Multiple Modes of Communication between Neurons and Oligodendrocyte Precursor Cells

Abstract

The surprising discovery of bona fide synapses between neurons and oligodendrocytes precursor cells (OPCs) 15 years ago placed these progenitors as real partners of neurons in the CNS. The role of these synapses has not been established yet, but a main hypothesis is that neuron-OPC synaptic activity is a signaling pathway controlling OPC proliferation/differentiation, influencing the myelination process. However, new evidences describing non-synaptic mechanisms of communication between neurons and OPCs have revealed that neuron-OPC interactions are more complex than expected. The activation of extrasynaptic receptors by ambient neurotransmitter or local spillover and the ability of OPCs to sense neuronal activity through a potassium channel suggest that distinct modes of communication mediate different functions of OPCs in the CNS. This review discusses different mechanisms used by OPCs to interact with neurons and their potential roles during postnatal development and in brain disorders.

NG2 Glia: Novel Roles beyond Re-/Myelination

“…In line with this view, confocal and electron microscopy studies showed that NG2 glia establish physical contacts with functionally relevant neuronal domains, including dendrites [41,42], somata [14,41,43,44], nodes of Ranvier [45,46] and synapses [47,48] (Figure 1C). About 30-50% of the nodes are contacted by both NG2 glia and astrocyte processes in the optic nerve, corpus callosum, and spinal cord of young adult rodents.…”

“…Such organization includes the tight alignment of neuron and NG2 glia cell membranes, the presence of an active zone with accumulation of synaptic vesicles on the neuronal side, and an electron dense postsynaptic density on the NG2 cell side. Notably, neuron-to-NG2 glia synapses are established in parallel with neuronal synaptogenesis [14,49], and are lost during NG2 glia progression in maturation [48,49]; this is in line with a specific role of this form of communication in undifferentiated NG2 glia. Remarkably, while glutamatergic neuron-to-NG2 glia synapses usually derive from long-range axons impinging almost exclusively on NG2 glia processes [50][51][52], GABAergic synapses derive from local interneurons [49,53] with a specific distribution of the synaptic contacts from fast spiking (located at NG2 glia somata and proximal parts of the processes) and non-fast spiking interneurons (located at the distal parts of NG2 glia processes) [49].…”

“…The expression of these receptors is not universal in NG2 cell populations (e.g., only 60% of the callosal NG2 cells are able to respond to NMDA [79]), indicating a certain degree of heterogeneity within NG2 glia as regards their potential to sense and respond to changes in neurotransmission. Despite the fact that some of these neurotransmitter receptors (i.e., AMPA and ionotropic GABA receptors) have been shown to mediate neuron-to-NG2 glia synaptic communication, activation of most of them is thought to occur through extrasynaptic mechanisms [48], and is associated with large, widespread intracellular Ca 2+ elevations [78].…”

“…A detailed and comprehensive examination of NG2 glia behaviors/molecular changes upon lesion will likely unveil some elements of cell heterogeneity (see above). Indeed, diverse NG2 glia subpopulations have also been described in the intact CNS based on their origin, proliferative activity, division modality, differentiation potential, expression of diverse transcription factors, Ca 2+ -binding molecules, neurotransmitter receptors, and ionic currents [5,23,48,69,212]. Thus, it is conceivable that subsets of functionally specialized NG2 glia may be differentially tailored to contribute to distinct aspects of CNS homeostasis, including oligodendrogenesis and additional/alternative functions.…”

Whole cell patch clamp analysis of non-synaptic and synaptic signaling in rodent and human supragranular neocortex

“…Direct synaptic junctions from neurons to non-neuronal cells appear to be restricted to connections linking neurons and NG2-expressing glial cells (Bergles et al, 2000;Lin and Bergles, 2004;Maldonado and Angulo, 2015) in the cerebral cortex. In spite of the apparent absence of synapses on other glial cells, the presence of GABA receptors and transporters is well established (Eulenburg and Gomeza, 2010;Porter and McCarthy, 1997), and depolarizing GABAergic responses are characteristic of glia (Kettenmann, Backus, and Schachner, 1984).…”