D1 but not D5 dopamine receptors are critical for LTP, spatial learning, and LTP-Induced arc and zif268 expression in the hippocampus.

Recent evidence suggests that glutamatergic and dopaminergic afferents must be activated to induce persistent long-term potentiation (LTP) in the hippocampus. Whereas extensive evidence supports the role of glutamate receptors in long-lasting synaptic plasticity and spatial learning and memory, there is less evidence regarding the role of dopamine receptors in these processes. Here, we used dopamine D(1) receptor knockout (D(1)R(-/-)) mice to explore the role of D(1)R in hippocampal LTP and its associated gene expression. We show that the magnitude of early and late phases of LTP (E-LTP and L-LTP) was markedly reduced in hippocampal slices from D(1)R(-/-) mice compared with wild-type mice. SCH23390, a D(1)/D(5)R antagonist, did not further reduce L-LTP in D(1)R(-/-) mice, suggesting that D(5)Rs are not involved. D(1)R(-/-) mice also showed a significant reduction of D(1)R-induced potentiation of N-Methyl-D-aspartic acid-mediated currents, via protein kinase activated by cyclic adenosine 3',5'-monophosphate activation. Finally, LTP-induced expression of the immediate early genes zif268 and arc in the hippocampal CA1 area was abolished in D(1)R(-/-) mice, and these mice showed impaired learning. These results indicate that D(1)R but not D(5)R are critical for hippocampal LTP and for the induction of Zif268 and Arc, proteins required for the transition from E-LTP to L-LTP and for memory consolidation in mammals.