Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Freie Universität Berlin, Institute for Biology/Genetics, Takustrasse 6, 14195 Berlin, Germany.
Development. 2020 Dec 16;147(24):dev191874. doi: 10.1242/dev.191874.
The balance among different subtypes of glutamate receptors (GluRs) is crucial for synaptic function and plasticity at excitatory synapses. However, the mechanisms balancing synaptic GluR subtypes remain unclear. Herein, we show that the two subtypes of GluRs (A and B) expressed at neuromuscular junction synapses mutually antagonize each other in terms of their relative synaptic levels and affect subsynaptic localization of each other, as shown by super-resolution microscopy. Upon temperature shift-induced neuromuscular junction plasticity, GluR subtype A increased but subtype B decreased with a timecourse of hours. Inhibition of the activity of GluR subtype A led to imbalance of GluR subtypes towards more GluRIIA. To gain a better understanding of the signalling pathways underlying the balance of GluR subtypes, we performed an RNA interference screen of candidate genes and found that postsynaptic-specific knockdown of , which encodes cAMP phosphodiesterase, increased levels of GluR subtype A but decreased subtype B. Furthermore, bidirectional alterations of postsynaptic cAMP signalling resulted in the same antagonistic regulation of the two GluR subtypes. Our findings thus identify a direct role of postsynaptic cAMP signalling in control of the plasticity-related balance of GluRs.
不同类型谷氨酸受体 (GluR) 之间的平衡对于兴奋性突触的突触功能和可塑性至关重要。然而，平衡突触 GluR 亚型的机制仍不清楚。在此，我们通过超分辨率显微镜显示，在神经肌肉接头突触上表达的两种 GluR 亚型 (A 和 B) 在其相对突触水平上相互拮抗，并影响彼此的亚突触定位。在温度诱导的神经肌肉接头可塑性过程中，GluR 亚型 A 的增加而亚型 B 的减少具有小时的时程。抑制 GluR 亚型 A 的活性会导致 GluR 亚型失衡，更多地向 GluRIIA 倾斜。为了更好地理解 GluR 亚型平衡背后的信号通路，我们对候选基因进行了 RNAi 筛选，发现编码 cAMP 磷酸二酯酶的突触后特异性 knockdown 会增加 GluR 亚型 A 的水平，但减少亚型 B。此外，突触后 cAMP 信号的双向改变导致两种 GluR 亚型的拮抗调节。因此，我们的发现确定了突触后 cAMP 信号在控制 GluR 与可塑性相关的平衡中的直接作用。
