Uncoupling the D1-N-methyl-D-aspartate (NMDA) receptor complex promotes NMDA-dependent long-term potentiation and working memory.
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.
Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, Toronto, ON M5T 1R8, Canada.
Qiang
Q
Nai
Shupeng
S
Li
Szu-Han
SH
Wang
Jing
J
Liu
Frank J S
FJ
Lee
Paul W
PW
Frankland
Fang
F
Liu
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001703:Biophysics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000737:chemistry / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D001552:Benzazepines; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D010455:Peptides; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; C067113:SK&F 81297; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2