Glia as architects of central nervous system formation and function

Abstract

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.

Figure 1.. Origin and overview of CNS glial cells.

A: Radial Glial Cell in an E14 mouse cortex, visualised following in utero electroporation of GFP (green), and co-­stained for apical centrosomes (pericentrin, red) and cell nuclei (DAPI, blue). Image courtesy of Sven Falk and Magdalena Goetz, Helmholtz Centre, Munich. B: Radial glial cells are the principal neuroepithelial progenitor cells of the central nervous system, and generate the majority of CNS neurons and glia, either directly (e.g. neurons), or indirectly through intermediate progenitors (e.g. OPCs). Microglia (yellow) enter the CNS during embryonic development. C: Neurons and glia interact in a myriad of ways (indicated by circles, explained in text and subsequent figures).

Figure 2.. Astrocytes

A: Astrocytes have a characteristic star-­like morphology and send out multiple branches that terminate in thousands of fine processes that interact with synapses, blood vessels, and other cells. Astrocytes regulate synapse formation, elimination and function (1), have endfeet that ensheath CNS vasculature (2), contributing to metabolic support and homeostatic function, and reciprocal interactions with neurons regulating circuit function (3). Astrocytes also make contact with nodes of Ranvier (4), the function of which is unclear, and interact bidirectionally with OPCs, oligodendrocytes and microglia (5), the relevance of which is emerging. B: Astrocyte image courtesy of The Cell Image Library, image CIL 48001, https://doi.org/doi:10.7295/W9CIL48001.

Figure 3.. Oligodendrocyte progenitor cells and oligodendrocytes

A: OPCs (blue) are the most proliferative cells of the CNS (1) and generate mature myelinating oligodendrocytes throughout life (2). OPCs interact with many other cells of the CNS (3), particularly in disease. OPCs extend processes that contact nodes of Ranvier, receive synapses from axons, and regulate synaptic function (4). Whether there are distinct subtypes of OPCs or simply different functional states remains unclear. Oligodendrocytes (dark green) produce lipid rich myelin sheaths that wrap around axons and regulate action potential conduction velocity. Dynamic regulation of myelination in response to neuronal signals (5) may be a fundamental mechanism by which neural circuit function is fine-tuned. Myelinating oligodendrocytes organise axonal domains (6), including nodes of Ranvier, where the voltage-gated Na²⁺ channels (yellow) that mediate action potential propagation are localised, provide metabolic support to axons (7) and facilitate ion homeostasis essential to normal action potential conduction, e.g. the uptake by myelin of K⁺ ions (8). B: OPC expressing membrane tethered fluorescent protein imaged in a living transgenic zebrafish larvae at 3 days post­fertilisation. C: Oligodendrocyte expressing membrane tethered GFP and cytoplasmic RFP imaged in a living transgenic zebrafish larvae at 4 days post-­fertilisation. Images courtesy of Dr. Marion Baraban, Lyons lab.

Figure 4.. Microglia

A: Microglia are the resident immune cells of the brain, entering during early development from the periphery (1). In addition to immune surveillance roles (not shown), microglia interact with multiple cell types of the CNS and regulate numerous developmental and functional processes, including synaptic pruning (2), clearing apoptotic neurons (3) and interacting with multiple CNS cell types, in health and disease (4). B: Microglia expressing GFP in mouse cortex (Cx3cr1-GFP), courtesy of Youtong Huang and Greg Lemke, Salk Institute.