Neurotransmitter-mediated signaling between axons and glial cells.

Neurotransmitter-mediated signaling is not restricted to the synaptic regions of the nervous system but also takes places along fiber tracts lacking vesicular means of releasing neuroactive substances. The first demonstration for dynamic signaling of this type came in the early 1970s from studies by Villegas and co-workers in squid axons and their satellite Schwann cells. In this invertebrate system, glutamate has been identified as the mediator of this signaling in being first released from the active axons thus setting off a series of cascades, leading to a cholinergic activation of the Schwann cell membrane. Recent evidence suggests that receptor-mediated signaling also exists between glial cells and axons in vertebrates. In the frog optic nerve, axonal activity facilitated the activity of glial ion channels. In the neonatal rat optic nerve, electrical activity of axons triggered oscillations in intracellular calcium in a subset of glial cells. These observations have been postulated to reflect receptor-mediated signaling, including a mechanism in which glutamate is released from axons via the reversal of a transporter and induces intracellular calcium spiking in glial cells via metabotropic glutamate receptors. The efficacy of "axon-to-glia" transmission may, like that in "neuron-to-neuron" transmission, be modulated by co-release of multiple neuroactive substances. One possibility is that adenosine, which is known to be released from fiber tracts, can modulate glutamate signaling in white matter by modulating the periaxonal glutamate concentration through an effect on the glial glutamate uptake system.