TY - JOUR
T1 - D1/D5 modulation of synaptic NMDA receptor currents
AU - Varela, Juan A.
AU - Hirsch, Silke J.
AU - Chapman, David
AU - Leverich, Leah S.
AU - Greene, Robert W.
PY - 2009/3/11
Y1 - 2009/3/11
N2 - Converging evidence suggests that salience-associated modulation of behavior is mediated by the release of monoamines and that monoaminergic activation of D1/D3 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 CAl 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 D 1/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-CAl input.
AB - Converging evidence suggests that salience-associated modulation of behavior is mediated by the release of monoamines and that monoaminergic activation of D1/D3 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 CAl 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 D 1/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-CAl input.
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U2 - 10.1523/JNEUROSCI.4746-08.2009
DO - 10.1523/JNEUROSCI.4746-08.2009
M3 - Article
C2 - 19279248
AN - SCOPUS:63849133443
SN - 0270-6474
VL - 29
SP - 3109
EP - 3119
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 10
ER -