Dopamine D1/5 Receptor Modulation of Excitatory Neurotransmission and Synaptic Plasticity

Dopamine D1/5 receptor (D1/5R) activation modulates glutamate-dependent neuroplasticity thought to underlie learning and memory. Disturbances in dopamine-glutamate signaling have been implicated in neuropsychiatric disorders such as schizophrenia and addiction. Despite its importance, a mechanism responsible for D1/5R modulation of glutamate-dependent neuroplasticity remains unknown. Here we present evidence using field potential recordings from hippocampal slices showing that D1/5R activation establishes a prolonged temporal window for the induction of NMDA receptor-dependent synaptic plasticity. We found that D1/5R activation increases synaptic responses and long-term potentiation (LTP) expression through a pathway involving NR2B-NMDARs, PKA, PKC, PKM zeta, and src-family tyrosine kinases. D1/5R activation produced sustained increases in the surface expression of NR2B and GluR1 subunits in hippocampal slices, and this increase required the activity of NR2B-NMDARs. Consistent with our field potential recordings, D1/5R activation during memory consolidation facilitates extinction learning to conditioned fear, providing functional relevance for a prolonged window of synaptic potentiation ediated by D1/5Rs at the level of behavioral output.