by our previous investigation of purinergic modulation of the murine locomotor CPG. 12 / 17 Modulation of Spinal Motor Networks by Glia Stimulation of glia does not influence the frequency of synchronous, disinhibited bursting generated and coordinated exclusively by excitatory components of the motor circuitry, consistent with our previous finding that exogenously applied adenosine has no effect on disinhibited bursting. We have previously demonstrated that disinhibited bursting remains sensitive to subtle neuromodulatory MedChemExpress 92-61-5 influences, suggesting that PAR1 activation would result in a measurable effect on disinhibited bursting if the excitatory neurons underlying this activity were sensitive to modulation by adenosine. Although it remains uncertain whether common circuit elements underlie both disinhibited and left-right alternating rhythms, the data presented here imply that adenosine acts on inhibitory interneurons to modulate the frequency of locomotor-related bursting, a conclusion supported by our recent finding that adenosine modulates inhibitory transmission onto ventral horn interneurons. A model in which adenosine acts on inhibitory interneurons to modulate locomotor-related activity may appear to contradict the recent finding by Carlsen and Perrier that glial cell-derived adenosine modulates excitatory transmission onto ventral horn interneurons. However, an indirect mechanism whereby adenosine modulated excitatory drive to inhibitory interneurons could also explain the loss of modulation in disinhibited preparations. Because adenosine does PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19756412 not affect the contralateral alternation of locomotor-related bursts, we have previously proposed that adenosine may modulate the activity of ipsilaterally projecting inhibitory interneurons, of which V1 local circuit inhibitory neurons are an example. The PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19755349 ablation or inactivation of V1 interneurons results in a reduction in the frequency of locomotor-like activity, making them a candidate for future studies aiming to decipher the cellular targets of modulatory adenosine. Modulation of V1 or a similar population of ipsilaterally projecting inhibitory interneurons could reflect either a direct action of adenosine on those neurons or an indirect action on the excitatory inputs they receive. Future experiments should seek to identify directly the population of neurons on which glial cell-derived adenosine acts to inhibit locomotor-related activity and the mechanism or mechanisms by which its action on individual neurons translates to regulation of the frequency of rhythmic activity at the network level. Finally, we provide evidence that the influence of endogenous adenosine on network output increases with the frequency of network activity, likely reflecting enhanced release of ATPadenosine from glia and implying a mechanism for the detection of neuronal activity by glia. In other preparations glial Ca2+ signalling is triggered by the spillover of neurotransmitters from synapses. A similar mechanism operating in the spinal cord may therefore involve the spillover of glutamate, glycine or GABA, all of which are endogenous neurotransmitters to which spinal glia have been shown to respond. Activity-dependent increases in extracellular adenosine have previously been detected in several preparations. Of particular relevance to this study is 
the Xenopus tadpole spinal cord, in which ATP is released during swimming episodes and enhances the excitability of motor networks. The hydrolysis of ATP by ecto