ReviewMicroglia function during brain development: New insights from animal models
Introduction
Microglia are the resident immune cells in the brain and much mystery surrounds their function. Despite being described by Rio Hortega over a hundred years ago, these cells did not receive any notice in studies of healthy brain development or function until the past decade. Much of our knowledge about microglia has been in the context of injury and disease. Long viewed as the brain’s defenders against biological threats and injury, these chameleon-like cells transform from a resting to ‘activated’, macrophage-like state when challenged. Following injury or disease, microglia are rapidly recruited to sites of damage where they engulf, or phagocytose, debris as well as unwanted and dying cells. Although critical for the immune response to infection or trauma, microglia also contribute to pathological neuroinflammation by releasing cytokines and neurotoxic proteins (Perry et al., 2010, Ransohoff and Perry, 2009).
The potential role of inflammation and microglial activation in neurodevelopmental and psychiatric disorders has been speculated for some time (Pardo et al., 2005). Postmortem studies suggest that microglial cell density and/or the number of ‘activated’ microglia may be increased in the brains of individuals with autism, including in regions important for regulating executive functions such as the dorsolateral prefrontal cortex (Morgan et al., 2010, Tetreault et al., 2012, Vargas et al., 2005). Schizophrenia postmortem studies have similar findings, also suggestive of increased microglial cell density and/or activation; further, PET imaging reveals signs of microglial activation in the brains of living individuals with recent-onset schizophrenia (Frick et al., 2013, Monji et al., 2009, van Berckel et al., 2008). Yet these and other intriguing observations in the human brain have remained poorly understood because it is not known whether microglia are mediators of the disease process in these conditions, or simply responders to neuronal dysfunction or both. Put another way, do microglia play an active role in the developmental processes that go awry in autism or schizophrenia, or is their increased activation a byproduct of the pathology? As with any other observation of cells in a pathology sample, the first point of inquiry is determining what these cells do under healthy conditions. Recent studies using animal models have provided key insight.
Significant strides were made in 2005 when pioneering in vivo imaging studies revealed that microglial processes are highly dynamic in the cortices of healthy adult mice—so active, even, that it’s estimated they may be able to survey the entire brain parenchyma in 1 h (Davalos et al., 2005, Nimmerjahn et al., 2005). Since these reports, a new line of research examining microglial roles in healthy CNS development has emerged.
It was long thought that microglia derive from peripheral macrophages that enter the brain after birth. In 2010, a landmark fate mapping study challenged this dogma by showing that microglia develop from myeloid progenitors in the yolk sac and make a pilgrimage into the brain very early in embryonic development (Ginhoux et al., 2010). The realization that microglia develop alongside neurons during this critical period of brain development has led to a sea change of thinking about microglia in the healthy brain. New data implicate microglia in many functions required to build and wire the developing CNS, ranging from neurogenesis to synaptic pruning. Here we review some of these key discoveries and highlight the models and emerging tools being used to probe microglia function and signaling in the healthy brain (Table 1, Table 2).
Section snippets
Patterning the developing CNS
Microglia have long been recognized as ׳professional׳ phagocytes that rapidly eliminate dead or dying cells and associated debris during CNS disease or injury. They are also known to signal to other CNS cells through a broad range of secreted factors—several that trigger apoptosis, such as tumor necrosis factor alpha (TNFα), reactive oxygen species and glutamate, some that promote survival or proliferation, and others that either promote or fight inflammation (Bessis et al., 2007, Harry, 2013,
Wiring the developing CNS
Just as the overarching cellular landscape of the nervous system is sculpted by programmed cell death (PCD), extranumerary synapses and axon branches are sculpted by the process of synapse elimination or pruning (Kano and Hashimoto, 2009, Lichtman and Colman, 2000; Katz and Shatz, 1996; Stretavan and Shatz 1984 ). Accumulating evidence implicate microglia in regulating synapse numbers, as well as synaptic function and maturation. The field of microglia–synapse interactions has blossomed and
Regulating circuits in the mature CNS
Emerging evidence suggests that microglia also play a key role in regulating neural circuits in the mature CNS. While different from the dramatic waves of apoptosis that occur sequentially across brain regions during development, the process of PCD does to some extent continue on in mature animals. A key example is related to the adult neurogenesis that occurs in the hippocampus, in the subgranular zone of the dentate gyrus. While some of the newborn neurons are incorporated into circuits, many
Effects on behavior
The growing awareness of microglial functions at the cellular, molecular and synaptic levels in healthy brains have led to new studies on the impact of these cells at the behavioral level, and also cast new light on observations of microglial abnormalities in a variety of brain disorders.
Neuropathology studies of autopsy samples in autism and schizophrenia have for some time indicated that these disorders have neurodevelopmental origins. There may be defects in cell and synapse number
Summary and conclusions
In the past decade a number of studies have investigated the role of microglial cells in healthy CNS development and function, in the rodent brain. These studies reveal that microglia are crucial for the patterning and wiring of the CNS. They can play both responder and mediator roles in the process of programmed cell death—serving as phagocytes that clear away dead cells, yet also having the capacity to actively promote death via secreted signals. During the process of circuit development,
Acknowledgments
We gratefully acknowledge the support of the International Rett Syndrome Foundation, the Simons Foundation Autism Research Initiative, and the National Institute of Neurological Disorders and Stroke (NIH RO1NS071008). We also thank Dorothy Schafer for providing guidance on the organization of this review and permission to reprint Figure 1.
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