Astrocytes are multi-functional glial cells in the central nervous system that play critical roles in modulation of metabolism, extracellular ion and neurotransmitter levels, and synaptic plasticity. Astrocyte-derived signaling molecules mediate many of these modulatory functions of astrocytes, including vesicular release of ATP. In the present study, we used a unique genetic mouse model to investigate the functional significance of astrocytic exocytosis of ATP. Using primary cultured astrocytes, we show that loss of vesicular nucleotide transporter (Vnut), a primary transporter responsible for loading cytosolic ATP into the secretory vesicles, dramatically reduces ATP loading into secretory lysosomes and ATP release, without any change in the molecular machinery of exocytosis or total intracellular ATP content. Deletion of astrocytic Vnut in adult mice leads to increased anxiety, depressive-like behaviors, and decreased motivation for reward, especially in females, without significant impact on food intake, systemic glucose metabolism, cognition, or sociability. These behavioral alterations are associated with significant decreases in the basal extracellular dopamine levels in the nucleus accumbens. Likewise, ex vivo brain slices from these mice show a strong trend toward a reduction in evoked dopamine release in the nucleus accumbens. Mechanistically, the reduced dopamine signaling we observed is likely due to an increased expression of monoamine oxidases. Together, these data demonstrate a key modulatory role of astrocytic exocytosis of ATP in anxiety, depressive-like behavior, and motivation for reward, by regulating the mesolimbic dopamine circuitry.

星形胶质细胞是中枢神经系统中的多功能神经胶质细胞，在调节新陈代谢、细胞外离子和神经递质水平以及突触可塑性方面发挥着关键作用。星形胶质细胞衍生的信号分子介导星形胶质细胞的许多调节功能，包括 ATP 的囊泡释放。在本研究中，我们使用独特的遗传小鼠模型来研究星形细胞 ATP 胞吐作用的功能意义。使用原代培养的星形胶质细胞，我们发现，囊泡核苷酸转运蛋白（Vnut）（一种负责将胞质 ATP 加载到分泌囊泡中的主要转运蛋白）的丢失，会显着减少 ATP 加载到分泌溶酶体中和 ATP 释放，而胞吐作用的分子机制没有任何变化或细胞内总 ATP 含量。删除成年小鼠的星形细胞Vnut会导致焦虑增加、抑郁样行为和奖励动机下降，尤其是雌性小鼠，但对食物摄入、全身葡萄糖代谢、认知或社交能力没有显着影响。这些行为改变与伏隔核中基础细胞外多巴胺水平的显着降低有关。同样，这些小鼠的离体脑切片显示出伏隔核中诱发的多巴胺释放减少的强烈趋势。从机制上讲，我们观察到的多巴胺信号传导减少可能是由于单胺氧化酶表达增加所致。总之，这些数据证明了 ATP 星形细胞胞吐作用通过调节中脑边缘多巴胺回路，在焦虑、抑郁样行为和奖励动机中发挥关键调节作用。