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Calcium Signaling of Glial Cells Along Mammalian Axons

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Calcium Signaling of Glial Cells Along Mammalian Axons The Journal of Neuroscience, October 1993, 73(10): 4229-4245 Calcium Signaling of Glial Cells along Mammalian Axons Steve Krieglerl and S. Y. Chiu2 ‘Biophysics Training Program and 2Department of Neurophysiology, University of Wisconsin, Madison, Wisconsin 53706 Glial [Ca2+li signaling was examined in a mammalian white et al., 1990; Barres, 1991) raises the possibility of ligand-me- matter lacking neuronal cell bodies and synapses. Rat optic diated, neuron-glial signaling. Different parts of the neuron can nerves (postnatal days 2 and 7) were stained with calcium signal glia. One is the presynaptic terminal that is encapsulated indicator dyes and confocal images of [Ca2+li were recorded by glial processes.The concentration ofglutamate at the synaptic at -25°C or -37°C. Glial cell bodies showed spiking or sus- cleft can reach - 1 mM during synaptic transmissions,and even tained [Ca2+], response to bath-applied glutamate (SO-500 though the releasingneuronal membrane directly faces another PM). The metabotropic glutamate agonist frans-ACPD elic- neuron rather than glia, someglutamate can leak out and signal ited transient, sometimes spiking, [Ca2+],responses, where- the glial membranesflanking the synapse(Dani et al., 1992). as ionotropic agonists kainate and AMPA elicited a 6,7-dini- Another part of the neuron that might signal glia is the axon. troquinoxaline-2,3-dione-sensitive, mostly sustained [Caz+li In the mammalian CNS, there are intimate contacts between response. Transient and spiking glial [Ca*+& responses also axons and a variety of glia, including the myelinating oligoden- were elicited by adenosine and ATP (0. l-l 00 PM). Repetitive drocytes, and O-2A glial progenitor cells and astrocytes that nerve stimulation (1 O-20 Hz) elicited [Caz+li spiking in 15- send processesto the axonal surface (Miller et al., 1989; Raff, 25% of glial cells in postnatal day 7 nerves, with spiking 1989). Even though there are no known vesicular mechanisms typically occurring 15-60 set after onset of nerve stimula- for releasing neuroactive substancesor excitatory amino acids tion. At 37”C, the frequency of glial [Ca2+li spikes increased in white matter, nerve fiber tracts in certain mammalsand frogs from -0.06 Hz to -0.11 Hz when axonal stimulation was have been shown to releaseglutamate (Wheeler et al., 1966; increased from 10 to 20 Hz. This activity-dependent glial Weinreich and Hammerschlag, 1975) and adenosine (Kuper- spiking was inhibited by TTX, could not be mimicked by man et al., 1964; Maire et al., 1984) during electrical stimula- increasing the bath K+ by 20 mM, and occurred when nerves tion. To date, the best-documentedcase for axon-glia signaling were stimulated in the absence of bath calcium. Activity- is that which takes placesbetween Schwann cells and the squid dependent and glutamate-induced glial spiking could be giant axon (Villegas, 1984; Lieberman et al., 1989; Lieberman, mimicked by altering ionic gradients known to favor release 199 1). Collectively, theseobservations suggestthat in the mam- of glutamate via glutamate transporters, including elevation malian nervous system, ligand-mediated signalingbetween neu- of intracellular Na+ by veratridine concurrent with external rons and glia can occur in both the synaptic and nonsynaptic K+ elevation. We suggest that glial [Ca2+li spiking observed regions. The relative importance of synapse versus axons in during electrical activity resulted from activation of glial re- signalingglia is unclear; for example, glutamate may be released ceptors (e.g., metabotropic glutamate receptor, adenosine at a higher density per unit membrane area at the synapsethan receptor) by substances (e.g., glutamate, adenosine) re- along axonal membranes, but the total axonal area is much leased from the optic nerve in a nonvesicular fashion, pos- larger. sibly through a reversal of sodium-coupled transporters when What are some of the detectable consequencesof ligand-me- Na+and K+ gradients are altered by prolonged nerve activity. diated activation in glia? Among the first to be measuredwere [Key words: metabotropic glutamate receptors, confocal changesin membrane potential, as is the case for ligand-me- imaging, optic nerve, white matter, axon-glial interactions, diated signaling in squid Schwann cells and glial cells of am- flue-3] phibian optic nerve (Villegas, 1984; Tang and Orkand, 1986; Lieberman et al., 1989). Recently, calcium imaging in mam- When a neuron undergoesexcitation, glutamate and other neu- malian glia has revealed a dynamic intracellular signaling in reactive substancesare released.The immediate target of these glia, specifically in the caseof glutamate. The first observations, substancesis another neuron. However, the recent discovery made in neuron-free astrocyte cultures, showed that glutamate that glial cells possessreceptors for glutamate and other neu- evoked calcium spikes(Enkvist et al., 1989; Cornell-Bell et al., reactive ligands(for review, seePearce