Dopamine D(2)R is Required for Hippocampal-dependent Memory and Plasticity at the CA3-CA1 Synapse

Dopamine receptors play an important role in motivational, emotional, and motor responses. In addition, growing evidence suggests a key role of hippocampal dopamine receptors in learning and memory. It is well known that associative learning and synaptic plasticity of CA3-CA1 requires the dopamine D(1) receptor (D(1)R). However, the specific role of the dopamine D(2) receptor (D(2)R) on memory-related neuroplasticity processes is still undefined. Here, by using two models of D(2)R loss, D(2)R knockout mice (Drd2(−/−)) and mice with intrahippocampal injections of Drd2-small interfering RNA (Drd2-siRNA), we aimed to investigate how D(2)R is involved in learning and memory as well as in long-term potentiation of the hippocampus. Our studies revealed that the genetic inactivation of D(2)R impaired the spatial memory, associative learning, and the classical conditioning of eyelid responses. Similarly, deletion of D(2)R reduced the activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. Our results demonstrate the first direct evidence that D(2)R is essential in behaving mice for trace eye blink conditioning and associated changes in hippocampal synaptic strength. Taken together, these results indicate a key role of D(2)R in regulating hippocampal plasticity changes and, in consequence, acquisition and consolidation of spatial and associative forms of memory.