6533b861fe1ef96bd12c4ea8

RESEARCH PRODUCT

D1/D5 modulation of synaptic NMDA receptor currents.

subject

description

Converging evidence suggests that salience-associated modulation of behavior is mediated by the release of monoamines and that monoaminergic activation of D1/D5receptors is required for normal hippocampal-dependent learning and memory. However, it is not understood how D1/D5modulation of hippocampal circuits can affect salience-associated learning and memory. We have observed in CA1 pyramidal neurons that D1/D5receptor 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/D5receptor 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/D5receptors. Thus, endogenous D1/D5activation 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.