Adenosine, a major neuromodulator in the central nervous system (CNS), is involved in a variety of regulatory functions such as the sleep/wake cycle. Because exogenous adenosine displays dark- and night-mimicking effects in the vertebrate retina, we tested the hypothesis that a circadian (24 h) clock in the retina uses adenosine to control neuronal light responses and information processing. Using a variety of techniques in the intact goldfish retina including measurements of adenosine overflow and content, tracer labeling, and electrical recording of the light responses of cone photoreceptor cells and cone horizontal cells (cHCs), which are post-synaptic to cones, we demonstrate that a circadian clock in the retina itself—but not activation of melatonin or dopamine receptors—controls extracellular and intracellular adenosine levels so that they are highest during the subjective night. Moreover, the results show that the clock increases extracellular adenosine at night by enhancing adenosine content so that inward adenosine transport ceases. Also, we report that circadian clock control of endogenous cone adenosine A_2A receptor activation increases rod-cone gap junction coupling and rod input to cones and cHCs at night. These results demonstrate that adenosine and A_2A receptor activity are controlled by a circadian clock in the retina, and are used by the clock to modulate rod-cone electrical synapses and the sensitivity of cones and cHCs to very dim light stimuli. Moreover, the adenosine system represents a separate circadian-controlled pathway in the retina that is independent of the melatonin/dopamine pathway but which nevertheless acts in concert to enhance the day/night difference in rod-cone coupling.

腺苷是中枢神经系统 (CNS) 中的主要神经调节剂，参与多种调节功能，例如睡眠/觉醒周期。因为外源性腺苷在脊椎动物视网膜中表现出模拟黑暗和夜间的作用，我们测试了视网膜中的昼夜节律（24 小时）时钟使用腺苷来控制神经元光反应和信息处理的假设。在完整的金鱼视网膜中使用各种技术，包括腺苷溢出和含量的测量、示踪剂标记以及锥体感光细胞和锥体水平细胞 (cHC) 的光响应的电记录，这些细胞是突触后的锥体，我们证明了视网膜本身的生物钟——但不是褪黑激素或多巴胺受体的激活——控制细胞外和细胞内腺苷水平，因此它们在主观夜间最高。此外，结果表明，时钟通过增加腺苷含量在夜间增加细胞外腺苷，从而停止向内的腺苷转运。此外，我们报告内源性锥腺苷 A 的生物钟控制_2A受体激活增加了夜间视锥细胞和 cHCs 的视杆-视锥间隙连接耦合和视杆输入。这些结果表明，腺苷和 A _2A受体活性受视网膜中的生物钟控制，并被生物钟用来调节视杆锥电突触以及视锥细胞和 cHCs 对非常微弱的光刺激的敏感性。此外，腺苷系统代表了视网膜中一个独立的昼夜节律控制通路，它独立于褪黑激素/多巴胺通路，但仍协同作用以增强视杆-视锥细胞耦合的昼夜差异。