D1/D5 modulation of synaptic NMDA receptor currents.
Converging evidence suggests that salience-associated modulation of behavior is mediated by the release of monoamines and that monoaminergic activation of D(1)/D(5) receptors is required for normal hippocampal-dependent learning and memory. However, it is not understood how D(1)/D(5) modulation of hippocampal circuits can affect salience-associated learning and memory. We have observed in CA1 pyramidal neurons that D(1)/D(5) receptor activation elicits a bidirectional long-term plasticity of NMDA receptor-mediated synaptic currents with the polarity of plasticity determined by NMDA receptor, NR2A/B subunit composition. This plasticity results in a decrease in the NR2A/NR2B ratio of subunit composition. Synaptic responses mediated by NMDA receptors that include NR2B subunits are potentiated by D(1)/D(5) receptor activation, whereas responses mediated by NMDA receptors that include NR2A subunits are depressed. Furthermore, these bidirectional, subunit-specific effects are mediated by distinctive intracellular signaling mechanisms. Because there is a predominance of NMDA receptors composed of NR2A subunits observed in entorhinal-CA1 inputs and a predominance of NMDA receptors composed of NR2B subunits in CA3-CA1 synapses, potentiation of synaptic NMDA currents predominates in the proximal CA3-CA1 synapses, whereas depression of synaptic NMDA currents predominates in the distal entorhinal-CA1 synapses. Finally, all of these effects are reproduced by the release of endogenous monoamines through activation of D(1)/D(5) receptors. Thus, endogenous D(1)/D(5) activation can (1) decrease the NR2A/NR2B ratio of NMDA receptor subunit composition at glutamatergic synapses, a rejuvenation to a composition similar to developmentally immature synapses, and, (2) in CA1, bias NMDA receptor responsiveness toward the more highly processed trisynaptic CA3-CA1 circuit and away from the direct entorhinal-CA1 input.
Varela
Juan A
JA
Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390, USA.
Hirsch
Silke J
SJ
Chapman
David
D
Leverich
Leah S
LS
Greene
Robert W
RW
D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D050641:Receptors, Dopamine D5 / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D050641:Receptors, Dopamine D5