Postsynaptic cAMP Signalling Regulates the Antagonistic Balance of Glutamate Receptor Subtypes

Kai Zhao, Huilin Hong, Lu Zhao, Sheng Huang, Ying Gao, Elsayed Metwally, Yuqiang Jiang, Stephan J. Sigrist, Yong Q. Zhang



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 Drosophilaneuromuscular junction (NMJ) synapses mutually antagonize each other in terms of their relative synaptic levels, and affect sub-synaptic localisation of each other as shown by super-resolution microscopy. Upon temperature-shift induced NMJ plasticity, GluR subtype A increased but subtype B decreased in the course of hours. Inhibiting the activity of GluR subtype A leads to imbalance of GluR subtypes towards more GluRIIA.To further understand signalling pathways underlying the balance of GluR subtypes, we performed an RNAi screen of candidate genes and found that postsynaptic specific knockdown of dunce, which encodes cAMP phosphodiesterase, increased A but decreased B GluR subtype levels. 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 controlling the plasticity-related balance of GluRs.