Action potential and Ca2+ dependent adenosine release in the cerebellum: release mechanisms and signalling properties

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Adenosine is a vital signalling molecule that plays important roles in normal and aberrant brain function. An abiding area of uncertainty is the cellular sources and mechanisms of adenosine release. We are now in a uniquely advantageous position to study this problem as we have developed novel technology to measure directly activity-dependent adenosine release from in-vitro rodent brain slices. Our measurements of adenosine have cast doubt on the entrenched consensus- that adenosine cannot be released by exocytosis (a universal mechanism of release). We therefore aim to demonstrate the cellular source of adenosine and whether or not direct exocytotic release of adenosine occurs in a brain region called the cerebellum. This demonstration has the potential to revolutionize our understanding of adenosine signalling by demonstrating that a hitherto largely discounted class of mechanism does indeed play a role. We shall then characterize important properties of adenosine signalling such as: how it depends upon patterns of neural activity; how it can be modulated; how adenosine diffuses to inhibit signalling between neighbouring neurones; and how far and for how long this inhibitory action extends. We shall create a detailed computational model that will aid our comprehension of how adenosine controls information flow in cerebellum.