| Abstract No.: | B-B2025 |
| Country: | Canada |
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| Title: | D1-LIKE DOPAMINE RECEPTORS MODULATE NR2B-CONTAINING NMDA CURRENTS VIA A PKA- AND FYN KINASE-DEPENDENT PATHWAY. |
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| Authors/Affiliations: | 1 Catherine H. Trepanier*; 1 Kai Yang; 1 Michelle E. Olah; 1 Ella Czerwinska; 1 Michael F. Jackson; 1 John F. MacDonald;
1 University of Toronto, ON, Canada
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| Content: | Interactions between N-methyl-D-aspartate receptors (NMDARs) and dopamine receptors in the hippocampus play an important role in learning and memory. In fact, drugs of abuse can hijack synaptic plasticity mechanisms in the mesolimbic dopamine system and contribute to the neural adaptations underlying addiction. The signaling cascade for the D1-NMDAR interaction is well established in the striatum and other brain regions, however little is known about how this pathway is conserved in the hippocampus. Since the hippocampus has an important role in learning and memory, this study sought to examine the regulation of NMDAR currents by the dopamine D1 receptor subclass (D1R) in identified CA1 hippocampal neurons. CA1 pyramidal neurons were isolated using enzymatic treatment directly from young adult hippocampal slices. Individual cells were examined immediately following isolation using the whole cell voltage-clamp and NMDARs were probed using a rapid (time constant of exchange of about 50 ms) perfusion system and applications of NMDA (3 s, 50 μM, 0.5 μM glycine). These currents characteristically formed a peak response followed by desensitization towards a steady-state value. Concurrent perfusion of the D1/D5 agonist, SKF 81297 (10 μM), for 5 min. potentiated the peak of the NMDA-evoked current in these acutely isolated CA1 pyramidal neurons. The observed potentiation did not reverse upon washout of the D1/D5 agonist, suggesting that some intracellular signaling mechanisms contributed to this effect rather than some direct protein-protein interactions between the D1R and NMDAR. Moreover, the observed enhancement was specific for the D1R as the D1 antagonist SCH 23390 (0.5 μM) completely blocked the enhancement of peak NMDAR currents. The D1R-mediated potentiation exhibited selectivity for the NR2B-containing NMDARs as its regulation was blocked by the NR2B-antagonist Ro 25-6981 (0.5 μM) but not by the NR2A-antagonist NVP-AAM007 (50 nM). Intracellular application of a peptide that selectively inhibits Fyn tyrosine kinase completely blocked the D1R effect on NMDAR currents whereas the Src inhibitory peptide, Src(40-58), had no effect. Furthermore, dialysis with the highly selective membrane-permeable protein kinase A (PKA) inhibitory peptide (PKI(14-22)) completely abolished the D1R-mediated effect on NMDAR currents. Overall, these results demonstrate that stimulation of D1Rs activates a signaling cascade, which recruits Fyn tyrosine kinase and selectively potentiates the NR2B-containing subtype of NMDARs in CA1 hippocampal neurons. Combined with previous findings on the D1R facilitation of long-term potentiation in the hippocampus, the results of the present study suggest a molecular signaling mechanism by which dopamine receptors target the NR2B subtype of receptor to modulate hippocampal synaptic plasticity. This work was supported by a CIHR grant to JFM (44008).
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