Trends in Neurosciences
ReviewMicroglia: actively surveying and shaping neuronal circuit structure and function
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.).
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Current address: Division of Brain Circuits, National Institute for Basic Biology, Okazaki, Japan.