NG2-glia and their functions in the central nervous system

Abstract

In the central nervous system, NG2-glia represent a neural cell population that is distinct from neurons, astrocytes, and oligodendrocytes. While in the past the main role ascribed to these cells was that of progenitors for oligodendrocytes, in the last years it has become more obvious that they have further functions in the brain. Here, we will discuss some of the most current and highly debated issues regarding NG2-glia: Do these cells represent a heterogeneous population? Can they give rise to different progenies, and does this change under pathological conditions? How do they respond to injury or pathology? What is the role of neurotransmitter signaling between neurons and NG2-glia? We will first give an overview on the developmental origin of NG2-glia, and then discuss whether their distinct properties in different brain regions are the result of environmental influences, or due to intrinsic differences. We will then review and discuss their in vitro differentiation potential and in vivo lineage under physiological and pathological conditions, together with their electrophysiological properties in distinct brain regions and at different developmental stages. Finally, we will focus on their potential to be used as therapeutic targets in demyelinating and neurodegenerative diseases. Therefore, this review article will highlight the importance of NG2-glia not only in the healthy, but also in the diseased brain.

Keywords: disease; heterogeneity; lineage potential; oligodendrocyte progenitors; physiology.

Figure 1. Regional heterogeneity of NG2-glia in the adult cerebral cortex

Transplantations of NG2-glia isolated either from the corpus callosum (white matter; WM) or the cerebral cortex (gray matter; GM) of the adult brain revealed that WM-derived cells generate mature, myelinating oligodendrocytes independently of the area of transplantation. In contrast, GM-derived NG2-glia remained as progenitors when transplanted homotopically, but differentiated into mature non-myelinating oligodendrocytes when grafted into the more permissive environment of the WM.

Figure 2. Progeny of NG2-glia at different developmental stages and in disease

While during development NG2-glia generate more NG2-glia, oligodendrocytes and astrocytes, in the adult CNS their progeny remains purely oligodendrogenic. However, under some pathological conditions of the adult brain, NG2-glia can also generate astrocytes and myelinating Schwann cells. Evidence in favor of generation of neurons from NG2-glia still remains highly contentious.

Figure 3. Neuron-NG2 synapses in the brain

NG2-glia form synaptic contacts with neurons in gray and white matter regions. In gray matter, NG2-glia receive synaptic inputs from both excitatory and inhibitory neurons. In white matter, NG2-glia receive excitatory synaptic inputs from axon collaterals. During development, functional synapses are detected at early developmental stages in NG2-glia (oligodendrocyte progenitors), but are downregulated in pre-oligodendrocytes, and are undetectable in mature oligodendrocytes. PRE-OL = pre-oligodendrocyte; OL = oligodendrocyte.