Dissecting the contribution of individual receptor subunits to the enhancement of N-methyl-D-aspartate currents by dopamine D1 receptor activation in striatum

Emily L Jocoy

doi:10.3389/fnsys.2011.00028

Abstract

Dopamine, via activation of D1 receptors, enhances N-methyl-d-aspartate (NMDA) receptor-mediated responses in striatal medium-sized spiny neurons. However, the role of specific NMDA receptor subunits in this enhancement remains unknown. Here we used genetic and pharmacological tools to dissect the contribution of NR1 and NR2A/B subunits to NMDA responses and their modulation by dopamine receptors. We demonstrate that D1 enhancement of NMDA responses does not occur or is significantly reduced in mice with genetic knock-down of NR1 subunits, indicating a critical role of these subunits. Interestingly, spontaneous and evoked α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptor-mediated responses were significantly enhanced in NR1 knock-down animals, probably as a compensatory mechanism for the marked reduction in NMDA receptor function. The NMDA receptor subunits NR2A and NR2B played differential roles in D1 modulation. Whereas genetic deletion or pharmacological blockade of NR2A subunits enhanced D1 potentiation of NMDA responses, blockade of NR2B subunits reduced this potentiation, suggesting that these regulatory subunits of the NMDA receptor counterbalance their respective functions. In addition, using D1 and D2 receptor EGFP-expressing mice, we demonstrate that NR2A subunits contribute more to NMDA responses in D1-MSSNs, whereas NR2B subunits contribute more to NMDA responses in D2 cells. The differential contribution of discrete receptor subunits to NMDA responses and dopamine modulation in the striatum has important implications for synaptic plasticity and selective neuronal vulnerability in disease states.

Highlights

Glutamate and dopamine (DA) receptor interactions are vital to numerous functions including learning and memory, motor coordination, and reward mechanisms (Calabresi et al, 2000; Surmeier et al, 2007; Schultz, 2010)
Using D1 and D2 receptor EGFP-expressing mice, we demonstrate that NR2A subunits contribute more to NMDA responses in D1-medium-sized spiny neurons (MSSNs), whereas NR2B subunits contribute more to NMDA responses in D2 cells
Because synaptic inputs are mostly eliminated in dissociated MSSNs, these results suggest that either the NR2A subunit does not contribute significantly to mostly extrasynaptic NMDA receptors, or that compensatory effects result from genetic ablation of this subunit

Summary

Introduction

Glutamate and dopamine (DA) receptor interactions are vital to numerous functions including learning and memory, motor coordination, and reward mechanisms (Calabresi et al, 2000; Surmeier et al, 2007; Schultz, 2010) When dysfunctional, these receptor interactions contribute to the manifestation of psychiatric and neurodegenerative disorders (Andre et al, 2010b). Modulation can occur through a variety of mechanisms including multiple transduction pathways, voltage-gated Ca2+ channels, receptor subunit phosphorylation and mobilization, changes in receptor surface expression, and direct protein–protein coupling (Cepeda et al, 1998; Snyder et al, 1998; Lee et al, 2002; Surmeier et al, 2007; Pascoli et al, 2011)

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