The ability to investigate the electrophysiological properties of individual cells in acute brain tissue led to the discovery that many glial cells have the capacity to respond rapidly to neuronal activity. In particular, a distinct class of neuroglial cells known as NG2 cells, which exhibit many of the properties that have been described for glial subtypes such as complex cells, polydendrocytes, synantocytes and GluR cells, express ionotropic receptors for glutamate and GABA. In both gray and white matter, NG2 cells form direct synaptic junctions with axons, which enable transient activation of these receptors. Electrophysiological analyses have shown that these neuron-glia synapses exhibit all the hallmarks of ‘classical’ neuron-neuron synapses, including rapid activation, quantized responses, facilitation and depression, and presynaptic inhibition. Electron microscopy indicates that axons form morphologically distinct junctions at discrete sites along processes of NG2 cells, suggesting that NG2 cells are an overt target of axonal projections. AMPA receptors expressed by NG2 cells exhibit varying degrees of Ca(2+) permeability, depending on the brain region and stage of development, and in white matter NG2 cells have also been shown to express functional NMDA receptors. Ca(2+) influx through AMPA receptors following repetitive stimulation can trigger long term potentiation of synaptic currents in NG2 cells. The expression of receptors with significant Ca(2+) permeability may increase the susceptibility of NG2 cells to excitotoxic injury. Future studies using transgenic mice in which expression of receptors can be manipulated selectively in NG2 cells have to define the functions of this enigmatic neuron-glia signaling in the normal and diseased CNS.
The mammalian CNS contains an abundant, widely distributed population of glial cells that serve as oligodendrocyte progenitors. It has been reported that these NG2-immunoreactive cells (NG2(+) cells) form synapses and generate action potentials, suggesting that neural-evoked excitation of these progenitors may regulate oligodendrogenesis. However, recent studies also suggest that NG2(+) cells are comprised of functionally distinct groups that differ in their ability to respond to neuronal activity, undergo differentiation, and experience injury following ischemia. To better define the physiological properties of NG2(+) cells, we used transgenic mice that allowed an unbiased sampling of this population and unambiguous identification of cells in discrete states of differentiation. Using acute brain slices prepared from developing and mature mice, we found that NG2(+) cells in diverse brain regions share a core set of physiological properties, including expression of voltage-gated Na(+) (NaV) channels and ionotropic glutamate receptors, and formation of synapses with glutamatergic neurons. Although small amplitude Na(+) spikes could be elicited in some NG2(+) cells during the first postnatal week, they were not capable of generating action potentials. Transition of these progenitors to the premyelinating stage was accompanied by the rapid removal of synaptic input, as well as downregulation of AMPA and NMDA receptors and NaV channels. Thus, prior reports of physiological heterogeneity among NG2(+) cells may reflect analysis of cells in later stages of maturation. These results suggest that NG2(+) cells are uniquely positioned within the oligodendrocyte lineage to monitor the firing patterns of surrounding neurons.
Chemical synaptic transmission provides the basis for much of the rapid signaling that occurs within neuronal networks. However, recent studies have provided compelling evidence that synapses are not used exclusively for communication between neurons. Physiological and anatomical studies indicate that a distinct class of glia known as NG2(+) cells also forms direct synaptic junctions with both glutamatergic and GABAergic neurons. Glutamatergic signaling can influence intracellular Ca(2+) levels in NG2(+) cells by activating Ca(2+) permeable AMPA receptors, and these inputs can be potentiated through high frequency stimulation. Although the significance of this highly differentiated form of communication remains to be established, these neuro-glia synapses might enable neurons to influence rapidly the behavior of this ubiquitous class of glial progenitors.
Rapid signaling between vertebrate neurons occurs primarily at synapses, intercellular junctions where quantal release of neurotransmitter triggers rapid changes in membrane conductance through activation of ionotropic receptors. Glial cells express many of these same ionotropic receptors, yet little is known about how receptors in glial cells become activated in situ. Because synapses were thought to be the sole provenance of neurons, it has been assumed that these receptors must be activated following diffusion of transmitter out of the synaptic cleft, or through nonsynaptic mechanisms such as transporter reversal. Two recent reports show that a ubiquitous class of progenitors that express the proteoglycan NG2 (NG2 cells) engage in rapid signaling with glutamatergic and gamma-aminobutyric acid (GABA)ergic neurons through direct neuron-glia synapses. Quantal release of transmitter from neurons at these sites triggers rapid activation of aminomethylisoxazole propionic acid (AMPA) or GABA(A) receptors in NG2 cells. These currents exhibit properties consistent with direct rather than spillover-mediated transmission, and electron micrographic analyses indicate that nerve terminals containing clusters of synaptic vesicles form discrete junctions with NG2 cell processes. Although activation of AMPA or GABA(A) receptors depolarize NG2 cells, these receptors are more likely to serve as routes for ion flux rather than as current sources for depolarization, because the amplitudes of the synaptic transients are small and the resting membrane potential of NG2 cells is highly negative. The ability of both glutamate and GABA to influence the morphology, physiology, and development of NG2 cells in vitro suggests that this rapid form of signaling may play important roles in adapting the behavior of these cells to the needs of surrounding neurons in vivo.
Fast excitatory neurotransmission in the central nervous system occurs at specialized synaptic junctions between neurons, where a high concentration of glutamate directly activates receptor channels. Low-affinity AMPA (alpha-amino-3-hydroxy-5-methyl isoxazole propionic acid) and kainate glutamate receptors are also expressed by some glial cells, including oligodendrocyte precursor cells (OPCs). However, the conditions that result in activation of glutamate receptors on these non-neuronal cells are not known. Here we report that stimulation of excitatory axons in the hippocampus elicits inward currents in OPCs that are mediated by AMPA receptors. The quantal nature of these responses and their rapid kinetics indicate that they are produced by the exocytosis of vesicles filled with glutamate directly opposite these receptors. Some of these AMPA receptors are permeable to calcium ions, providing a link between axonal activity and internal calcium levels in OPCs. Electron microscopic analysis revealed that vesicle-filled axon terminals make synaptic junctions with the processes of OPCs in both the young and adult hippocampus. These results demonstrate the existence of a rapid signalling pathway from pyramidal neurons to OPCs in the mammalian hippocampus that is mediated by excitatory, glutamatergic synapses.