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Mechanisms underlying the synaptic trafficking of the glutamate delta receptor GluD1

Abstract

Ionotropic glutamate delta receptors do not bind glutamate and do not generate ionic current, resulting in difficulty in studying the function and trafficking of these receptors. Here, we utilize chimeric constructs, in which the ligand-binding domain of GluD1 is replaced by that of GluK1, to examine its synaptic trafficking and plasticity. GluD1 trafficked to the synapse, but was incapable of expressing long-term potentiation (LTP). The C-terminal domain (CT) of GluD1 has a classic PDZ-binding motif, which is critical for the synaptic trafficking of other glutamate receptors, but we found that its binding to PSD-95 was very weak, and deleting the PDZ-binding motif failed to alter synaptic trafficking. However, deletion of the entire CT abolished synaptic trafficking, but not surface expression. We found that mutation of threonine (T) T923 to an alanine disrupted synaptic trafficking. Therefore, GluD1 receptors have strikingly different trafficking mechanisms compared with AMPARs. These results highlight the diversity of ionotropic glutamate receptor trafficking rules at a single type of synapse. Since this receptor is genetically associated with schizophrenia, our findings may provide an important clue to understand schizophrenia.

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Acknowledgements

We thank Dr. Michael Hollmann for the GluD1 and GluD1-K2 plasmids and Dr. Menglong Zeng for helping with the experiments on the GluD1/PSD-95 binding assay. We thank members of the Nicoll lab for comments on the paper. We appreciate the technical assistance from Dan Qin. This research was supported by grants from NIMH and RGC of Hong Kong.

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Correspondence to Roger A. Nicoll.

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Tao, W., Ma, C., Bemben, M. et al. Mechanisms underlying the synaptic trafficking of the glutamate delta receptor GluD1. Mol Psychiatry 24, 1451–1460 (2019). https://doi.org/10.1038/s41380-019-0378-4

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