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Localised adenosine signalling provides fine-tuned negative feedback over a wide dynamic range of neocortical network activities
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Wall, Mark J. and Richardson, Magnus J. E. (2015) Localised adenosine signalling provides fine-tuned negative feedback over a wide dynamic range of neocortical network activities. Journal of Neurophysiology, 113 (3). pp. 871-882. doi:10.1152/jn.00620.2014
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Official URL: http://dx.doi.org/10.1152/jn.00620.2014
Abstract
Although the patterns of activity produced by neocortical networks are becoming better understood, how these states are activated, sustained and terminated still remains unclear. Negative feedback by the endogenous neuromodulator adenosine could potentially play an important role, as it can be released by activity and there is dense A1 receptor expression in the neocortex. Using electrophysiology, biosensors and modelling, we have investigated the properties of adenosine signalling during physiological and pathological network activity in rat neocortical slices. Both low and high-rate network activities were reduced by A1 receptor activation and enhanced by block of A1 receptors, consistent with activity-dependent adenosine release. Since the A1 receptors were neither saturated nor completely unoccupied during either low or high-rate activity, adenosine signalling provides a negative feedback mechanism with a wide dynamic range. Modelling and biosensor experiments show that during high-rate activity, increases in extracellular adenosine concentration are highly localised and are uncorrelated over short distances that are certainly less than 500 μm. Modelling also predicts that the slow time course of the purine waveform cannot be from diffusion from distal release sites but more likely results from uptake and metabolism. The inability to directly measure adenosine release during low-rate activity, although it is present, is probably a consequence of small localised increases in adenosine concentration which are rapidly diminished by diffusion and active removal mechanisms. Saturation of such removal mechanisms when higher concentrations of adenosine are released, results in the accumulation of inosine, explaining the strong purine signal during high-rate activity.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science > Life Sciences (2010- ) | ||||||
| Journal or Publication Title: | Journal of Neurophysiology | ||||||
| Publisher: | American Physiological Society | ||||||
| ISSN: | 0022-3077 | ||||||
| Official Date: | 1 February 2015 | ||||||
| Dates: |
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| Date of first compliant deposit: | 28 December 2015 | ||||||
| Volume: | 113 | ||||||
| Number: | 3 | ||||||
| Page Range: | pp. 871-882 | ||||||
| DOI: | 10.1152/jn.00620.2014 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access |
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