Dopamine D1 but not D3 receptor is critical for spatial learning and related signaling in the hippocampus.

Experimental evidence suggests the involvement of the brain dopaminergic system in learning and memory processes, although the associated molecular mechanism has yet to be fully characterized. Memory formation occurs via a number of signaling pathways associated with activation of many synaptic plasticity-related proteins, including the N-Methyl-D-aspartic acid (NMDA) receptor, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), mitogen-activated protein kinases (MAPKs) and the cAMP-response element binding protein (CREB). To evaluate the roles of dopamine D(1) and D(3) receptors in spatial learning and memory and underlying molecular events, we have used genetically modified mice carrying either the D(1) or D(3) receptor gene mutations to explore the intracellular signaling pathways using Morris water maze (MWM) tasks. We show that D(1) receptor mutant mice do not acquire spatial memory and do not show hippocampal activation of extracellular signal-regulated kinase (ERK) compared to wild-type mice. D(3) receptor mutant mice exhibit apparent normal learning abilities in the MWM test and normal activation of MAPK signaling. Furthermore, activation of the NMDA receptor R1 subunit (NR1), CaMKII and CREB in the hippocampus is also significantly lower in D(1) receptor mutant mice compared to wild-type and D(3) receptor mutant mice. These results suggest that dopamine D(1) but not D(3) receptor is critical for spatial learning. D(1) receptor-mediated signaling, associated with activation of NR1, CaMKII, ERK and CREB, is highly involved in the encoding of spatial learning and memory.