and Murphy, 1988; Gallo 1990a; Glaum et al., 1990; Jensenand Chiu, 1990) and calcium waves in astrocytes network (Cornell-Bell et al., 1990a). Sub- sequently, Dani et al. (1992) showed that in organotypic brain Received Jan. 4, 1993; revised Apr. 7, 1993; accepted Apr. 15, 1993. slices,neuronal electrical activity triggered glial calcium waves We thank C. K. Chang for software assistance in image analysis, and Carol and spiking. While the simplest explanation for the Dani et al. Dizack and Terry Stewart for help in illustration and photography. This work was (1992) observation is that the glial calcium signalsin brain slices supported in part by Grants NS-23375 from the U.S. Public Health Service and RG-1839 from the U.S. National Multiple Sclerosis Society, and a Pew Scholar were elicited by glutamate (or other neuroactive substances) award in the Biomedical Sciences to S.Y.C. releasedat the synapse,an interesting issueis whether someof Correspondence should be addressed to S. Y. Chiu, University of Wisconsin, the glial signaling may result from substancesreleased from Department of Neurophysiology, 283 Medical Sciences Building, 1300 University Avenue, Madison, WI 53706. axons. Copyright 0 1993 Society for Neuroscience 0270-6474/93/134229-17$05.00/O In this report, we examine whitther axons alone can trigger 4230 Kriegler and Chiu * Glial Calcium Signaling along Axons ghal calcium signaling by performing calcium imaging on neo- was reported as fluo-3 fluorescence without calibration for absolute natal rat optic nerves. By using the portion of the nerve between values. In some figures, a AF/F,, value was calculated as described pre- viously (Jensen and Chiu, 1991). Experiments were done either at the eye and the optic chiasm, neuronal cell bodies and synapses -37°C (using a stage-mounted, air-heated incubator enclosing the ob- are eliminated, leaving only glia and axons as the major cellular servation platform of the Nikon microscope) or at room temperature elements. Premyelinated nerves at postnatal day 7 (P7) were of -25°C. used to maximize the axonal surface available for releasing sub- Bath application of glutamate and other agents. The solution bathing the nerve was perfused first with a normal Krebs’ solution for 30-60 stances,which otherwise might not be possiblein fully myelin- set to obtain a baseline, and then the solution was switched to one ated nerves where most of the axonal area has been sealed containing glutamate or other agents. The bath volume was about 0.5 up. A method was developed to stain the axons and glial cells ml, and the perfusion rate was about 5 ml/min. so that an intact nerve could be subjected to confocal calcium Electrical stimulation of axons. A different chamber was used for imaging as early as 30 min after nerve removal. We first bath- electrical stimulation studies. The stimulation chamber has two pairs of platinum wire separated by a distance of about 0.5 cm. The nerve applied glutamate and other neuroactive ligands to seeif optic was gently laid across the two pairs of wires, and one end of the nerve nerve glia are capable of ligand-mediated calcium signaling. We was used for stimulation while the other end for recording ofcompound then altered Na+ and K+ gradients in a fashion known to reverse action potentials. A brief(O. l-0.4 msec), supramaximal stimulation was the glutamate transporter to see if optic nerves are capable of applied, and the frequency of stimulation was 5-20 Hz. Calcium images were collected from the nerve segment in between the two pairs of wires releasingglutamate by this mechanism.We then stimulated the at a rate of one image every l-3 sec. In some experiments, images were axons electrically to see if this triggered glial responsesthat collected at video rate. Only the nerve segment between the electrodes mimicked the results obtained by direct ligand application, par- was locally perfused with a pair of glass pipettes. Two pieces of moist- ticularly with respect to glutamate. ened tissue paper were placed over the nerve segments in contact with the platinum wires to prevent the ends of the nerve from drying during Materials and Methods an experiment. To prevent evaporation further, the entire chamber was covered with a thick, wetted piece of cotton pad. The- tips of the glass Dye loading of neonatal rat optic nerves. Rat optic nerves (P2 and P7) pipettes were about 2 mm apart, and were placed along side the nerve were excised, stripped of the outermost dura matter, and stained with segment. Oxygenated Krebs’ solutions were continuously delivered via the calcium indicator flue-31acetomethoxyester (AM) (Kao et al., 1989) one pipette by gravity, and sucked out gently via the other pipette. Both or calcium green/AM. In our earlier studies, we incubated the nerves pipette tips and the nerve segment were positioned underneath a small in solutions containing the indicator, but found that after 2 hr only the piece of nylon gauze. The nylon gauze provided a meniscus surface for outermost layers of cells were stained; apparently, the nerve was still the perfusing solution to dissipate over the entire nerve segment.
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