title: D1R/GluN1 complexes in the striatum integrate dopamine and glutamate signalling to control synaptic plasticity and cocaine-induced responses.
abstract: Convergent dopamine and glutamate signalling onto the extracellular signal-regulated kinase (ERK) pathway in medium spiny neurons (MSNs) of the striatum controls psychostimulant-initiated adaptive processes underlying long-lasting behavioural changes. We hypothesised that the physical proximity of dopamine D1 (D1R) and glutamate NMDA (NMDAR) receptors, achieved through the formation of D1R/NMDAR complexes, may act as a molecular bridge that controls the synergistic action of dopamine and glutamate on striatal plasticity and behavioural responses to drugs of abuse. We found that concomitant stimulation of D1R and NMDAR drove complex formation between endogenous D1R and the GluN1 subunit of NMDAR. Conversely, preventing D1R/GluN1 association with a cell-permeable peptide (TAT-GluN1C1) left individual D1R and NMDAR-dependent signalling intact, but prevented D1R-mediated facilitation of NMDAR-calcium influx and subsequent ERK activation. Electrophysiological recordings in striatal slices from mice revealed that D1R/GluN1 complexes control the D1R-dependent enhancement of NMDAR currents and long-term potentiation in D1R-MSN. Finally, intra-striatal delivery of TAT-GluN1C1 did not affect acute responses to cocaine but reduced behavioural sensitization. Our findings uncover D1R/GluN1 complexes as a major substrate for the dopamine-glutamate interaction in MSN that is usurped by addictive drugs to elicit persistent behavioural alterations. They also identify D1R/GluN1 complexes as molecular targets with a therapeutic potential for the vast spectrum of psychiatric diseases associated with an imbalance between dopamine and glutamate transmission.
authors: 1] INSERM, UMR-S 1130, Neuroscience Paris Seine, Paris, France [2] CNRS, UMR 8246, Neuroscience Paris Seine, Paris, France [3] Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine, Paris, France.
authors: E
authors: E
authors: Cahill
authors: Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland.
authors: V
authors: V
authors: Pascoli
authors: 1] Nutrition and Integrative Neurobiology, INRA UMR 1286, Bordeaux, France [2] University of Bordeaux, Bordeaux, France [3] Center for Neuroscience. Columbia University, Kolb Research Building, New York, NY, USA.
authors: P
authors: P
authors: Trifilieff
authors: 1] INSERM, UMR-S 1130, Neuroscience Paris Seine, Paris, France [2] CNRS, UMR 8246, Neuroscience Paris Seine, Paris, France [3] Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine, Paris, France.
authors: D
authors: D
authors: Savoldi
authors: 1] INSERM, UMR-S 1130, Neuroscience Paris Seine, Paris, France [2] CNRS, UMR 8246, Neuroscience Paris Seine, Paris, France [3] Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine, Paris, France.
authors: V
authors: V
authors: Kappès
authors: 1] Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland [2] Department of Clinical Neuroscience, Geneva University Hospital, Geneva, Switzerland.
authors: C
authors: C
authors: Lüscher
authors: 1] INSERM, UMR-S 1130, Neuroscience Paris Seine, Paris, France [2] CNRS, UMR 8246, Neuroscience Paris Seine, Paris, France [3] Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine, Paris, France.
authors: J
authors: J
authors: Caboche
authors: 1] INSERM, UMR-S 1130, Neuroscience Paris Seine, Paris, France [2] CNRS, UMR 8246, Neuroscience Paris Seine, Paris, France [3] Sorbonne Universités, UPMC Université Paris 06, UMR-S 8246, Neuroscience Paris Seine, Paris, France.
authors: P
authors: P
authors: Vanhoutte
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D002118:Calcium; D003042:Cocaine; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate