Dopamine and tyrosine phosphorylation of NR2B (Y1472) in the hippocampus is fundamental for ERK2 activation and novel learning: 23rd Biennial Meeting of ISN/ESN, Athens, Greece, 28 August ‐ 1 September 2011

We have previously shown that dopamine and NMDA (N-methyl-D-aspartate) converge on Extra cellular Regulated Kinase -Mitogen-Activated Protein Kinase signalling in the rat hippocampusand that ERK activation by dopamine is NMDA receptor dependent(Kaphzan et al., 2006). The complex interaction between dopamineand NMDA receptors is significant for different normal andabnormal learning processes. Here, we tested the hypothesis thatdopamine interacts with NMDA receptors via tyrosine phosphor-ylation of the NR2 subunits A and B and that this interaction isupstream to MAPK cascade activation. We found that dopamineinduces tyrosine phosphorylation of NR2A Y1325 (1.38 ± 0.09,p < 0.001, n > 10 vs. control) and NR2B Y1472 (1.47 ± 0.12,p < 0.001, n > 10 vs.control). Phosphory%ADlation of NR2BY1472 correlated with ERK2 activation (r = 0.41, p < 0.05,n = 14). Moreover, dopamine leads to induction in the phosphor-ylation of Src Y418 and the Src-protein tyrosine kinaseinhibitor4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine(PP2) inhibits the dopamine effect on ERK2 (1.11 ± 0.05, p < 0.05,n = 20 vs. dopamine) and NR2BY1472 (1.01 ± 0.07, p < 0.01,n = 18 vs. dopamine), but not on NR2A Y1325 (1.39 ± 0.14,p < 0.05, n = 20 vs.control). In order to test causality betweenNR2B Y1472 phosphorylation and ERK2 activation by dopamine,we carried out similar pharmacological manipulations in hippo-campal slices of WT and NR2B 1472 KI mice and detect clearinduction in the WT, but no changes were observed in the KI mice.Since dopamine signaling is known to play key role in noveltylearning, we tested the KI mice in different behavioral paradigms ofnovelty and found clear attenuation in the KI compared with the WTmice in novel place, novel object and novel taste learning for 0.5%saccharin. These results demonstrate that dopamine signaling viatyrosine phosphorylation of NR2B subunit is playing pivotal role innovel learning and ERK activation. It is plausible that the specificsites of post-translation modifications of the NMDA receptor canserve as new targets for therapy of psychiatric diseases such asSchizophrenia.