Localized adenosine signaling provides fine-tuned negative feedback over a wide dynamic range of neocortical network activities

• Published in: Journal of neurophysiology 2015-02, Vol.113 (3), p.871-882
• Main Authors: Wall, Mark J, Richardson, Magnus J E
• Format: Article
• Language: English
• Subjects: Action Potentials; Adenosine - metabolism; Animals; Feedback, Physiological; Male; Models, Neurological; Neocortex - metabolism; Neocortex - physiology; Neural Circuits; Rats; Rats, Wistar; Signal Transduction
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.00620.2014

Although the patterns of activity produced by neocortical networks are now better understood, how these states are activated, sustained, and terminated still remains unclear. Negative feedback by the endogenous neuromodulator adenosine may 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 modeling, we have investigated the properties of adenosine signaling 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 signaling provides a negative-feedback mechanism with a wide dynamic range. Modeling and biosensor experiments show that during high-rate activity increases in extracellular adenosine concentration are highly localized and are uncorrelated over short distances that are certainly