Calcium signaling of glial cells along mammalian axons

Abstract

Glial [Ca2+]i signaling was examined in a mammalian white matter lacking neuronal cell bodies and synapses. Rat optic nerves (postnatal days 2 and 7) were stained with calcium indicator dyes and confocal images of [Ca2+bdi were recorded at approximately 25 degrees C or approximately 37 degrees C. Glial cell bodies showed spiking or sustained [Ca2+], response to bath-applied glutamate (50-500 microM). The metabotropic glutamate agonist trans-ACPD elicited transient, sometimes spiking, [Ca2+], responses, whereas ionotropic agonists kainate and AMPA elicited a 6,7-dinitroquinoxaline-2,3-dione-sensitive, mostly sustained [Ca2+]i response. Transient and spiking glial [Ca2+]i responses also were elicited by adenosine and ATP (0.1-100 microM). Repetitive nerve stimulation (10-20 Hz) elicited [Ca2+bdi spiking in 15-25% of glial cells in postnatal day 7 nerves, with spiking typically occurring 15-60 sec after onset of nerve stimulation. At 37 degrees C, the frequency of glial [Ca2+]i spikes increased from approximately 0.06 Hz to approximately 0.11 Hz when axonal stimulation was increased from 10 to 20 Hz. This activity-dependent glial spiking was inhibited by TTX, could not be mimicked by increasing the bath K+ by 20 mM, and occurred when nerves were stimulated in the absence of bath calcium. Activity-dependent and glutamate-induced glial spiking could be mimicked by altering ionic gradients known to favor release of glutamate via glutamate transporters, including elevation of intracellular Na+ by veratridine concurrent with external K+ elevation. We suggest that glial [Ca2+]i spiking observed during electrical activity resulted from activation of glial receptors (e.g., metabotropic glutamate receptor, adenosine receptor) by substances (e.g., glutamate, adenosine) released from the optic nerve in a nonvesicular fashion, possibly through a reversal of sodium-coupled transporters when Na+ and K+ gradients are altered by prolonged nerve activity.

Control of Drosophila perineurial glial growth by interacting neurotransmitter-mediated signaling pathways

“…This observation raises the possibility that Drosophila peripheral glia might respond to Amn and NT released from motor nerve terminals, and propagate these signals along the length of the nerve via gap junctions. However, the alternative possibility of NT release from along the length of axons, as has been suggested in other systems (28,29), cannot be ruled out. In addition, mammalian Schwann cells release trophic factors such as Desert Hedge Hog (Dhh) to induce growth of the surrounding perineurium (6), and astrocytes can respond to glutamate application by releasing a substance that affects blood vessels (30).…”

Functions of optic nerve glia: axoglial signalling in physiology and pathology

“…29. In the optic nerve, glutamate is released during axonal electrical conduction and evokes increased glial [Ca 2 þ ] i in an activity-dependent manner (Figure 3d-g). 30 Glutamate is released either from axons at nodes of Ranvier or from astrocytes in response to activation by axonal action potential propagation at nodes. 31,32 The actions of glutamate in the optic nerve indicate an unresolved physiological role for Ca 2 þ signalling in oligodendrocytes.…”

“…42 Astrocytes are functionally coupled via CÂ 43 gap junctions and following stimulation Ca 2 þ waves are propagated through the network at a rate of 7-27 mm/s. [42][43][44] Glutamate may be the primary axon-to-glial signaling molecule (Figure 3d-g), 30,42,44 but ATP is the primary signalling molecule between astrocytes throughout the CNS [45][46][47] and in the optic nerve ( Figure 5). [48][49][50] Astrocytes release ATP and glutamate in response to physiological stimulation and modulate the activity of adjacent neurons in culture and in the retina.…”

“…[48][49][50] Astrocytes release ATP and glutamate in response to physiological stimulation and modulate the activity of adjacent neurons in culture and in the retina. [51][52][53] There is circumstantial evidence that axonal electrical activity in the optic nerve also triggers glutamate-and ATP-mediated glial Ca 2 þ signalling (Figure 3d-g), 30 and glutamate and adenosine, the breakdown product of ATP, have been shown respectively to compromise and protect axons in ischaemia. 10,54 Physiologically, it may be more significant that Ca 2 þ signalling triggered by glutamate released by axons and propagated by astroglial ATP can couple axonal activity and astrocyte functions, including K þ regulation and metabolism.…”

Electrical signalling properties of oligodendrocyte precursor cells

“…Perhaps these mechanisms operate on different spatial scales, with the PDGF signal operating over long distances to generally stimulate proliferation in an active axon fibre tract, while the glutamate signal is more spatially localised (due to efficient uptake by transporters) and inhibits proliferation when OPCs form a close apposition with an axon. If glutamate release from myelinated axons (Kriegler and Chiu, 1993) occurs from nodes of Ranvier, it might serve to tonically repress proliferation of OPCs, which have processes contacting the nodes (Butt et al, 1999) apparently in order to prevent axonal sprouting at that point (Huang et al, 2005). The glutamate released by action potentials may also regulate OPC migration (Wang et al, 1996;Gudz et al, 2006).…”