Glia as Architects of Central Nervous System

 

Science  12 Oct 2018: Vol. 362, Issue 6411, pp. 181-185

Glia as architects of central nervous system formation and function

Nicola J. Allen, et.al.

Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

Centre for Discovery Brain Sciences, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK.

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Glia constitute roughly half of the cells of the central nervous system (CNS) but were long-considered to be static bystanders to its formation and function. Here we provide an overview of how the diverse and dynamic functions of glial cells orchestrate essentially all aspects of nervous system formation and function.    Radial glia, astrocytes, oligodendrocyte progenitor cells, oligodendrocytes, and microglia each influence nervous system development, from neuronal birth, migration, axon specification, and growth through circuit assembly and synaptogenesis. As neural circuits mature, distinct glia fulfill key roles in synaptic communication, plasticity, homeostasis, and network-level activity through dynamic monitoring and alteration of CNS structure and function. Continued elucidation of glial cell biology, and the dynamic interactions of neurons and glia, will enrich our understanding of nervous system formation, health, and function.

Here we provide an overview of insights that are now addressing the question posed by Ramon y Cajal in 1909, “What is the function of glia?” We focus on the function of glia of the vertebrate CNS:    radial glia, astrocytes, oligodendrocyte progenitor cells (OPCs, also called NG2 cells), oligodendrocytes, and microglia. For example, we now know that radial glia are CNS progenitors that generate the majority of our neurons and glia, either directly or via intermediate progenitors. Astrocytes, star-shaped cells with thousands of processes that interact with likely all cell types of the CNS, exhibit a range of functions that help drive nervous system development and sculpt its activity. OPCs are the most proliferative cells in the CNS,    generate myelinating oligodendrocytes throughout life, and likely serve additional yet-to-be-identified roles in circuit formation and function. Mature oligodendrocytes generate myelin sheaths that speed up nerve impulse conduction and provide metabolic support to axons, and it now appears that dynamic regulation of myelination may regulate the precise timing of information propagation and communication across functional circuits. Finally, microglia are the guests of the CNS, best known as the brain’s resident macrophages, but with increasingly evident roles during multiple stages of nervous system development and activity.

One of the most quoted “facts” about glia is that they outnumber neurons by 10 to 1 in the human brain, but it is now clear that we have a roughly equal proportion of neurons and glia. The relative proportions vary by region (e.g., gray matter versus white matter), developmental stage, and species, but as a very general rule, human brains are composed of 20% astrocytes,    3 to 10% OPCs,    25% oligodendrocytes,    and 5 to 15% microglia. We have known of neuronal diversity for more than 100 years, and it is now emerging that glia also exhibit important functional diversity, likely to be driven by both intrinsic programs based on developmental origins and extrinsic interactions with their environment. In this review, we take a chronological perspective that aims to chart how glia first drive neurogenesis    and subsequently regulate neuronal migration,    axon growth,    synapse formation,    and, ultimately, circuit function. We focus on the role of glia and their reciprocal interactions with neurons in regulating healthy nervous system formation and function and refer interested readers to other excellent sources on the development of glia and the myriad roles of glia in disease.

Glia are the principle regulators of cell number in the CNS

During embryonic development, neuroepithelial progenitors take on characteristics of astrocytes, including the expression of factors such as glutamate transporters, glycogen granules, and intermediate filaments. These neuroeiptheial cell–derived “radial glia” go on to generate neurons during embryonic stages of mammalian development and then switch to generating mature glia, which they do either directly by generating proliferating astrocytes or through generation of intermediate progenitors, such as OPCs.

Glia influence neuronal migration, axon specification, and growth

Following their birth, neurons in the CNS migrate, either radially through the neuroepithelium—for example, establishing specific cortical layers—or tangentially, as exemplified by interneuron migration from the ganglionic eminences to the cortex. The role of glia in regulating tangential migration has not been intensively studied, although microglia have been implicated. By contrast, it is well known that radial glia support radial migration of neurons, and the underlying mechanisms have been extensively investigated.

