Elsevier

Biological Psychiatry

Volume 67, Issue 3, 1 February 2010, Pages 246-254
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2009.08.011Get rights and content

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 Morris Water Maze following administration of the TAT-D1-t2 peptide.

Results

Electrophysiology experiments showed that activation of D1 receptor upregulates NMDA receptor-mediated LTP 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 peptide. Interestingly, animals injected with TAT-D1-t2 peptide 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.

Section snippets

Primary Cell Culture

Hippocampal neurons from fetal (E18) Wistar rats were cultured as described previously (23). The cells were plated on glass coverslips coated with .1 mg/mL poly-d-lysine in borate buffer (25). The cultures were maintained by feeding twice a week by replacing half medium with fresh feeding medium. After 6 days of plating, 5 μmol/L Ara-C was added to stop the growth of glial cells.

Electrophysiology

Miniature excitatory postsynaptic currents (mEPSCs) were recorded from cultured hippocampal neurons 17 days after

Activation of D1R Upregulated NMDAR-Dependent LTP of mEPSCs in Hippocampal Neurons Through the D1–NR1 Direct Protein–Protein Interaction

The glycine-induced LTP model in hippocampal primary cultures is a validated model of LTP, similar to the electrically evoked EPSCs in CA1 neurons in hippocampal slices as previously described (23, 26, 28). Before determining the effect of D1R activation on synaptic activity, we used the glycine (200 μmol/L; 3 min) to validate our experimental system (data not shown). Once confirmed, we then tested whether activation of D1R can modulate mEPSC in hippocampal primary culture. SKF 81297 (10

Discussion

Consistent with previous studies demonstrating that D1R agonists stimulation increases LTP of field EPSPs (11, 35, 36), we have demonstrated that D1R stimulation can augment LTP of mEPSC in dissociated primary cultured rat hippocampal neurons in vitro. Moreover, we have shown that the D1R-induced increase in LTP is mediated by the D1R–NR1 interaction. Previous studies have suggested the involvement of both glutamate and dopamine in both LTP and in spatial working memory in the hippocampus (37,

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    Authors QN, SL, and S-HW contributed equally to this work.

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