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The Journal of Neuroscience, March 11, 2009, 29(10):3109-3119; doi:10.1523/JNEUROSCI.4746-08.2009

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Cellular/Molecular
D₁/D₅ Modulation of Synaptic NMDA Receptor Currents

Juan A. Varela,¹ Silke J. Hirsch,² David Chapman,¹ Leah S. Leverich,¹ and Robert W. Greene^1,3

¹Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390, ²Department of Physiology, University of Mainz, D-55099 Mainz, Germany, and ³Veterans Affairs Medical Center, Dallas, Texas 75216

Correspondence should be addressed to Robert W. Greene, 5323 Harry Hines Boulevard, Dallas, TX 75390. Email: robertw.greene{at}utsouthwestern.edu

Converging evidence suggests that salience-associated modulation of behavior is mediated by the release of monoamines and that monoaminergic activation of D₁/D₅ receptors is required for normal hippocampal-dependent learning and memory. However, it is not understood how D₁/D₅ modulation of hippocampal circuits can affect salience-associated learning and memory. We have observed in CA1 pyramidal neurons that D₁/D₅ 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 D₁/D₅ 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 D₁/D₅ receptors. Thus, endogenous D₁/D₅ 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.

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Received Oct. 2, 2008; revised Jan. 19, 2009; accepted Jan. 20, 2009.

Correspondence should be addressed to Robert W. Greene, 5323 Harry Hines Boulevard, Dallas, TX 75390. Email: robertw.greene{at}utsouthwestern.edu

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