In addition, microglia, astrocytes, and OPCs have been shown to subsequently help guide axons to their destinations, and analogous roles for glia in axon specification and guidance have also been identified.

Glia can coordinate circuit-wide neuronal differentiation

Our understanding of the mechanisms that coordinate neuronal differentiation across circuits is rudimentary, but it is now clear that glial cells can coordinate the timing of axon-driven target neuron differentiation. In the Drosophila visual system, photoreceptor neurons first secrete a signal to their associated wrapping glia (analogous to myelinating glia), which then secrete cues that induce target neuron differentiation. This indirect signaling via glia introduces a delay that controls the timely differentiation of target neurons, because the wrapping glia arrive at specific target locations with a delay relative to axons. The mechanisms that might coordinate differentiation of neurons distributed across local and long-range circuits in vertebrates are unclear. However, given that invertebrate models have served as mechanistic pathfinders for many aspects of vertebrate neural development, the prospective role of glia in regulating circuit-level neuron differentiation warrants further investigation.

Glia regulate synapse formation and pruning

After neurogenesis,    neuronal migration,    and axon guidance are complete, prospective partner neurons begin to make synaptic connections.    Synaptogenesis involves a series of formation,    strengthening,    and remodeling steps, with glia playing distinct roles at each stage. The timing of initial synaptogenesis coincides with the generation of astrocytes, putting them in the right place at the right time.

Toward the end of the synaptogenic period,    weak and inappropriate synapses    are eliminated    by astrocytes and microglia, ultimately leaving neurons with their adult connectivity.

Glia in regulating CNS function

Once neuronal circuits are assembled, glia regulate numerous aspects of nervous system function. They do so by affecting synaptic function,    ion homeostasis,    and metabolism.

Glia adjust synaptic communication and plasticity

Glia regulate many aspects of synaptic function.    Astrocytes regulate neurotransmitter uptake, for example, via glutamate transporters, which is dynamically regulated;    glutamate transporters on astrocyte processes are up-regulated by high activity    and down-regulated during prolonged periods of low activity,    providing a way to modulate the concentration of transmitter available at synapses

Glial regulation of ion homeostasis affects circuit function

Glia can affect neuronal excitability by regulating ion homeostasis, for example, by clearing potassium (K+) ions from the extracellular space, which facilitates neuronal membrane repolarization after an action potential and thus continued firing.

Neuro-glial-vascular coupling provides metabolic support

Interactions between the vasculature and cells of the CNS are increasingly implicated in brain health. CNS blood vessels have specialized barrier properties, known as the blood-brain barrier, which limit movement of substances, including nutrients, between the blood and the brain. However, astrocytes are ideally positioned to actively supply neurons with nutrients because they extend processes that contact both blood vessels and neurons.

Astrocytes dynamically alter brain states

There is now compelling evidence of glial involvement in dynamic regulation of circuit-level function. For example, networks of astrocytes in the mouse visual cortex can be activated by the neuromodulator norepinephrine in line with dynamic changes in the arousal state of the animal. This increased astrocyte activity can in turn enhance the ability of astrocytes to detect altered neuronal activity. The regulation of circuit function via astrocytes has also been demonstrated in Drosophila, where octopaminergic neurons signal through astrocytes to control downstream neurons and behavior.

Myelination dynamically alters circuit function

Myelination of axons by oligodendrocytes has long been known to increase conduction velocity. In addition to whether an axon is myelinated or not, changes to the number, distribution, length, and thickness of myelin sheaths all, in principle, affect conduction velocity and thus the timing of information propagation, prompting speculation that dynamic regulation of myelination in response to neural activity may fine-tune the timing of communication between neurons in a circuit.

Conclusions

The study of glia reminds us that nervous system development does not end at birth, nor indeed at adolescence, and that the dynamic behavior of glial cells and ongoing neuron-glial interactions actively sculpt and remodel the CNS throughout life. We expect that further insight into how the brain forms, functions, and ages in a healthy manner will derive from integrating our understanding of how neurons interact with glia, how different glial cells interact with each other, and how the brain interacts with the rest of the body.

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