NG2 cells (polydendrocytes): listeners to the neural network with diverse properties

Abstract

NG2 cells (polydendrocytes) are the fourth major non-neuronal cell type in the central nervous system parenchyma. They exhibit diverse properties, ranging from their well-established role as oligodendrocyte precursors to their ability to respond to neurotransmitters released by synaptic and non-synaptic mechanisms. The functional diversity of NG2 cells has prompted the question of whether they represent a single cellular entity or multiple distinct cell populations. This review first summarizes recent findings on the nature and mechanism underlying the diversity of NG2 cells with regard to their proliferative and differentiation behavior. This will be followed by a synopsis of observations on how their microenvironment, particularly neuronal activity, influences their dynamic behavior, and how these changes in NG2 cells could in turn influence neural function and animal behavior.

Keywords: PDGF; demyelination; myelin; oligodendrocyte; oligodendrocyte precursor cell; plasticity; polydendrocyte; white matter.

Figure 1

Heterogeneous origin and fate of NG2 cells in the forebrain. During mid-gestation, NG2 cells in the forebrain are generated from the ventral germinal zones of medial and lateral ganglionic eminences (MGE (purple) and LGE (blue), respectively) defined by the transcriptional factors Nkx2.1 and Gsh2, respectively. The LGE-derived cells expand and constitute the majority of NG2 cells in the subpallial forebrain but also migrate dorsally to populate the corpus callosum and to a lesser extent the neocortex. Subsequently, from late embryonic stages to early postnatal period, additional NG2 cells are generated from the dorsal VZ defined by the Emx1 transcriptional factor (Emx1, green). After the VZ has ceased to produce new neurons and glia, a minor population of NG2 cells is generated from the SVZ (red). NG2 cells produced from all of these sources are capable of generating oligodendrocytes. In addition, those from the ventral germinal zones differentiate into protoplasmic astrocytes, constituting up to 40% of the protoplasmic astrocytes in the ventral posterior gray matter of the forebrain. It is not yet known whether the astrogliogenic NG2 cells originate in MGE or LGE or both. As soon as NG2 cells exit the germinal zone, they acquire one or more processes, thus already exhibiting the polydendrocytic morphology from as early as mid-embryonic stages.

Figure 2

Different functional outcomes from heterogeneous properties of NG2 cells between gray and white matter. Top: Cell intrinsic differences between gray and white matter NG2 cells. The more oxidized state of white matter NG2 cells could lead to increased PI3K signal or PDGFRα activation (left). White matter NG2 cells are also reported to be more depolarized and thus may have higher intracellular calcium concentrations. Middle: Differences in the ability of gray and white matter NG2 cells to sense their environment. Even in the presence of similar amounts of extracellular PDGF and cell surface PDGFRα, NG2 cells in white matter may undergo greater PDGFRα activation due to differences in receptor activation mechanisms. Bottom: The cell intrinsic and cell surface mechanisms shown above will define the specific outcomes that are detected as differences in the rate of proliferation and oligodendrocyte differentiation between gray and white matter NG2 cells.

Figure 3

Possible outcomes and routes for how changes in neuronal activity influence NG2 cells. A. Changes in neuronal activity (Δ neuronal activity) have been shown to alter NG2 cell proliferation (left), oligodendrocyte differentiation (middle), or survival of NG2 cells or newly differentiated oligodendrocytes (right). B. Two possible routes of neuron-to-NG2 cell communication. Left: Direct synaptic input to NG2 cells allows specificity of the NG2 cell response to the activity of the specific axon from which it receives synaptic input and can be frequency coded. Right: Nonsynaptically released neurotransmitters from axons or astrocytes can exert a more generalized effect on multiple NG2 cells in the micro-region.

Figure 4

Possible mechanisms of activity-dependent myelination and myelin plasticity. A. Different ways in which oligodendrocytes can be signaled to myelinate. 1. The oligodendrocyte could receive activity-dependent signals and myelinate only active axons. 2. The myelination signal could consist of physical properties of the axon such as axon caliber. 3. The signal to myelinate could be an intrinsic or extracellular mechanism that is independent of axonal activity or caliber. B. Possible ways in which activity-dependent myelin plasticity could be achieved. Left: Neuronal activity could affect the release of neurotransmitters or other active substances from the nodes of Ranvier, signal to astrocyte, or NG2 cell processes at the node, or slightly shift the position of the node and change the internode length. Right: Neuronal activity could also result in changes in the thickness of myelin. Both of these mechanisms could potentially bring about dynamic changes in conduction.