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

腺苷是一种重要的信号分子，在正常和异常的大脑功能中发挥着重要作用。腺苷释放的细胞来源和机制一直是一个不确定的领域。我们现在处于一个独特的有利地位来研究这个问题，因为我们已经开发了新的技术来直接测量体外啮齿动物脑片的活性依赖的腺苷释放。我们对腺苷的测量对根深蒂固的共识--腺苷不能通过胞吐作用(一种普遍的释放机制)释放--提出了质疑。因此，我们的目标是证明腺苷的细胞来源，以及腺苷的直接胞吐释放是否发生在称为小脑的大脑区域。这一演示有可能彻底改变我们对腺苷信号的理解，因为它证明了迄今为止被广泛打折扣的一类机制确实发挥了作用。然后，我们将描述腺苷信号的重要特性，例如：它如何依赖于神经活动的模式；它如何被调制；腺苷如何扩散以抑制相邻神经元之间的信号传递；以及这种抑制作用持续多远和多久。我们将创建一个详细的计算模型，帮助我们理解腺苷是如何控制小脑中的信息流的。

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.