Single-molecule imaging of the functional crosstalk between surface NMDA and dopamine D1 receptors

Abstract

Dopamine is a powerful modulator of glutamatergic neurotransmission and NMDA receptor-dependent synaptic plasticity. Although several intracellular cascades participating in this functional dialogue have been identified over the last few decades, the molecular crosstalk between surface dopamine and glutamate NMDA receptor (NMDAR) signaling still remains poorly understood. Using a combination of single-molecule detection imaging and electrophysiology in live hippocampal neurons, we demonstrate here that dopamine D1 receptors (D1Rs) and NMDARs form dynamic surface clusters in the vicinity of glutamate synapses. Strikingly, D1R activation or D1R/NMDAR direct interaction disruption decreases the size of these clusters, increases NMDAR synaptic content through a fast lateral redistribution of the receptors, and favors long-term synaptic potentiation. Together, these data demonstrate the presence of dynamic D1R/NMDAR perisynaptic reservoirs favoring a rapid and bidirectional surface crosstalk between receptors and set the plasma membrane as the primary stage of the dopamineglutamate interplay.single-molecule tracking | neuromodulation | receptor diffusion | hippocampus | glutamate plasticity H ippocampal dopaminergic neuromodulation participates in several cognitive functions including novelty detection and long-term memory storage (1, 2). As a consequence, impairments in hippocampal neuromodulatory transmission affect synaptic plasticity at glutamatergic synapses, prevent learning and memory formation, and have been proposed to be a cellular substrate for neurodevelopmental psychiatric disorders such as schizophrenia (3). In the hippocampus and cortex, pyramidal neurons express mostly dopamine D1 and D5 receptors along their dendritic tree (4-6). Their recruitment affects the trafficking and surface expression of glutamate NMDA receptors (NMDARs), two processes that are essential for excitatory neurotransmission and synaptic plasticity. Indeed, activating dopamine D1 receptors (D1Rs) promotes the surface expression and function of NMDAR and thereby favors the long-term potentiation of excitatory glutamate synapses (7-10). Reciprocally, the activation of NMDAR modulates D1R surface expression and signaling (11). The bidirectional dialogue between dopamine and glutamate NMDARassociated signaling thus involves changes in membrane receptor content and trafficking.Although this functional interaction is usually considered as relying on intracellular protein kinase signaling cascades (7,10,12), physical interactions between D1R and NMDAR at the plasma membrane were recently reported to stabilize laterally diffusing surface D1R in spines, modulate D1R-and NMDAR-mediated signaling, and influence working memory (13-16). Thus, direct interactions between these receptors could contribute to the regulation of their surface distributions and play a major role in the dopamine-glutamate interplay (15,17). In particular, because the regulation of NMDAR synaptic content involves surface diffusion processes in and out of synaptic and ...

Single nanoparticle tracking of N -methyl-d-aspartate receptors in cultured and intact brain tissue

“…[11][12][13] Using single-molecule approaches, differences in molecular behaviors have been uncovered among and within families of receptors including the excitatory glutamate alpha-amino-3-hydroxy-5-methylisoazol-4-propionate and N-methyl-D-aspartate (NMDA) receptors, inhibitory glycinergic and GABA A receptors, and modulatory dopamine receptors. 7,[14][15][16][17] Noteworthy, similar outcomes have been obtained when exploring the surface dynamics of neurotransmitter transporters in neurons and astrocytes (glutamate transporter GLT1 and dopamine transporter). 18,19 Among the glutamatergic receptors, NMDA receptors (NMDAR) have attracted much attention since they play a key role in synaptic plasticity processes, network maturation, cognitive functions, and because impairments in NMDAR signaling have been associated with severe neuropsychiatric conditions.…”

WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine

“…Previously, our studies showed that stimulation of striatal slices with a D1 agonist or NMDA led to dephosphorylation of WAVE1 at Ser310, Ser397, and Ser441, indicating neuronal activity-mediated stimulation of WAVE1 (4, 7). We anticipated that WAVE1 would be dephosphorylated in response to cocaine administration in vivo, because cocaine increases synaptic levels of dopamine, and activation of D1 is known to increase NMDA-receptor-mediated signaling (13,28,29). However, there was no significant change in phosphorylation, or of the total protein level, of WAVE1 in the striatum in response to acute injection of cocaine (45 min after 15 mg/kg) or chronic injection of cocaine (15 mg/kg daily for 14 d; 45 min after the last injection).…”

Hippocampal receptor complexes paralleling LTP reinforcement in the spatial memory holeboard test in the rat

“…activation of NMDARs recruits D1Rs to the synaptic membrane retaining D1Rs in close proximity to NMDARs in the membrane [82,72]. In addition, it was reported that D1Rs and NMDARs are in direct interaction in the hippocampus [57,55,56]. On the other hand, coexpression of GluN2 with D1 is necessary to recruit the D1-NMDAR complex to the synaptic membrane [9].…”