Abstract
Despite considerable evidence that glia can release modulators to influence the excitability of neighbouring neurons, the importance of gliotransmission for the operation of neural networks and in shaping behaviour remains controversial. Here we characterise the contribution of glia to the modulation of the mammalian spinal central pattern generator for locomotion, the output of which is directly relatable to a defined behaviour. Glia were stimulated by specific activation of protease-activated receptor-1 (PAR1), an endogenous G-protein coupled receptor preferentially expressed by spinal glia during ongoing activity of the spinal central pattern generator for locomotion. Selective activation of PAR1 by the agonist TFLLR resulted in a reversible reduction in the frequency of locomotor-related bursting recorded from ventral roots of spinal cord preparations isolated from neonatal mice. In the presence of the gliotoxins methionine sulfoximine or fluoroacetate, TFLLR had no effect, confirming the specificity of PAR1 activation to glia. The modulation of burst frequency upon PAR1 activation was blocked by the non-selective adenosine-receptor antagonist theophylline and by the A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, but not by the A2A-receptor antagonist SCH5826, indicating production of extracellular adenosine upon glial stimulation, followed by A1-receptor mediated inhibition of neuronal activity. Modulation of network output following glial stimulation was also blocked by the ectonucleotidase inhibitor ARL67156, indicating glial release of ATP and its subsequent degradation to adenosine rather than direct release of adenosine. Glial stimulation had no effect on rhythmic activity recorded following blockade of inhibitory transmission, suggesting that glial cell-derived adenosine acts via inhibitory circuit components to modulate locomotor-related output. Finally, the modulation of network output by endogenous adenosine was found to scale with the frequency of network activity, implying activity-dependent release of adenosine. Together, these data indicate that glia play an active role in the modulation of mammalian locomotor networks, providing negative feedback control that may stabilise network activity.
Highlights
There is considerable evidence from electrophysiological and Ca2+-imaging studies that glia can both respond to activity at the synapses they enwrap with elevations in cytosolic Ca2+ and modulate the excitability of neighbouring neurons via the Ca2+-dependent release of socalled gliotransmitters [1,2]
Our findings suggest that adenosine is the primary glial cell-derived modulator of spinal motor networks and implicate glia as active participants in the modulation of these networks and of locomotor behaviour
Protease activated receptor-1 (PAR1), an endogenous G-protein coupled receptor (GPCR), is preferentially expressed by astrocytes in the brain and brainstem [43,44], and application of the peptide agonist TFLLR has been shown to elicit Ca2+ signalling selectively in cortical astrocytes [33,34,45]
Summary
There is considerable evidence from electrophysiological and Ca2+-imaging studies that glia can both respond to activity at the synapses they enwrap with elevations in cytosolic Ca2+ and modulate the excitability of neighbouring neurons via the Ca2+-dependent release of socalled gliotransmitters [1,2]. In this study we examine the role of gliotransmission in spinal motor networks. These networks coordinate the rhythmic activation of flexor and extensor muscles within and between limbs during locomotion, and for this reason their output is immediately relatable to a defined behaviour [7]. Many modulators are neuronal in origin, previous studies have reported modulation of spinal cord and brainstem CPGs following release of glutamate and the purines ATP and adenosine from glia [10,11,12]
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