classically studied for their roles in pathology, it is becoming increasingly clear that even under homeostatic conditions, microglia are not quiescent sentinels but actively survey and patrol the CNS and are able to respond rapidly to chemotactic cues [1,2]. As they do so, they make frequent transient contacts with neural elements [3], eliminate synapses [4,5], and influence the

Cerebellar microglia show unique functional dynamics

As mentioned, microglial dynamics have thus far been studied largely in the context of cortical microglia. Cortical microglia are highly ramified and regularly tile the neocortex, maintaining nonoverlapping territories. In vivo and brain slice time-lapse imaging experiments have shown that the cell bodies of these microglia are fairly stationary, while a very motile process arbor samples the defined territory of each cell. These microglia also rapidly respond to injury. For instance, following

Microglia are essential to cerebellar development

Microglia are integral to the developing nervous system and have been shown to influence synaptic remodeling in diverse regions such as the developing lateral geniculate nucleus (LGN) [4,5], primary visual [3,7,29] and somatosensory [6,70] cortices, and the hippocampus [14,15,71]. In these areas, microglia interact with synapses to restructure synaptic inputs, often in an activity-/experience-dependent manner that has been linked to their ability to phagocytose or trogocytose synaptic material [

Concluding remarks and future directions

Mounting evidence suggests that cerebellar microglia are distinct from other microglial cell populations, as demonstrated by their differential morphology, distribution, and dynamics [29]. These characteristics arise from altered transcriptomics, epigenetics, and signaling pathways within cerebellar microglia and cerebellum-specific environmental cues [11,19,20,66]. Many of these differences may have their origins in cerebellar development, where microglia clear entire apoptotic neuronal cell

Acknowledgments

This work was supported by National Institutes of Health (NIH) grants R01 NS114480, AA02711 (A.K.M.), and F31NS120609 (M.B.S.), as well as by grants from the Schmitt Program in Integrative Neuroscience and Harry T. Mangurian Jr. Foundation.

Declaration of interests

The authors declare no competing interests in relation to this work.

Glossary

Climbing fiber (CF)
a projection fiber from the inferior olivary nucleus to cerebellar Purkinje cells, thought to encode sensory information. Each Purkinje cell is innervated by a single climbing fiber, although this single fiber makes thousands of synapses onto the Purkinje cell dendritic arbor. The CF is one of the two excitatory inputs to Purkinje cells.
Disease-associated microglia (DAM)
a transcriptomic signature defined as suites of differentially expressed genes in microglia during disease

References (136)

  • K. Ashwell

    Microglia and cell death in the developing mouse cerebellum

    Dev. Brain Res.

    (1990)
  • L.J. Lawson

    Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain

    Neuroscience

    (1990)
  • U.B. Eyo

    P2Y12R-dependent translocation mechanisms gate the changing microglial landscape

    Cell Rep.

    (2018)
  • C. Jakubzick

    Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes

    Immunity

    (2013)
  • S. Krasemann

    The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases

    Immunity

    (2017)
  • E.J. Davis

    Cellular forms and functions of brain microglia

    Brain Res. Bull.

    (1994)
  • E.L. Wong

    Developmental alcohol exposure impairs synaptic plasticity without overtly altering microglial function in mouse visual cortex

    Brain Behav. Immun.

    (2018)
  • R.M. Ritzel

    Age- and location-related changes in microglial function

    Neurobiol. Aging

    (2015)
  • A.D. Hart

    Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences

    Brain Behav. Immun.

    (2012)
  • D. Gosselin

    Environment drives selection and function of enhancers controlling tissue-specific macrophage identities

    Cell

    (2014)
  • M. Datta

    Histone deacetylases 1 and 2 regulate microglia function during development, homeostasis, and neurodegeneration in a context-dependent manner

    Immunity

    (2018)
  • H. Keren-Shaul

    A unique microglia type associated with restricting development of Alzheimer’s disease

    Cell

    (2017)
  • F. De Santa

    The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing

    Cell

    (2007)
  • S. Nandi

    The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation

    Dev. Biol.

    (2012)
  • M.R.P. Elmore

    Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain

    Neuron

    (2014)
  • M. Greter

    Stroma-derived interleukin-34 controls the development and maintenance of Langerhans cells and the maintenance of microglia

    Immunity

    (2012)
  • T.R. Hammond

    Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes

    Immunity

    (2019)
  • J.L. Marín-Teva

    Microglia promote the death of developing Purkinje cells

    Neuron

    (2004)
  • A. Sierra

    Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis

    Cell Stem Cell

    (2010)
  • J.L. Wallace

    Development and refinement of functional properties of adult-born neurons

    Neuron

    (2017)
  • K. Hashimoto

    Translocation of a ‘winner’ climbing fiber to the Purkinje cell dendrite and subsequent elimination of ‘losers’ from the soma in developing cerebellum

    Neuron

    (2009)
  • H. Nakayama

    GABAergic inhibition regulates developmental synapse elimination in the cerebellum

    Neuron

    (2012)
  • L. Cheadle

    Sensory experience engages microglia to shape neural connectivity through a non-phagocytic mechanism

    Neuron

    (2020)
  • G. Ohtsuki

    SK2 channel modulation contributes to compartment-specific dendritic plasticity in cerebellar Purkinje cells

    Neuron

    (2012)
  • C.R. Goodlett

    A single day of alcohol exposure during the brain growth spurt induces brain-weight restriction and cerebellar Purkinje-cell loss

    Alcohol

    (1990)
  • N.C. Andreasen et al.

    The role of the cerebellum in schizophrenia

    Biol. Psychiatry

    (2008)
  • A. Nimmerjahn

    Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo

    Science

    (2005)
  • D. Davalos

    ATP mediates rapid microglial response to local brain injury in vivo

    Nat. Neurosci.

    (2005)
  • M.Ě. Tremblay

    Microglial interactions with synapses are modulated by visual experience

    PLoS Biol.

    (2010)
  • A. Miyamoto

    Microglia contact induces synapse formation in developing somatosensory cortex

    Nat. Commun.

    (2016)
  • G.O. Sipe

    Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex

    Nat. Commun.

    (2016)
  • R.D. Stowell

    Noradrenergic signaling in wakeful states inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex

    Nat. Neurosci.

    (2019)
  • M. Hoshiko

    Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex

    J. Neurosci.

    (2012)
  • Paolicelli, R.C. et al. (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 33,...
  • Y. Zhan

    Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior

    Nat. Neurosci.

    (2014)
  • Ginhoux, F. et al. (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science...
  • K. Kierdorf

    Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways

    Nat. Neurosci.

    (2013)
  • O. Matcovitch-Natan

    Microglia development follows a stepwise program to regulate brain homeostasis

    Science

    (2016)
  • P. Ayata

    Epigenetic regulation of brain region-specific microglia clearance activity

    Nat. Neurosci.

    (2018)
  • K. Grabert

    Microglial brain region-dependent diversity and selective regional sensitivities to aging

    Nat. Neurosci.

    (2016)
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