Uncoupling the D1-N-Methyl-D-Aspartate (NMDA) Receptor Complex Promotes NMDA-Dependent Long-Term Potentiation and Working Memory

Qiang Nai, Shupeng Li, Szu-Han Wang, Jing Liu, Frank J. S. Lee, Paul W. Frankland, Fang Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Although dopamine D1 receptors are involved in working memory, how D1 receptors contribute to this process remains unclear. Numerous studies have shown that D1 receptors have extensive functional interaction with N-methyl-D-aspartate (NMDA) receptor. Our group previously demonstrated that D1 receptors were able to regulate NMDA receptor functions through direct protein-protein interactions involving the carboxyl terminals of D1 receptors and NMDA receptor NR1a and NR2A subunits respectively. In this study, we explored the effects of the D1-NR1 interaction on NMDA receptor-dependent long-term potentiation (LTP) and working memory by using the TAT-conjugated interfering peptide (TAT-D1-t2).

Methods: Miniature excitatory postsynaptic currents are recorded in rat hippocampal primary cultures. Coimmunoprecipitation and calcium/calmodulin-dependent protein kinase II (CaMKII) activity are measured in hippocampal slices and hippocampal neurons under the specified experimental conditions, respectively. Working memory was assessed using a delayed match-to-place protocol in the MorrisWaterMaze following administration of the TAT-D1-t2 peptide.

Results: Electrophysiology experiments showed that activation of D1 receptor upregulates NMDA receptor-mediated LTIP in a CaMKII-dependent manner. Furthermore, D1 receptor agonist stimulation promotes the NR1-CaMKII coupling and enhances the CaMKII activity; and the D1 receptor-mediated effects can be blocked by the application of the TAT-D1-t2 pepticle. Interestingly, animals injected with TAT-D1-t2 pepticle exhibited significantly impaired working memory.

Conclusions: Our study showed a critical role of NMDA-D1 direct protein-protein interaction in NMDA receptor-mediated LTP and working memory and implicated the involvement of CaMKII in this process.

Original languageEnglish
Pages (from-to)246-254
Number of pages9
JournalBiological Psychiatry
Volume67
Issue number3
DOIs
Publication statusPublished - 1 Feb 2010

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