Astrocytes contribute to synapse elimination via type 2 inositol 1,4,5-trisphosphate receptor-dependent release of ATP.
Astrocytes contribute to synapse elimination via type 2 inositol 1,4,5-trisphosphate receptor-dependent release of ATP.
复制标题
星形胶质细胞通过 2 型肌醇 1,4,5-三磷酸受体依赖性 ATP 释放来促进突触消除。
作者：
Yang J;Yang H;Liu Y;Li X;Qin L;Lou H;Duan S;Wang H
选择性消除不需要的突触对于发育期间神经元回路的精确形成至关重要，但其潜在机制仍不清楚。使用肌醇1，4，5-三磷酸受体2型敲除（Itpr 2 −/−）小鼠特异性干扰星形胶质细胞中的体细胞Ca 2+信号，我们发现腹后内侧核中继突触的发育消除受损。有趣的是，脑室内注射ATP而不是腺苷，挽救了Itpr 2 −/−小鼠突触消除的缺陷。进一步的研究表明，P2 ry 1 −/−小鼠的发育性突触消除也受到损害，并且不能被ATP拯救，这表明嘌呤能信号可能发挥作用。这一假设得到了MRS-2365的证实，MRS-2365是一种选择性P2 Y1激动剂，也可以挽救Itpr 2 −/−小鼠中突触消除的缺陷。我们的研究结果揭示了一种新的机制，表明星形胶质细胞以IP 3R 2依赖的方式释放ATP来调节突触消除。http://dx.doi.org/10.7554/eLife.15043.001相邻的神经元通过称为突触的结构相互连接并共享信息。随着大脑的发育，许多突触变得多余。就像花园里的树木需要修剪一样，这些多余的突触必须被修剪，以便在不同的神经元之间形成正确的连接模式。称为星形胶质细胞的脑细胞在突触修剪中发挥着关键作用，但目前尚不清楚星形胶质细胞到底如何协调这一过程。星形胶质细胞与神经元交流的一个重要方式是通过一个称为钙信号传导的过程，在这个过程中，钙离子进出细胞会在星形胶质细胞内引发一连串的活动。Yang等人现在已经研究了缺乏星形胶质细胞中钙信号传导所必需的基因的发育小鼠。出生两周后，这些小鼠仍然有多余的突触，这些突触通常在出生后丢失。然而，给发育中的大脑注射一种叫做ATP的物质可以防止这种缺陷，并允许突触被正确修剪。这可能是因为星形胶质细胞也使用ATP与神经元通信，ATP补偿了丢失的钙信号。实验还发现了一种特殊的结构-称为P2 Y1受体-在神经元的外表面上，ATP锁定在其上以帮助消除突触。现在需要进一步的工作来揭示激活P2 Y1受体如何协调突触的去除。DOI：http://dx.doi.org/10.7554/eLife.15043.002网站
Selective elimination of unwanted synapses is vital for the precise formation of neuronal circuits during development, but the underlying mechanisms remain unclear. Using inositol 1,4,5-trisphosphate receptor type 2 knockout (Itpr2−/−) mice to specifically disturb somatic Ca2+ signaling in astrocytes, we showed that developmental elimination of the ventral posteromedial nucleus relay synapse was impaired. Interestingly, intracerebroventricular injection of ATP, but not adenosine, rescued the deficit in synapse elimination in Itpr2−/− mice. Further studies showed that developmental synapse elimination was also impaired in P2ry1−/− mice and was not rescued by ATP, indicating a possible role of purinergic signaling. This hypothesis was confirmed by MRS-2365, a selective P2Y1 agonist, could also rescue the deficient of synapse elimination in Itpr2−/− mice. Our results uncovered a novel mechanism suggesting that astrocytes release ATP in an IP3R2-dependent manner to regulate synapse elimination. DOI: http://dx.doi.org/10.7554/eLife.15043.001 Neighbouring neurons connect to each other and share information through structures known as synapses. As the brain develops, many synapses turn out to be redundant. Just like trees in a garden that need to be trimmed, these redundant synapses must be pruned in order to form the right pattern of connections between different neurons. Brain cells called astrocytes play a key role in synaptic pruning, but it is unclear exactly how astrocytes coordinate this process. One important way in which astrocytes communicate with neurons is through a process called calcium signaling, in which the movement of calcium ions into or out of the cell sets off a cascade of activity inside the astrocytes. Yang et al. have now studied developing mice that lacked a gene that is essential for calcium signaling in astrocytes. Two weeks after they were born, these mice still had redundant synapses that are normally lost after birth. However, injecting the developing brain with a substance called ATP prevented this defect and allowed synapses to be correctly pruned. This is likely to be because astrocytes also use ATP to communicate with neurons, and ATP compensated for the missing calcium signaling. The experiments also uncovered the specific structure – called the P2Y1 receptor – on the outer surface of a neuron that ATP latches on to in order to help remove synapses. Further work is now needed to reveal how activating the P2Y1 receptor coordinates synaptic removal. DOI: http://dx.doi.org/10.7554/eLife.15043.002